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FDA Approves New First-line Treatment Option for Metastatic Pancreatic Cancer: What You Need to Know

by Erin Post  —  Feb 13, 2024

For the first time in more than a decade, the FDA has approved a new first-line treatment for patients with metastatic pancreatic cancer . After a clinical trial showed a positive survival benefit, the combination chemotherapy called NALIRIFOX is now approved for patients who have not received any previous treatment. For a disease with limited treatment options, today’s FDA announcement is exciting news.

“We are pleased that the U.S. Food and Drug Administration has issued this new approval of the NALIRIFOX regimen. With each new approved treatment, there is more hope for those who will be diagnosed in the future and people currently living with pancreatic cancer may have more time with their loved ones,” said PanCAN President and CEO Julie Fleshman, JD, MBA, in a press release from the pharmaceutical company Ipsen announcing the approval. “We are thankful to the patients who participated in this clinical trial as they play a crucial role in advancing treatments for pancreatic cancer.”

Here, PanCAN answers questions related to this new treatment option.

What is NALIRIFOX?

NALIRIFOX is a chemotherapy treatment. It is a combination of three previously approved pancreatic cancer drugs, liposomal irinotecan (Nal-IRI or Onivyde®), made by the pharmaceutical company Ipsen, plus 5 fluorouracil (5-FU)/leucovorin and oxaliplatin. NALIRIFOX will be delivered intravenously (IV, through a vein under the skin).

What does this FDA approval mean?

NALIRIFOX has been approved by the FDA as a new first-line treatment for metastatic pancreatic cancer. This means patients whose cancer has spread and who have not had treatment yet can now receive this drug combination.

Are these new drugs?

No. All of the drugs in NALIRIFOX have already been approved for other purposes; what is new is the combination of these drugs together as a first-line treatment.

Liposomal irinotecan, in combination with 5-FU/leucovorin, is already approved for people with metastatic pancreatic cancer that has continued to grow after being treated with another chemotherapy called gemcitabine (Gemzar®). Oxaliplatin has also been approved and used to treat other cancers for a long time.

NALIRIFOX is a combination of liposomal irinotecan, 5-FU/leucovorin and oxaliplatin. This combination has now been approved for a new group of patients, those with metastatic pancreatic cancer who have not had any other treatment. This is the first approval for a first-line treatment for metastatic pancreatic cancer in over ten years.

What is the survival benefit?

In a clinical trial, the NALIRIFOX regimen was compared to gemcitabine (Gemzar) plus nab-paclitaxel (Abraxane®), which is one of the current standard-of-care treatments for patients with metastatic pancreatic cancer. The results, published in October 2023 , showed that patients treated with NALIRIFOX had an overall survival of 11.1 months, which was a statistically significant improvement over the 9.2-month overall survival with gemcitabine and nab-paclitaxel.

What are the side effects?

In the clinical trial, patients took NALIRIFOX for a median of six weeks longer than those receiving gemcitabine and nab-paclitaxel, showing that NALIRIFOX was relatively well tolerated. The most frequent side effects reported in the NALIRIFOX group included neutropenia (low levels of a type of immune cell called neutrophils) and hypokalemia (low potassium level), and gastrointestinal disorders like diarrhea and nausea.

Is NALIRIFOX the same as FOLFIRINOX?

The combination chemotherapy FOLFIRINOX is composed of 5-FU, leucovorin, irinotecan and oxaliplatin. In 2010, a clinical trial showed that FOLFIRINOX was effective for the treatment of metastatic pancreatic cancer in people who hadn’t received prior treatment.

The drug liposomal irinotecan replaces irinotecan to make NALIRIFOX. Liposomal irinotecan is a modified form of irinotecan, designed to stay in the body longer before it gets broken down.

Does insurance cover this treatment?

FDA approval means this drug combination is safe and effective, and although the FDA does not decide what is covered by insurance, when a drug gets FDA approval Medicare and Medicaid will usually cover it.  Coverage for chemotherapy drugs will vary based on the specific plan and insurance company a person uses.

Contact PanCAN Patient Services for more information on financial assistance programs for those experiencing or anticipating cost-related barriers to care.

I am a patient with pancreatic cancer interested in NALIRIFOX. What should I do?

People diagnosed with pancreatic cancer should talk to their healthcare team about this treatment option. Since this approval is for first-line treatment (the first or initial treatment a person receives after diagnosis), it will impact people who have not received treatment for their pancreatic cancer yet.

For people who have already received treatment with a drug called gemcitabine, a similar chemotherapy containing one of the drugs in NALIRIFOX, liposomal irinotecan, is also approved.

Contact PanCAN Patient Services for additional information and support, including information on what questions to ask and how to seek out a second opinion. Our Case Managers can help you understand your options and connect you with resources to learn more.

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New drug combo shows early potential for treating pancreatic cancer

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Pancreatic cancer, which affects about 60,000 Americans every year, is one of the deadliest forms of cancer. After diagnosis, fewer than 10 percent of patients survive for five years. 

While some chemotherapies are initially effective, pancreatic tumors often become resistant to them. The disease has also proven difficult to treat with newer approaches such as immunotherapy. However, a team of MIT researchers has now developed an immunotherapy strategy and shown that it can eliminate pancreatic tumors in mice.

The new therapy, which is a combination of three drugs that help boost the body’s own immune defenses against tumors, is expected to enter clinical trials later this year.

“We don’t have a lot of good options for treating pancreatic cancer. It’s a devastating disease clinically,” says William Freed-Pastor, a senior postdoc at MIT’s Koch Institute for Integrative Cancer Research. “If this approach led to durable responses in patients, it would make a big impact in at least a subset of patients’ lives, but we need to see how it will actually perform in trials.”

Freed-Pastor, who is also a medical oncologist at Dana-Farber Cancer Institute, is the lead author of the new study , which appears today in Cancer Cell . Tyler Jacks, the David H. Koch Professor of Biology and a member of the Koch Institute, is the paper’s senior author.

Immune attack

The body’s immune system contains T cells that can recognize and destroy cells that express cancerous proteins, but most tumors create a highly immunosuppressive environment that disables these T cells, helping the tumor to survive.

Immune checkpoint therapy (the most common form of immunotherapy currently being used clinically) works by removing the brakes on these T cells, rejuvenating them so they can destroy tumors. One class of immunotherapy drug that has shown success in treating many types of cancer targets the interactions between PD-L1, a cancer-linked protein that turns off T cells, and PD-1, the T cell protein that PD-L1 binds to. Drugs that block PD-L1 or PD-1, also called checkpoint inhibitors, have been approved to treat cancers such as melanoma and lung cancer, but they have very little effect on pancreatic tumors.

Some researchers had hypothesized that this failure could be due to the possibility that pancreatic tumors don’t express as many cancerous proteins, known as neoantigens. This would give T cells fewer targets to attack, so that even when T cells were stimulated by checkpoint inhibitors, they wouldn’t be able to identify and destroy tumor cells.

However, some recent studies had shown, and the new MIT study confirmed, that many pancreatic tumors do in fact express cancer-specific neoantigens. This finding led the researchers to suspect that perhaps a different type of brake, other than the PD-1/PD-L1 system, was disabling T cells in pancreatic cancer patients.

In a study using mouse models of pancreatic cancer, the researchers found that in fact, PD-L1 is not highly expressed on pancreatic cancer cells. Instead, most pancreatic cancer cells express a protein called CD155, which activates a receptor on T cells known as TIGIT.

When TIGIT is activated, the T cells enter a state known as “T cell exhaustion,” in which they are unable to mount an attack on pancreatic tumor cells. In an analysis of tumors removed from pancreatic cancer patients, the researchers observed TIGIT expression and T cell exhaustion from about 60 percent of patients, and they also found high levels of CD155 on tumor cells from patients.

“The CD155/TIGIT axis functions in a very similar way to the more established PD-L1/PD-1 axis. TIGIT is expressed on T cells and serves as a brake to those T cells,” Freed-Pastor says. “When a TIGIT-positive T cell encounters any cell expressing high levels of CD155, it can essentially shut that T cell down.”

Drug combination

The researchers then set out to see if they could use this knowledge to rejuvenate exhausted T cells and stimulate them to attack pancreatic tumor cells. They tested a variety of combinations of experimental drugs that inhibit PD-1 and TIGIT, along with another type of drug called a CD40 agonist antibody.

CD40 agonist antibodies, some of which are currently being clinically evaluated to treat pancreatic cancer, are drugs that activate T cells and drive them into tumors. In tests in mice, the MIT team found that drugs against PD-1 had little effect on their own, as has previously been shown for pancreatic cancer. They also found that a CD40 agonist antibody combined with either a PD-1 inhibitor or a TIGIT inhibitor was able to halt tumor growth in some animals, but did not substantially shrink tumors.

However, when they combined CD40 agonist antibodies with both a PD-1 inhibitor and a TIGIT inhibitor, they found a dramatic effect. Pancreatic tumors shrank in about half of the animals given this treatment, and in 25 percent of the mice, the tumors disappeared completely. Furthermore, the tumors did not regrow after the treatment was stopped. “We were obviously quite excited about that,” Freed-Pastor says.

Working with the Lustgarten Foundation for Pancreatic Cancer Research, which helped to fund this study, the MIT team sought out two pharmaceutical companies who between them have a PD-1 inhibitor, TIGIT inhibitor, and CD40 agonist antibody in development. None of these drugs are FDA-approved yet, but they have each reached phase 2 clinical trials. A clinical trial on the triple combination is expected to begin later this year.

“This work uses highly sophisticated, genetically engineered mouse models to investigate the details of immune suppression in pancreas cancer, and the results have pointed to potential new therapies for this devastating disease,” Jacks says. “We are pushing as quickly as possible to test these therapies in patients and are grateful for the Lustgarten Foundation and Stand Up to Cancer for their help in supporting the research.”

Alongside the clinical trial, the MIT team plans to analyze which types of pancreatic tumors might respond best to this drug combination. They are also doing further animal studies to see if they can boost the treatment’s effectiveness beyond the 50 percent that they saw in this study.

In addition to the Lustgarten Foundation, the research was funded by Stand Up To Cancer, the Howard Hughes Medical Institute, Dana-Farber/Harvard Cancer Center, the Damon Runyon Cancer Research Foundation, and the National Institutes of Health.

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Boston Herald reporter Rick Sobey writes that a new drug combination has shown potential in treating pancreatic cancer. “The trio drug combination is a CD40 agonist antibody, a PD-1 inhibitor and a TIGIT inhibitor. The researchers found that this combination led to pancreatic tumors shrinking in about 50% of the animals that were given this treatment,” writes Sobey.

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Experimental Therapy Shows Promise in Pancreatic Cancer Clinical Trial

Posted in News Release  |  Tagged clinical trials , pancreatic cancer , translational research

Media Contact

Karen Teber [email protected]

WASHINGTON (June 1, 2024) — Clinicians at Georgetown University’s Lombardi Comprehensive Cancer Center reported promising preliminary findings based on outcomes in the first six patients with metastatic pancreatic cancer enrolled in a phase 2 clinical trial of the experimental drug BXCL701 in combination with the immunotherapy drug pembrolizumab (Keytruda). Immunotherapy drugs alone have not shown to be responsive to pancreatic cancer.

The findings were presented at the American Society of Clinical Oncology 2024 annual meeting in Chicago on June 1, 2024.

BXCL701, made by BioXcel Therapeutics, is an oral drug called an immune activator. It acts by inflaming the microenvironment surrounding the tumor and thereby augmenting the activity of immunotherapies like pembrolizumab. BXCL701 has received Orphan Drug Designation from the U.S. Food and Drug Administration in pancreatic cancer and three other cancer types: acute myelogenous leukemia, stage IIb to IV melanoma, and soft tissue sarcoma.

Pancreatic cancer is the third leading cause of cancer death. The five-year survival rate for all stages of the disease is 13%, but there’s no early detection method and therefore patients are often diagnosed with later stage disease. For those with disease that has spread beyond the pancreas, the five-year survival rates are an extremely low 3%.

“Pancreatic cancer is a devastating disease that is difficult to treat with standard methods, including chemotherapy,” says Benjamin Adam Weinberg, MD, an associate professor of medicine at Georgetown Lombardi and lead investigator of this trial. “Using immunotherapy alone to harness the body’s own immune system has also generally not worked due to the inability of immune cells to infiltrate pancreatic tumors due to dense fibrous tissue that walls tumors off microscopically from the immune system. Hence the need to find another approach.”

In preclinical mouse studies published in 2021 , researchers led by Louis Weiner, MD, director of Georgetown University’s Lombardi Comprehensive Cancer Center, showed that when combined with an immunotherapy drug, BXCL701 boosted the animals’ natural immune systems, slowing or even stopping pancreatic tumor growth. The mouse studies found evidence that tumors had been flooded by natural killer immune cells, a sign that the drug had accomplished its goal of making cancer cells receptive to the immune system. In short order, these mouse studies led directly to this first-in-human trial of the drug in pancreatic cancer.

For the initial part of the trial looking primarily at the safety aspect of the drug combination, three women and three men with a median age of 57 were enrolled. One patient showed no signs of disease progressing after 18 weeks on the trial and one patient had stable disease at nine weeks but was not yet evaluable for the 18-week landmark. The progression-free survival rate (no change or even signs of regression in the tumor) as determined by imaging was 50%.

Three patients had significant reductions in a marker that indicates the presence of pancreatic cancer, CA19-9, with 100%, 97% and 73% reductions. Weinberg says that CA19-9 is the best marker they have in pancreatic cancer, but it is not as good a screening test as PSA is for prostate cancer. He believes, however, that it can be useful for monitoring disease activity in patients with advanced cancers. Not every patient’s tumor makes CA19-9, but so far in this study all patients have had elevated CA19-9 levels.

According to Weinberg, the main side effect so far is low blood pressure, which can be mitigated by giving BXCL701 at a lower dose during the first week of treatment. The clinicians are also seeing anemia, nausea and immune-related arthritis, which has responded to oral steroids.

“Historically, no one has responded to immunotherapy in pancreatic cancer, so even one response and another with stable disease could be early signs of efficacy,” says Weinberg. “A third patient had an initial drop in their CA19-9 marker even though they had disease progression on imaging, and this may be more early evidence that this drug combination has anti-cancer effects.”

In addition to Weinberg, authors include Alexander Lekan, Allison Fitzgerald, Zoe Malchiodi, Martin Gutierrez, Anteneh A. Tesfaye, Ming Tony Tan, Marcus Smith Noel, Aiwu Ruth He, Reetu Mukherji, John Marshall, Princess Jones, Pascal Borderies, Vincent O’Neill and Louis M. Weiner at Georgetown and the Georgetown-affiliated John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, New Jersey.

This research was supported by BioXcel Therapeutics, New Haven, Connecticut.

Weinberg reports having no personal financial interests related to the study. Weiner’s research is supported in part by BioXcel Therapeutics, Inc., the company developing BXCL701. Support for his work is also provided by the Edwin and Linda Siegel Family Foundation. Weiner reports no other conflicts related to the study. The clinical trial is supported by BioXcel Therapeutics, Inc. and Merck.

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May 23, 2023

An mRNA vaccine to treat pancreatic cancer

At a glance.

• A personalized mRNA vaccine against pancreatic cancer created a strong anti-tumor immune response in half the participants in a small study.
• The vaccine will soon be tested in a larger clinical trial. The approach may also have potential for treating other deadly cancer types.

Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, is one of the deadliest cancer types. Despite modern therapies, only about 12% of people diagnosed with this cancer will be alive five years after treatment.

Immunotherapies—drugs that help the body’s immune system attack tumors—have revolutionized the treatment of many tumor types. But to date, they have proven ineffective in PDAC. Whether pancreatic cancer cells produce neoantigens—proteins that can be effectively targeted by the immune system—hasn’t been clear.

An NIH-funded research team led by Dr. Vinod Balachandran from Memorial Sloan Kettering Cancer Center (MSKCC) have been developing a personalized mRNA cancer-treatment vaccine approach. It is designed to help immune cells recognize specific neoantigens on patients’ pancreatic cancer cells. Results from a small clinical trial of their experimental treatment were published on May 10, 2023, in Nature .

After surgery to remove PDAC, the team sent tumor samples from 19 people to partners at BioNTech, the company that produced one of the COVID-19 mRNA vaccines. BioNTech performed gene sequencing on the tumors to find proteins that might trigger an immune response. They then used that information to create a personalized mRNA vaccine for each patient. Each vaccine targeted up to 20 neoantigens.

Customized vaccines were successfully created for 18 of the 19 study participants. The process, from surgery to delivery of the first dose of the vaccine, took an average of about nine weeks.

All patients received a drug called atezolizumab before vaccination. This drug, called an immune checkpoint inhibitor, prevents cancer cells from suppressing the immune system. The vaccine was then given in nine doses over several months. After the first eight doses, study participants also started standard chemotherapy drugs for PDAC, followed by a ninth booster dose.

Sixteen volunteers stayed healthy enough to receive at least some of the vaccine doses. In half these patients, the vaccines activated powerful immune cells, called T cells, that could recognize the pancreatic cancer specific to the patient. To track the T cells made after vaccination, the research team developed a novel computational strategy with the lab of Dr. Benjamin Greenbaum at MSKCC. Their analysis showed that T cells that recognized the neoantigens were not found in the blood before vaccination. Among the eight patients with strong immune responses, half had T cells target more than one vaccine neoantigen.

By a year and a half after treatment, the cancer had not returned in any of the people who had a strong T cell response to the vaccine. In contrast, among those whose immune systems didn’t respond to the vaccine, the cancer recurred within an average of just over a year. In one patient with a strong response, T cells produced by the vaccine even appeared to eliminate a small tumor that had spread to the liver. These results suggest that the T cells activated by the vaccines kept the pancreatic cancers in check.

“It’s exciting to see that a personalized vaccine could enlist the immune system to fight pancreatic cancer—which urgently needs better treatments,” Balachandran says. “It’s also motivating as we may be able to use such personalized vaccines to treat other deadly cancers.”

More work is needed to understand why half the people did not have a strong immune response to their personalized vaccines. The researchers are currently planning to launch a larger clinical trial of the vaccine.

—by Sharon Reynolds

Related Links

• Using mRNA Technology for a Universal Flu Vaccine
• Experimental mRNA HIV Vaccine Shows Promise in Animals
• Experimental Vaccine Protects Against Multiple Coronaviruses
• Method for Early Detection of Pancreatic Cancer
• Can mRNA Vaccines Help Treat Cancer?
• Pancreatic Cancer
• Cancer Treatment Vaccines

References:  Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Rojas LA, Sethna Z, Soares KC, Olcese C, Pang N, Patterson E, Lihm J, Ceglia N, Guasp P, Chu A, Yu R, Chandra AK, Waters T, Ruan J, Amisaki M, Zebboudj A, Odgerel Z, Payne G, Derhovanessian E, Müller F, Rhee I, Yadav M, Dobrin A, Sadelain M, Łuksza M, Cohen N, Tang L, Basturk O, Gönen M, Katz S, Do RK, Epstein AS, Momtaz P, Park W, Sugarman R, Varghese AM, Won E, Desai A, Wei AC, D'Angelica MI, Kingham TP, Mellman I, Merghoub T, Wolchok JD, Sahin U, Türeci Ö, Greenbaum BD, Jarnagin WR, Drebin J, O'Reilly EM, Balachandran VP. Nature . 2023 May 10:1-7. doi: 10.1038/s41586-023-06063-y. Online ahead of print. PMID: 37165196.

Funding:  NIH’s National Cancer Institute (NCI); Stand Up to Cancer; Lustgarten Foundation; Damon Runyon Cancer Research Foundation; Ben and Rose Cole Charitable PRIA Foundation; Mark Foundation; Pershing Square Sohn Cancer Research Alliance; Pew Charitable Trusts; Cycle for Survival; Marie-Josée and Henry R. Kravis Center for Molecular Oncology; Memorial Sloan Kettering Cancer Center; imCORE Network; Genentech; BioNTech.

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Advances in Pancreatic Cancer Research

Pancreatic cancer cells (blue) growing as a sphere encased in membranes (red).

NCI-funded researchers are working to advance our understanding of how to prevent, detect, and treat pancreatic cancer, which includes pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumors (PNET). PNET is much less common than PDAC and has a better prognosis .

This page highlights some of the latest research in pancreatic adenocarcinoma, including clinical advances that may soon translate into improved care, NCI-supported programs that are fueling progress, and research findings from recent studies.

Early Detection of Pancreatic Cancer

Currently, no screening tests exist that can catch pancreatic cancer early, before symptoms develop. NCI is now funding several large research projects that are working to develop such an early-detection tool. 

One known risk factor for developing pancreatic cancer is a new diagnosis of diabetes, sometimes called new-onset diabetes . About 1 in 100 people with new onset diabetes are diagnosed with pancreatic cancer within 3 years after learning they have diabetes. And 1 in 4 people who get pancreatic cancer had already been diagnosed with diabetes.

The NCI-funded New Onset Diabetes (NOD) Study , which is scheduled to run through 2025, is currently enrolling 10,000 people with new-onset diabetes or hyperglycemia (also known as prediabetes). The NOD researchers hope to develop a blood test that can identify the few individuals with a new diabetes diagnosis who may need further testing for pancreatic cancer.

Other NCI-funded teams, coordinated through the Pancreatic Cancer Detection Consortium (PCDC) , are trying to create a blood test that could pick up early pancreatic cancer in the general population. PCDC researchers are also working to improve imaging of the pancreas, by developing methods that may be able to pick up tiny deposits of tumor cells.

Pancreatic Cancer Treatment

  Pancreatic cancer can be hard to treat surgically due to the location of the organ, and because the disease has often spread in the body by the time it is diagnosed.

Standard treatment for pancreatic cancer usually consists of surgery , chemotherapy , radiation , or combinations of each, depending on the cancer’s stage. Beyond these standard treatments, NCI scientists continue to look for ways to treat pancreatic cancer more effectively. Researchers are looking at the potential of new drugs, ways to combine standard drugs, and new modalities (such as immunotherapy ) to give to patients.

Patients with pancreatic cancer are generally recommended to have both biomarker testing and testing for inherited genetic changes. Both types of testing can help suggest possible treatments and can indicate with a patient’s family members might have an increased risk for pancreatic cancer or other types of cancer.

Testing treatments for early-stage pancreatic cancer

Therapies for early-stage disease that are being tested in clinical trials right now include

• new adjuvant chemotherapy drug combinations Some of these postsurgical drug combinations are already known to extend the lives of patients with metastatic disease, but it's not clear if they are better at killing cancer cells left behind after surgery than standard treatments.
• neoadjuvant  chemotherapy   This form of chemotherapy is given before surgery, with the goal of improving outcomes by shrinking the tumor before it’s removed. Pre-surgical chemotherapy also may help by killing cancer cells that have escaped from the tumor that would continue to grow as the patient recovers from surgery.
• cancer treatment vaccines  Cancer treatment vaccines help the body’s immune system recognize and destroy cancer cells. Cancer cells contain substances, called tumor-associated antigens, that are not present in normal cells or, if present, are at lower levels. Treatment vaccines can help the immune system learn to recognize and react to these antigens and destroy cancer cells that contain them.

Testing treatments for advanced pancreatic cancer

New treatments for metastatic pancreatic cancer that are being investigated in clinical trials include immunotherapy and targeted therapy . Immunotherapy uses substances to stimulate or suppress the immune system to help the body fight cancer. Targeted therapy uses drugs or other substances to target specific molecules that cancer cells need to survive and spread.

Drug Targets Common Mutation in Pancreatic Cancer

In mice, experimental drug MRTX1133 shrank pancreatic tumors with KRAS G12D mutations.

For a list of specific drugs, see Drugs Approved for Pancreatic Cancer .

• Ras-directed therapies . The RAS gene s makes proteins that take part in signaling pathways that control cell growth. Altered forms of these genes are found in more than 90% of pancreatic cancers. Drugs that target mutant forms of RAS are now being tested. One example is a drug that targets a form of RAS that has a mutation called G12C and another drug that targets a more common mutation, G12D. 
• olaparib . Olaparib (Lynparza) is used as maintenance therapy  in adults with metastatic cancer that has not progressed after platinum chemotherapy and has certain mutations in the BRCA1 or BRCA2 gene. 
• pembrolizumab . In rare cases, people with pancreatic cancer have mutations in their tumor that cause  high microsatellite instability (MSI) .  Pembrolizumab (Keytruda)  is an immune checkpoint inhibitor approved for patients with pancreatic cancer that has high MSI. 
• novel immune checkpoint inhibitors and combinations . Using one drug for immunotherapy treatment has not been effective for most people with pancreatic cancer. Therefore, researchers are combining several immunotherapies that can act on different parts of the immune system.
• combinations of immunotherapy drugs with other treatments . These include radiation therapy, stromal modifying agents, and other targeted drugs.
• cell therapies . Researchers are exploring the use of cell-based therapies for pancreatic cancer. These therapies use immune cells such as T cells and natural killer cells that are altered in the lab to kill cancer cells. 
• the stroma is the fibrous  tissue around a tumor that does not contain cancer cells. It is mostly made up of connective tissue , blood vessels , lymphatic vessels , and nerves . Some of these components can help to support cancer cells and/ or prevent the immune system from recognizing cancer cells.
• pancreatic cancers have much denser stroma than most tumors. Agents that help break down or remodel this stroma may help more chemotherapy drugs reach cancer cells. Or they may help reduce cancer cell resistance to killing by other agents.

Clinical Trials

Because of the complex nature of pancreatic cancer, many experts believe it’s important for all patients to join a clinical trial , even if they have early-stage disease. NCI funds and oversees both early- and late-phase clinical trials to develop new treatments and improve patient care. Trials are available for pancreatic cancer treatment .

NCI-Supported Research Programs

Many NCI-funded researchers at the NIH campus, and across the United States and world, are seeking ways to address pancreatic cancer more effectively. Some research is basic, exploring questions as diverse as the biological underpinnings of cancer and the social factors that affect cancer risk. And some is more clinical, seeking to translate this basic information into improved patient outcomes. The programs listed below are a small sampling of NCI’s research efforts in pancreatic cancer.

• The  Pancreatic Cancer Cohort Consortium  consists of more than a dozen prospective epidemiologic cohort studies that investigate the causes and natural history of pancreatic cancer. This includes the launching of a genome-wide association study (GWAS) known as PanScan .
• The  Pancreatic Cancer Detection Consortium (PCDC) develops and tests  biomarkers  to detect early stage pancreatic cancer and identify individuals at high risk for the disease.
• The Pancreatic Ductal Adenocarcinoma (PDAC) Stromal Reprogramming Consortium (PSRC) is a multidisciplinary community of PDAC researchers that will bridge biological research with preclinical/translational research. The goal is to identify and evaluate elements in the tumor microenvironment that drive PDAC progression and response to therapy.
• The  Pancreatic Specialized Programs of Research Excellence (Pancreatic SPOREs) are designed to quickly move basic scientific findings into clinical settings. The Pancreatic SPORE grants support new and diverse approaches to the prevention, early detection, diagnosis, and treatment of pancreatic cancer. Two of NCI's  Gastrointestinal (GI) SPOREs  also conduct research in pancreatic cancer.
• The RAS Initiative looks to understand mutations in  RAS genes  to ultimately create effective, new therapies for  RAS -related cancers. More than 90% of pancreatic cancers are caused by mutations in the RAS family of genes. 

Pancreatic Cancer Research Results

The following are some of our latest news articles on pancreatic cancer research:

• Can Chemo Help KRAS Inhibitors Work Better Against Pancreatic Cancer?
• Screening People at High Risk for Pancreatic Cancer May Help Them Live Longer
• Blood Test Accurately Detects Early-Stage Pancreatic Cancer
• No Glucose? Pancreatic Cancer May Have a Ready Energy Alternative
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• Year in Review
• Published: 16 December 2022

Pancreatic cancer in 2022

The war on pancreatic cancer: progress and promise

• Christine A. Iacobuzio-Donahue   ORCID: orcid.org/0000-0002-4672-3023 1 , 2  

Nature Reviews Gastroenterology & Hepatology volume  20 ,  pages 75–76 ( 2023 ) Cite this article

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The year 2022 was notable for substantial research progress related to pancreatic ductal adenocarcinoma (PDAC). The first single-cell and spatial transcriptomic atlases of PDAC were reported, a mechanism for how Schwann cells promote perineural invasion was explored, and, finally, the role of exercise in abrogating immunosuppression was shown.

Key advances

Spatial transcriptomics and other single-cell technologies reveal distinct transitional populations linking acinar-to-ductal metaplasia to pancreatic intraepithelial neoplasia and enrichment of metallothionein-expressing inflammatory cancer-associated fibroblasts in chemoresistant pancreatic cancer 3 .

Schwann cells within the tumour microenvironment organize into tumour-activated Schwann cell tracts that promote migration along nerves via activation of JUN 6 .

Aerobic exercise restrains pancreatic cancer growth in mice through IL-15–IL-15RA-mediated activation of CD8 + T cells, and evidence for this relationship was found in humans 7 .

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Iacobuzio-Donahue, C.A. The war on pancreatic cancer: progress and promise. Nat Rev Gastroenterol Hepatol 20 , 75–76 (2023). https://doi.org/10.1038/s41575-022-00728-1

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People with pancreatic cancer are living longer, thanks to improved approaches

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By Jessica Saenz

A diagnosis of pancreatic cancer is almost synonymous with hopelessness. As the least survivable type of cancer, the perception is understandable. "As soon as patients were diagnosed, they were often told by their physician to start making arrangements," says Mark Truty, M.D. , a surgical oncologist at Mayo Clinic who specializes in pancreatic surgery.

But the tides are turning, thanks to new and improved treatment methods that are helping people with pancreatic cancer live longer. Dr. Truty and Robert McWilliams, M.D. , a medical oncologist at Mayo Clinic, talk about Mayo Clinic's approach to pancreatic cancer care , and how it's leading to improved survival and quality of life.

Capturing the full picture from the time of diagnosis and beyond

Before moving forward with treatment, Dr. Truty says it's critical to understand as much about each person's cancer as possible. "When a patient is first diagnosed, they need really good imaging and molecular testing to see, not just where the tumor is, but if there's any evidence of spread. We do a lot of tests at the beginning and throughout to make sure that the cancer is truly localized and has not spread."

In most instances, a CT scan or MRI scan is used to identify the location of the cancer and possible spread, but Dr. Truty says standard scans are just one piece of the puzzle. "Historically, patients have gotten a scan where the tumor appears to be localized, and then they underwent surgery. But that paradigm has not resulted in the outcomes we wanted."

This is where PET scans and additional molecular testing play an important role.

Dr. Truty says that PET scans and newer genetic testing are key to staging the cancer and assessing its behavior accurately. They can help determine if treatment is working effectively to shrink the tumor, whereas traditional CT scans have distinct limitations in assessing response in pancreatic primary tumors. "If we see a response we’re anticipating on the PET scan, those are the patients that do very well. If we're not seeing a response, then we have to pivot and switch their therapy to see if we can achieve a better outcome," he says. "We've also been using novel genetic testing developed at Mayo Clinic to test the blood of patients, as well as the fluid of the abdomen through laparoscopy , to see if we can pick up some cancer DNA."

This method is helping cancer experts at Mayo Clinic determine who might be at risk for pancreatic cancer recurrence and individualize their treatment to reduce the risk of the cancer returning. "We're the first center to do this routinely for every single patient we see," Dr. Truty says.

Tailoring testing and treatment for each person

Initial testing and staging of pancreatic cancer can help uncover weaknesses or potential threats for each unique pancreatic cancer case. "As we've learned more about the genetics of pancreatic cancer — and how to find patients who can benefit — we've been able to tailor therapies according to the patient's genetics and their DNA, or the DNA changes that are specific to the cancer itself," says Dr. McWilliams.

In a study led by Mayo Clinic Center for Individualized Medicine , researchers found that nearly 1 in 6 people diagnosed with pancreatic cancer had an inherited cancer-related gene mutation that may have predisposed them to pancreatic cancer. The most common genetic mutation in those patients was the BRCA2 gene, which is linked to breast cancer.

Niloy Jewel Samadder, M.D. , a Mayo Clinic gastroenterologist and hepatologist, and the study's senior author, said that patients with mutations had a 50% longer survival. Data from this study and others have led to recent changes in guidelines that advocate for genetic testing for all pancreatic cancer patients, regardless of their cancer stage or family history of cancer.

Though the majority of people with pancreatic cancer do not have a germline mutation, Dr. McWilliams says it's important to use all the tools available for each patient. While it may not achieve a cure, it can help select therapies to improve quality of life so patients can live longer and more comfortably.

"There's a national trial, called the POLO Trial , which showed that patients on chemotherapy with BRCA1 or BRCA2 mutations are eligible for a maintenance therapy with just a pill, rather than IV chemotherapy, which is really good from a side effects standpoint," says Dr. McWilliams.

Redefining what is considered inoperable

Dr. Truty says patients who are able to have surgery to remove their pancreatic cancer can live significantly longer, but in cases where the tumor has grown outside of the pancreas to encase critical blood vessels, pancreatic cancer has been considered inoperable.

About one-third of pancreatic cancer tumors grow to surround blood vessels outside the pancreas. "Those patients have historically not been considered for surgery," he says. "Theoretically, 50% of patients with diagnosed pancreatic cancer have the potential to undergo an operation. The question is: How do we get them to surgery? And how do we optimize their outcomes to make sure that they live as long as they possibly can?"

Drs. Truty, McWilliams and pancreatic cancer experts at Mayo Clinic use an approach called neoadjuvant therapy, which delivers chemotherapy — or a combination of chemotherapy and radiation — to destroy microscopic cancer cells in the body before surgery. By combining this method with personalized surgery for each patient's anatomy, they can remove tumors entirely and reconstruct blood vessels as needed. This has resulted in the ability to operate on patients who previously did not have that option, leading to better results than ever before.

"We're creating custom surgeries for each patient that aren't being done anywhere else on the planet. That's why so many people come to us after they've been told their tumors are inoperable," says Dr. Truty.

Though surgery can lead to the best outcomes in many cases, Dr. Truty emphasizes that the goal of pancreatic cancer treatment is not surgery. "The goal for anyone with cancer is to extend their life and maintain a reasonable quality of life. Sometimes an operation is necessary to achieve this, and sometimes it will decrease the likelihood of one or the other, or both. That's why before we even consider an operation, we have to make sure that operation has the highest probability that we'll achieve both of those goals."

Pancreatic cancer continues to have the highest mortality rate, but Dr. McWilliams says there's plenty of reason for patients to be hopeful. "It's a very serious cancer. It's something that is life-threatening for a lot of people, but it's not necessarily a death sentence," he says. "It's something that we have treatments for, and our treatments are only getting better."

And this progress, he says, is driven by clinical trials. "Clinical trials are how we advance the science. For patients who are looking for the latest and greatest, and want to help advance the options for their cancer, participation in clinical trials is crucial."

Dr. Truty says he hopes more people with pancreatic cancer seek out second opinions from cancer centers who are leveraging new approaches and providing patients more options. "Historically, it's been such a nihilistic disease, but things have really changed. We have not settled for the standard of care — this results in standard outcomes which have not been good. We have to treat patients differently — starting from the beginning," he says. "And if you can do that all the way through treatment, then those patients really do have exceptional outcomes."

Learn more about panc r eatic cancer and find a pancreatic cancer clinical trial at Mayo Clinic.

Read these articles:

• " 5 things to know about pancreatic cancer "
• " PET/MRI biomarkers guide personalized treatment for people with pancreatic cancer, study finds "
• " Identifying inherited gene mutations in pancreatic cancer can lead to targeted therapies, better survival "
• " Aggressive Approach to Pancreatic Cancer Yields Outstanding Outcome "

Also watch this video: " Mayo Clinic Minute: Advances in pancreatic cancer treatment extending lives

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Advances in the management of pancreatic cancer

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• Peer review
• Marco Del Chiaro , professor, division chief , clinical director 1 2 ,
• Toshitaka Sugawara , assistant clinical professor 1 3 ,
• Sana D Karam , professor 2 4 ,
• Wells A Messersmith , professor , division head, , associate director 2 5
• 1 Division of Surgical Oncology, Department of Surgery, University of Colorado School of Medicine, Aurora, CO, USA
• 2 University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, CO, USA
• 3 Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
• 4 Department of Radiation Oncology, University of Colorado School of Medicine, Aurora, CO, USA
• 5 Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA
• Corresponding Author: M Del Chiaro marco.delchiaro{at}cuanschutz.edu

Pancreatic cancer remains among the malignancies with the worst outcomes. Survival has been improving, but at a slower rate than other cancers. Multimodal treatment, including chemotherapy, surgical resection, and radiotherapy, has been under investigation for many years. Because of the anatomical characteristics of the pancreas, more emphasis on treatment selection has been placed on local extension into major vessels. Recently, the development of more effective treatment regimens has opened up new treatment strategies, but urgent research questions have also become apparent. This review outlines the current management of pancreatic cancer, and the recent advances in its treatment. The review discusses future treatment pathways aimed at integrating novel findings of translational and clinical research.

Introduction

Pancreatic cancer has been considered a deadly disease with a very small probability of long term survival. 1 Despite slow progress, long term survival rates have greatly improved, especially for resected patients. From 1975 to 2011, the five year survival for resected pancreatic cancer improved from 1.5% to 17.4%. 2 However, more recent data show that five year survival for all pancreatic cancers between 2012-18 reached only 11.5% in the United States. 3

As a systemic disease, the changes in the survival of patients with pancreatic cancer have been affected most by the improvements in systemic treatments. 4 5 Consequently, the anatomical factors influencing the resectability of pancreatic cancer, which are defined in the National Comprehensive Cancer Network (NCCN) clinical practice guidelines, 6 have diminished in importance owing to better local and systemic control with higher response rates.

This review summarizes and contextualizes recent studies on the management of pancreatic cancer, and discusses potential treatments that are on the horizon. A detailed discussion of the preclinical or translational studies of diagnosis tools, drugs, and procedures is outside the scope of this review.

Sources and selection criteria

We searched Pubmed, the Cochrane database, and the Central Register of Controlled Trials (clinicaltrials.gov) between January 2000 and December 2022 for English language literature. We used the following keywords and keywords combinations: “pancreatic cancer”, “molecular characteristics”, “biology”, “resectability”, “metastatic”, “treatment”, “surgery”, “chemotherapy”, “radiation therapy”, “immunotherapy”, “prevention”, “precursor”, and “risk factor”. We also included the NCCN clinical practice guidelines, 6 the European Society for Medical Oncology (ESMO) clinical practice guidelines, 7 and the clinical practice guidelines from the Japan Pancreas Society. 8 We included studies based on the level of evidence; randomized controlled trials, meta-analyses, systematic reviews, and large retrospective cohort studies were prioritized. Meta-analyses included retrospective and prospective studies unless otherwise specified. We prioritized the most recent studies and excluded narrative reviews, case series, and case reports. We included additional landmark studies published before January 2000, as well as after December 2022.

Epidemiology

Pancreatic cancer is reported to account for 495 773 new cases and 466 003 deaths worldwide as of 2020, with the incidence and mortality rates stable or slightly increased in many countries. 9 In the US, the estimated incidence of pancreatic cancer is increasing, with more than 50 000 new cases in 2020. Mortality rates have also increased moderately in men, to 12.7 per 100 000 men in 2020; but have remained stable in women, ranging from 9.3 to 9.6 per 100 000 women. Accordingly, pancreatic cancer is the third most common cause of cancer related death in 2023, and is predicted to become the second leading cause of cancer mortality by 2040. 3 10

Clinical presentation/features

Symptoms of pancreatic cancer are mostly non-specific, and generally manifest after the tumor has grown and metastasized. In a multicenter prospective study of 391 patients who were referred for suspicion of pancreatic cancer (119 had pancreatic cancer), the most common initial symptoms were decreased appetite (28%), indigestion (27%), and change in bowel habits (27%). 11 The initial symptoms were similar between the pancreatic cancer group and the non-cancer group, though several subsequent symptoms were associated with pancreatic cancer: jaundice (49% v 12%), fatigue (51% v 26%), decreased appetite (48% v 26%), weight loss (55% v 22%), and change in bowel habits (41% v 16%).

Risk factors

Box 1 summarizes the risk factors for pancreatic cancer. Research is continuing into subtypes and modifiers of familial syndromes.

Factors that increase the risk of pancreatic cancer

Family history.

Up to 10% of all pancreatic cancers are estimated to be familial (meaning that at least two first degree relatives have pancreatic cancer)

Patients who have two first degree relatives with pancreatic cancer have a standardized incidence ratio of 6.4 (lifetime risk 8-12%) 12

Patients who have three first degree relatives with pancreatic cancer have a standardized incidence ratio of 32.0 (lifetime risk 40%) 12

Approximately 20% of these families have a germline mutation that is already reported and known

Germline mutation and hereditary syndrome

LKB1/STK11: Peutz-Jeghers syndrome; relative risk 132 13

CDKN2A/p16: familial atypical multiple mole melanoma syndrome; relative risk 13-22 14

PRSS1/CPA1/CTRC/SPINK1: hereditary pancreatitis; relative risk 53-87 15

BRCA1 and BRCA2: hereditary breast ovarian cancer syndrome; relative risk 2 and 10, respectively 16

MLH1/MSH2/MSH6/PMS2: Lynch syndrome; relative risk up to 8.6 17

PALB2/ATM: relative risk unknown

Lifestyle factors

Smoking: current smoker relative risk 1.8; former smoker relative risk 1.2 18

Obesity: five unit increment in body mass index relative risk 1.10 19

Diabetes mellitus * : relative risk 1.94 20

Chronic pancreatitis: relative risk 16.16 21

*Diabetes mellitus is also a symptom of pancreatic cancer; new onset diabetes in older people could be an early sign of pancreatic cancer and can lead to early diagnosis. 22 The association between diabetes and pancreatic cancer is currently undergoing further research. 23

Precancerous lesion

Molecular research has proposed two evolutionary models of pancreatic cancer: the classic “stepwise” model, with gradual accumulation of driver gene mutations, and the novel “punctuated” model, 24 in which driver gene mutation occurs simultaneously by chromosomal rearrangements. The stepwise model is characterized by tumor evolution from a precancerous lesion (low grade or high grade dysplasia) to invasive cancer, and is believed to be the main evolutionary pattern. Pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasms (IPMNs) are well known precancerous lesions. By contrast to PanIN, which is a microscopic neoplastic lesion, IPMNs can be detected and followed by imaging studies. Consequently, extensive studies have been conducted to evaluate the association between imaging findings and pathological findings of IPMNs. Branch duct IPMNs have been reported to have a low malignant nature (1.0% patient years), 25 but harbor a risk of concomitant pancreatic cancer (0.8%). 26 Main duct IPMNs have been reported to be a high risk factor for pancreatic cancer (odds ratio 5.66). 27

Screening and early detection

Because early stage (ie, stage I, T1N0M0) disease or precancerous lesions are more likely to be curable, the goal of screening or surveillance for pancreatic cancer is to detect lesions of 2 cm or smaller, or patients with high grade dysplasia. 28 Several studies have estimated an interval of several years between a high grade dysplasia lesion (high grade PanIN and IPMN) and invasive cancer, which can give opportunities for early detection and intervention: 2.3-11 years for high grade PanIN, 29 30 and more than three years for high grade IPMN. 31 The International Cancer of the Pancreas Screening (CAPS) consortium has published consensus guidelines about screening for high risk patients who have high risk germline mutations or relatives with pancreatic cancer, or both. 28 A recent prospective cohort study (CAPS5) from the CAPS group including 1461 high risk patients showed positive results of surveillance 25 ; seven of nine patients (77.8%) who developed pancreatic cancer had stage I cancer. However, only three of the eight patients (37.5%) who had IPMNs with worrisome features had high grade dysplasia (five had low grade dysplasia). A multicenter retrospective study (n=2552) of the CAPS consortium showed that 13 of the 28 patients (46.4%) who developed high grade dysplasia or cancer developed the new lesion during the scheduled examination interval. 32 Regarding IPMNs in the general population, a recent retrospective study showed that only 177 of 1439 patients with resected IPMN (12.3%) had high grade dysplasia, and 497 (34.5%) had a diagnosis of invasive cancer. 33 These results suggest that a novel strategy distinct from current guidelines 34 35 is needed for IPMN lesions, and new diagnostic tests are needed to detect tiny tumors.

The United States Preventive Services Task Force (USPSTF) 36 recommends avoiding pancreatic cancer screening in asymptomatic adults with average risk, considering the relatively low prevalence (estimated 64 050 new cases in 2023). 36 However, the USPSTF does not discuss screening in patients with risk factors of age and lifestyle, and neither do the consensus guidelines of the CAPS consortium. A risk assessment model including all known risk factors ( box 1 ) could help to identify good candidates for pancreatic cancer screening.

Carbohydrate antigen 19-9 (CA19-9) is a cell surface tetrasaccharide often elevated in pancreatic cancer, as well as in other cancers and some benign diseases. Historically, CA19-9 has not been used for early detection, owing to its insufficient sensitivity for early stage pancreatic cancer. 37 We also know that 5-10% of the population does not synthesize CA19-9, owing to a deficiency of a fucosyltransferase enzyme. However, a recent large retrospective cohort study showed that CA19-9 levels increase from two years before diagnosis of pancreatic cancer, with a sensitivity of 50% and specificity of 99% within 0-6 months before diagnosis in early stage disease. In addition, in cases with CA19-9 levels below the cut-off value, the combination of LRG1 and TIMP1 could complement CA19-9, leading to the identification of cases missed by CA19-9 alone. 38 Novel tests (ie, cytology 39 and DNA alterations 40 ) using pancreatic juice and cystic fluid have been reported to play a promising role in identifying high grade dysplasia and invasive cancer with high specificity. However, the sensitivity of these tests is low (˂50%). Extensive studies have investigated the role of liquid biopsy in pancreatic cancer: circulating tumor cells, 41 circulating tumor DNA, 42 43 microRNA, 44 exosomes, 45 and methylation signatures of cell free DNA. 46 Although these new biomarkers show promise, many problems remain unsolved with regard to standardization of testing techniques and cut-off values ( table 1 ). However, advances in this field could increase survival drastically.

Summary of novel techniques for diagnosis and early detection of pancreatic cancer

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Diagnosis and evaluation

The performance of diagnosis tools is summarized in box 2 .

Imaging study and biomarker for diagnosis of pancreatic cancer

CT (computed tomography) is the standard modality; accuracy 89% (95% confidence interval 85 to 93) 47

MRI (magnetic resonance imaging) has a similar performance to CT; accuracy 90% (95% confidence interval 86 to 94) 47

PET (positron emission tomography) has a worse performance; accuracy 84% (95% confidence interval 79 to 89) 47

Endoscopic ultrasound has a similar performance to CT; accuracy 89% (95% confidence interval 87 to 92) 47

Endoscopic ultrasound can identify masses that are indeterminate by CT; accuracy 75% (95% confidence interval 67 to 82) 48

CA19-9 is the most widely used and validated biomarker; area under curve 0.83-0.91 49

Imaging study for evaluation

CT (computed tomography) is the standard tool to evaluate the extent of the primary tumor and determine its anatomical resectability. Two meta-analyses showed similar performance of CT (sensitivity 70%, specificity 95%) and MRI (magnetic resonance imaging) (sensitivity 65%, specificity 95%) in the diagnosis of vascular involvement. 50 51 A meta-analysis showed that endoscopic ultrasound performed similarly to CT in evaluating vascular invasion. 52 A multimodal approach (ie, CT plus MRI plus endoscopic ultrasound) provides a better assessment of resectability. Several studies have attempted to evaluate the response to chemotherapy with imaging studies to determine the course of treatment (ie, proceeding to surgery or continuing chemotherapy). However, the currently used response evaluation criteria in solid tumors (RECIST) are not sufficient to reassess local response after chemotherapy in pancreatic cancer, especially regarding the involvement of vessels. Distinguishing scar areas with fibrosis that occur with treatment from cancer cell death from viable tumor associated desmoplasia is challenging; both are common in pancreatic cancer. A meta-analysis including six studies with 217 patients showed the difficulty of using CT scans to predict margin negative resection after preoperative treatment; the sensitivity was 81% and specificity was as low as 42%. 53 MRI 54 55 and fluorodeoxyglucose PET (positron emission tomography)/CT or PET/MRI 56 have been reported to be associated with the pathological response to preoperative treatment, though the ability to evaluate the vessel involvement and resectability is unclear. However, it should also be noted that even in the setting of histological response assessment, moderate inter-rater reliability differences have been reported between pathologists. 57

Biomarker for evaluation

CA19-9 has been used to assess response to treatment and predict prognosis. A meta-analysis showed that CA19-9 was associated with the effect of preoperative treatment, and suggested that either normalization of CA19-9 or a decrease of more than 50% from the baseline level are positive predictors of survival. 58 A recent retrospective study analyzing the combination of CT and CA19-9 showed a good predictive performance of survival after chemoradiotherapy. 59 However, the optimal evaluation of response to treatment remains unclear. The ability of liquid biopsy ( table 1 ) to detect minimal residual disease following all planned treatment could identify a new subset of patients who require further treatment, and would lead to a true precision medicine approach, as has been achieved with other cancer types. 60

Cancer cell intrinsic and tumor microenvironment factor

Transcriptional studies have proposed several classifications of pancreatic cancer. A recent bioinformatic study 61 from The Cancer Genome Atlas research network supported the two subgroup model 62 : the basal-like subtype, which has low levels of GATA6 expression, and the classic subtype. In a prospective translational trial, the basal-like subtype was reported to be associated with a poor response to chemotherapy with FOLFIRINOX (combined leucovorin calcium (folinic acid), fluorouracil, irinotecan, and oxaliplatin) for patients with advanced cancer. 63 However, a more recent study using single cell analysis suggested that pancreatic cancer consists of a mixture of tumor cells with both molecular subtypes, and the composition is plastic and unstable. 64

In addition to the cancer cells themselves, the tumor microenvironment has been identified as being an essential factor associated with tumor progressions and tumor immunity. Pancreatic cancer is notorious for poor tumor cellularity and an abundant, fibrotic extracellular matrix. Although the dense extracellular matrix has been known to impair drug delivery and immune cell migration, it appears to have an essential role in maintaining the tumor microenvironment and supporting the progression of tumor cells. 65 Therefore, the efficacy of controlling the extracellular matrix by targeting its components (ie, collagen, cancer associated fibroblasts, and hyaluronan) and cytokines (ie, transforming growth factor β and sonic hedgehog) has been evaluated.

Figure 1 outlines the current management for pancreatic cancer based on the anatomic resectability of the tumor, with the first consensus statement defined in 2009, 66 before the advent of more effective systemic treatments. In primary resectable disease, upfront surgery followed by adjuvant chemotherapy has been considered the standard of care. By contrast, for borderline resectable and locally advanced diseases, preoperative treatment is generally proposed, because of the high likelihood of micrometastasis and the low likelihood of margin negative resection in these tumors. 67 However, the improvement of medical treatment is challenging this concept; neoadjuvant treatment for resectable diseases is under investigation. At present, the recommendation is that the decision for treatment should be made at a multidisciplinary conference at a high volume center.

Current management for pancreatic cancer. CA19-9=carbohydrate antigen 19-9

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Systemic treatment

The standard drug treatment for systemic treatment is still cytotoxic chemotherapy, and the efficacy of targeted treatment or immunotherapy remains unproven. Table 2 summarizes the clinical trials of medical treatment.

Summary of key studies of medical treatment of pancreatic cancer

Systemic treatment for metastatic disease

Gemcitabine became the standard chemotherapy drug for pancreatic cancer more than 20 years ago. In 1997, gemcitabine showed clinical benefit and marginally improved overall survival compared with fluorouracil (median survival 5.65 v 4.41 months) in a small randomized controlled trial that included 63 patients in each arm. 68 Consequently, several trials were performed investigating combinations with gemcitabine. 69 70 71 However, most studies did not show a significant improvement in overall survival; the combinations tested included fluorouracil, 72 irinotecan, 73 oxaliplatin, 74 75 cisplatin, 76 77 and capecitabine. 78 79 80 Unfortunately, the addition of targeted treatment to gemcitabine based chemotherapy also did not show a survival benefit, with any of tipifarnib, 81 cetuximab, 82 bevacizumab, 83 84 axitinib, 85 and vandetanib. 86 In 2011, a landmark randomized phase 2/3 trial (PRODIGE 4/ACCORD 11) defined a new standard chemotherapy for metastatic pancreatic cancer. 71 This multicenter trial enrolled 171 patients in each arm and showed a significant improvement in survival, with a median overall survival of 11.1 months in the FOLFIRINOX group, compared with 6.8 months in the gemcitabine group (hazard ratio 0.57; 95% confidence interval 0.45 to 0.73). FOLFIRINOX also had a higher response rate (31.6%) than gemcitabine (9.4%). Subsequently, the MPACT trial, a large randomized phase 3 study, showed another cytotoxic combination option (gemcitabine/nab-paclitaxel) for metastatic pancreatic cancer. 87 This study included 861 patients, and showed that gemcitabine/nab-paclitaxel improved survival compared with gemcitabine alone (median survival 8.5 v 6.7 months; hazard ratio 0.72; 95% confidence interval 0.62 to 0.83). FOLFIRINOX and gemcitabine/nab-paclitaxel have formed the cytotoxic “backbones” for multiple clinical trials.

Nanoliposomal irinotecan is a drug encapsulating irinotecan sucrosofate salt payload in tiny pegylated liposomal particles, which theoretically can enhance the exposure of irinotecan to tumor cells. A recent randomized phase 3 trial (NAPOLI-3) enrolled 770 patients with metastatic pancreatic cancer and compared NALIRIFOX (combined liposomal irinotecan, fluorouracil, folinic acid, and oxaliplatin) (n=383) to gemcitabine/nab-paclitaxel (n=387) as the first line treatment. 88 Preliminary results showed an improved overall survival (median 11.1 v 9.2 months; hazard ratio 0.84; 95% confidence interval 0.71 to 0.99), which was the primary endpoint, and an improved progression free survival (7.4 v 5.6 months; 0.70; 0.59 to 0.84). For Asian populations, S-1 (an oral fluoropyrimidine derivative) is another treatment option, after it showed non-inferiority to gemcitabine for advanced pancreatic cancer in a randomized phase 3 study (GEST). 89

Second line systemic treatment for advanced disease

Second line regimens after gemcitabine based chemotherapy for advanced pancreatic cancer have been studied in several trials. The CONKO-003 randomized phase 3 trial showed that the addition of oxaliplatin to folinic acid and fluorouracil (5FU/LV) significantly improved overall survival (median 5.9 v 3.3 months, hazard ratio 0.66; 95% confidence interval 0.48 to 0.91). 90 By contrast, another randomized phase 3 trial (PANCREOX) found a deleterious effect on survival of oxaliplatin (mFOLFOX6) over infusional fluorouracil/leucovorin (hazard ratio 1.78; 95% confidence interval 1.08 to 2.93) in the second line setting. 91

A large randomized phase 3 trial (NAPOLI-1) investigated the efficacy of nanoliposomal irinotecan to 5FU/LV for metastatic disease after gemcitabine based treatment. 92 The results showed that nanoliposomal irinotecan plus 5FU/LV incrementally improved survival compared with 5FU/LV (6.1 v 4.2 months, hazard ratio 0.67; 95% confidence interval 0.49 to 0.92). Patients who received nanoliposomal irinotecan monotherapy, however, had similar survival to those who received 5FU/LV (4.9 v 4.2 months, 0.99; 0.77 to 1.28). Further studies on second line regimens after FOLFIRINOX or gemcitabine/nab-paclitaxel are warranted.

Maintenance systemic treatment for advanced disease

A poly adenosine diphosphate ribose polymerase (PARP) inhibitor was investigated as the maintenance treatment in patients who had germline loss-of-function mutations in BRCA1 or BRCA2, and platinum sensitive advanced disease. A randomized double blind phase 3 trial (POLO) showed no survival benefit of olaparib (n=62) compared with placebo (n=92) (median overall survival 19.0 v 19.2 months; hazard ratio 0.83; 95% confidence interval 0.56 to 1.22), but did show an improvement in progression free survival, which resulted in US Food and Drug Administration approval. 93 94 Another PARP inhibitor, niraparib, combined with an anti-CTLA-4 (ipilimumab) drug, showed a median overall survival of 17.3 months (95% confidence interval 12.8 to 21.9 months) in a phase 1b/2 trial. 95 Maintenance treatment for non-BRCA mutated patients with metastatic diseases following FOLFIRINOX was evaluated in the PANOPTIMOX-PRODIGE 35 phase 2 trial. 96 This study randomly assigned 273 patients to six month FOLFIRINOX (n=91), four month FOLFIRINOX followed by leucovorin/5-FU maintenance (n=92), or a sequential treatment alternating gemcitabine and FOLFIRI.3 every two months (n=90). The results showed a comparable six month progression free survival rate and median progression free survival in the maintenance arm eliminating oxaliplatin (44%, 5.7 months), and the worst survival in the gemcitabine/FOLFIRI approach (34%, 4.5 months) compared with the six month FOLFIRINOX arm (47%, 6.3 months).

Adjuvant systemic treatment

Adjuvant systemic treatment is recommended for all eligible resected patients. The first large randomized phase 3 trial that showed the survival benefit of adjuvant chemotherapy was the ESPAC-1 trial, which assigned resected patients (n=289) to 5-FU/LV versus control. 4 97 Adjuvant chemotherapy prolonged the median overall survival by 4.6 months (hazard ratio 0.71; 95% confidence interval 0.55 to 0.92). 4 The CONKO-001 randomized phase 3 trial showed that adjuvant gemcitabine (n=179) improved overall survival compared with observation (n=172) (median 22.8 v 20.2 months; hazard ratio 0.76; 95% confidence interval 0.61 to 0.95). 98 When 5FU/LV and gemcitabine were compared head-to-head, no difference in overall survival was found, but gemcitabine had less toxicity in the ESPAC-3 randomized phase 3 trial. 99 Subsequently, multiple trials tried to find a new effective combination treatment with gemcitabine. A randomized phase 3 trial combining erlotinib with gemcitabine was negative, 100 but the addition of capecitabine had a survival benefit over gemcitabine alone (28.0 v 25.5 months; 0.82; 0.68 to 0.98) in the ESPAC-4 phase 3 trial. 101 However, this combination treatment was short lived; FOLFIRINOX drastically changed the survival of patients and became the new standard regimen for adjuvant treatment. The PRODIGE 24/CCTG PA6 phase 3 trial randomly assigned 493 resected patients to receive adjuvant modified (dose reduced) FOLFIRINOX (mFOLFIRINOX) or gemcitabine for 24 weeks. The mFOLFIRINOX group (n=247) showed a significantly improved median overall survival (53.5 v 35.5 months; 0.68; 0.54 to 0.85). 5 102 By contrast, gemcitabine/nab-paclitaxel failed to show a survival benefit over gemcitabine alone in a randomized phase 3 trial (APACT). 103 It did not meet the primary endpoint of disease free survival by central review, 103 although overall survival improved marginally in the gemcitabine/nab-paclitaxel group (40.5 v 36.2 months; 0.82; 0.680 to 0.996). In Asia, S-1 is the standard regimen, based on the results of a randomized phase 3 trial. 104 The role of adjuvant treatment after neoadjuvant chemotherapy and surgical resection is still debatable. A recent large retrospective study showed a potential benefit in survival for patients able to receive adjuvant chemotherapy after neoadjuvant and surgery. 105

Neoadjuvant systemic treatment

One of the underpinnings of neoadjuvant treatment is that 36% of patients with pancreatic cancer are unable to receive adjuvant chemotherapy after resection, 106 and surgical resection alone does not achieve long term survival for most patients. The rationale for neoadjuvant treatment is to increase the dose intensity and tolerance of planned systemic treatment before patients are weakened by surgery, and to avoid delayed treatment of micrometastatic disease, which is the main cause of mortality. 107 Two prospective single arm phase 2 studies showed the safety of neoadjuvant gemcitabine plus a platinum based drug. 108 109

The only published phase 3 trial of neoadjuvant systemic treatment (PREOPANC-1) randomly assigned 246 patients with resectable (54.1%) or borderline resectable disease (45.9%) to neoadjuvant chemoradiotherapy (n=119) or upfront surgery (n=127). 110 111 The neoadjuvant chemoradiotherapy arm received three cycles of neoadjuvant gemcitabine with 36 Gy radiotherapy in 15 fractions and four cycles of adjuvant gemcitabine, whereas the upfront surgery arm received six cycles of adjuvant gemcitabine. Long term results showed a consistent survival benefit of neoadjuvant treatment regardless of the resectability of the primary tumors, for borderline resectable diseases (hazard ratio 0.67; 95% confidence interval 0.45 to 0.99) and resectable diseases (0.79; 0.54 to 1.16). However, the chemotherapy regimen (gemcitabine alone) was outdated. The recent ESPAC-5 phase 2 trial 112 randomly assigned 90 patients with borderline resectable diseases to neoadjuvant treatment (n=56), which included multiagent neoadjuvant chemotherapy and single agent chemoradiotherapy, or upfront surgery (n=33). It showed a better one year overall survival in the neoadjuvant treatment groups compared with the upfront surgery group (76% v 39%; hazard ratio 0.29; 95% confidence interval 0.14 to 0.60), although it did not provide evidence of the optimal regimen owing to the small sample size.

Regarding resectable diseases, one concern of neoadjuvant treatment is the possibility of disease progression during neoadjuvant treatment, which could cause patients to miss the opportunity for surgical resection. Indeed, the role of neoadjuvant treatment for resectable disease is still under investigation. A randomized phase 2 trial (PACT-15) showed that neoadjuvant chemotherapy with the PEFG regimen (cisplatin, epirubicin, fluorouracil, and gemcitabine) improved overall survival compared with adjuvant gemcitabine and adjuvant PEFG regimen for resectable disease. 113 The Prep-02/JSAP-05 phase 2/3 trial randomly assigned patients with resectable (about 80%) or borderline resectable diseases to one month neoadjuvant gemcitabine plus S-1 (n=182), or upfront surgery (n=180). Both arms received six month S-1 as the adjuvant treatment. 114 The results showed improved overall survival in the neoadjuvant chemotherapy arm (36.7 v 26.6 months; hazard ratio 0.72; 95% confidence interval 0.55 to 0.94). Conversely, studies of FOLFIRINOX have not shown positive results. 115 116 The SWOG S1505 phase 2 study showed equivalent efficacy of neoadjuvant mFOLFIRINOX versus nab-paclitaxel/gemcitabine for three months for resectable disease. 115 The median overall survival in both arms (23.2 and 23.6 months) did not show improvement compared with previous trials of adjuvant treatment.

A recent phase 2 trial (NORPACT-1) randomly assigned 140 patients with resectable diseases to the neoadjuvant FOLFIRINOX arm (n=77) or the upfront surgery arm (n=63), and found no survival benefit of neoadjuvant FOLFIRINOX. However, the results have several problems. While not significant, the median survival was 13.4 months shorter (25.1 v 38.5 months) in the neoadjuvant FOLFIRINOX arm, despite the higher rates of node negative (N0) and margin negative (R0) resection in that arm. Given the high resection rate (n=63, 82%) despite the low completion rate of neoadjuvant chemotherapy (n=40, 52%), and the high rate of adjuvant chemotherapy other than FOLFIRINOX (75%) in the neoadjuvant group, it seems that the neoadjuvant group did not receive sufficient FOLFIRINOX chemotherapy. In addition, whether two months is sufficient for neoadjuvant FOLFIRINOX is unclear. Three ongoing large randomized phase 3 trials might provide some insight into the optimal sequence and the number of cycles of FOLFIRINOX; two are recruiting patients (ALLIANCE-A021806 and PREOPANC-3), and one recently opened ( NCT05529940 ). The first two trials plan to enrol more than 300 patients with resectable disease to assess the overall survival of perioperative FOLFIRINOX (eight cycles of neoadjuvant and four cycles of adjuvant) compared with adjuvant FOLFIRINOX (12 cycles). The NCT05529940 trial plans to enrol more than 600 patients and evaluate the two year survival of perioperative FOLFIRINOX (six cycles of neoadjuvant and six cycles of adjuvant) compared with adjuvant FOLFIRINOX (12 cycles).

Systemic treatment for locally advanced disease

After the positive results of FOLFIRINOX and gemcitabine/nab-paclitaxel for metastatic disease, several studies have investigated its efficacy in locally advanced diseases. A systematic review that analyzed 315 patients with locally advanced diseases from 11 studies between 1994 and 2015 showed that FOLFIRINOX was associated with a longer median overall survival of 24.2 months (95% confidence interval 21.7 to 26.8 months). 117 The proportion of patients who underwent surgical resection after FOLFIRINOX ranged from 0-43%. A phase 2 study (LAPACT) investigated gemcitabine/nab-paclitaxel for 106 patients 118 ; the median overall survival was 18.8 months (90% confidence interval 15.0 to 24.0 months). In total, 62 patients (58%) completed induction gemcitabine/nab-paclitaxel, and 17 patients (16%) underwent surgical resection. Another randomized phase 2 study (NEOLAP-AIO-PAK-0113) showed high surgical conversion rates of gemcitabine/nab-paclitaxel (23/64, 35.9%) and gemcitabine/nab-paclitaxel followed by FOLFIRINOX (29/66, 43.9%). 119 No survival differences were observed between the two arms (hazard ratio 0.86; 95% confidence interval 0.55 to 1.36). These results suggest a new potential treatment strategy for surgical conversion of locally advanced disease, which could achieve longer survival in selected patients.

Surgical treatment

Pancreatectomy, especially pancreaticoduodenectomy, has been considered a high risk surgery. The centralization of pancreatectomy has played an essential role in the improvement of perioperative outcomes. The 90 day mortality is reported to be under 5-10% in experienced high volume centers. 120 121 A recent meta-analysis including 46 retrospective studies (2015-2021) showed a significantly lower postoperative morbidity rate in high volume centers compared with low volume centers (47.1% v 56.2%; odds ratio 0.75; 95% confidence interval 0.65 to 0.88). 121

Surgery for locally advanced and borderline disease

Some experts have pushed for more aggressive operations for patients with borderline resectable and locally advanced diseases with the advent of more effective systemic drugs. Resection after neoadjuvant treatment was reported to have similar short term outcomes compared with upfront resection in a meta-analysis 122 including randomized controlled trials and a subgroup report of a randomized phase 3 trial. 123 However, data on arterial resection and reconstruction are more controversial, and depend on the resected artery and the technical approach; the mortality rates were reported as 5.7% for resection of the superior mesenteric artery, 124 and 1.7% for resection of the celiac axis. 125 More recently, arterial divestment has been proposed as an alternative to arterial resection in selected patients. A retrospective study of a high volume center reported a mortality rate of 7.0% for arterial resections and 2.3% for arterial divestment from 2015 to 2019, although the breakdown of resected arteries was not shown by periods. 126 To be clear, these aggressive procedures should be performed only when long term survival is expected. A previous meta-analysis including 13 studies (2005-2015) with 355 locally advanced tumors showed no significant association between the resection rate after chemotherapy and overall survival. 117 However, large, retrospective studies recently showed that conversion surgery for locally advanced diseases after FOLFIRINOX was associated with improved survival in a selected subgroup. 127 128 Further studies are expected.

Surgery for patients with metastatic disease

Macroscopic distant metastasis is a contraindication to surgical resection in general. However, several studies have reported a potential role of resection in highly selected patients with limited metastatic diseases. A meta-analysis including three retrospective studies (2016-2019) showed a longer overall survival (23-56 months v 11-16 months) in patients with synchronous liver metastasis who underwent resection after chemotherapy (n=44) compared with those who did not (n=166). 129 In another review, lung metastasectomy was associated with a longer survival with a median overall survival after resection ranging from 18.6 to 38.3 months. 130 A large retrospective study suggested that only patients who achieved a complete pathological response of metastasis could derive a survival benefit from resection. 131 Further studies are expected to provide data on patient selection criteria and metastatic sites. A single arm phase 2 study ( NCT04617457 ) and a randomized phase 3 trial ( NCT03398291 ) are recruiting patients with oligometastasis in liver from pancreatic cancer to evaluate the efficacy of resection after chemotherapy.

Minimally invasive surgery

Minimally invasive surgery for pancreatic cancer had until recently been lagging behind that for other cancers. Results of a recent randomized trial 132 (n=656) and a meta-analysis of three randomized controlled trials 133 (n=224) showed that laparoscopic pancreatoduodenectomy was associated with a shorter hospital stay, but a similar postoperative morbidity rate. Box 3 summarizes the studies comparing robotic pancreatoduodenectomy with open or laparoscopic pancreatoduodenectomy. Notably, all studies on pancreatoduodenectomy to date have included patients with diseases other than pancreatic cancer. Another meta-analysis including 12 randomized or matched studies (n=4346) showed a similar morbidity rate, but a higher margin negative resection rate (odds ratio 1.46) and shorter time to adjuvant treatment, in the laparoscopic distal pancreatectomy group. 139 Most recently, an international randomized trial (DIPLOMA) 140 including 117 patients with resectable pancreatic cancer in the minimally invasive distal pancreatectomy group and 114 patients in the open distal pancreatectomy group showed the non-inferiority of the oncological safety of minimally invasive distal pancreatectomy: a higher margin negative resection rate (73% v 69%) and comparable lymph node yield and intraperitoneal recurrence.

Comparison between robotic pancreaticoduodenectomy and open pancreatoduodenectomy or laparoscopic pancreatoduodenectomy

Robotic pancreatoduodenectomy ( v open pancreatoduodenectomy ) 134 135 136 | robotic pancreatoduodenectomy ( v laparoscopic pancreatoduodenectomy ) 135 137 138.

R0 resection: Comparable 135 136 or higher 134 | Comparable 135

Lymph nodes harvested: Comparable 135 136 or more 134 | Comparable 135 or more 137 138

Operating time: Longer 134 135 136 | Comparable 135 137 138

Estimated blood loss: Less 134 135 136 | Comparable 138 or less 135 137

Conversion rate: Not applicable | Lower 137 138

Overall mortality rate: Comparable 134 or lower 136 | Comparable 138

Overall morbidity rate: Comparable 134 135 or lower 136 | Comparable 135 137 138

Surgical site infection: Less 134 135 | Comparable 135 138

Pancreatic fistula: Comparable 134 135 or less 136 | Comparable 135 137 138

Hemorrhage: Comparable 135 | Comparable 135

Delayed gastric emptying: Comparable 134 136 or less 135 | Comparable 135 137 138

Length of stay: Comparable 134 135 or longer 136 | Comparable 135 137 or shorter 138

Radiotherapy

Radiotherapy is used as a part of local treatment for pancreatic cancer, generally combined with chemotherapy. Since the gold standard for this disease remains surgical resection, 67 the role of radiotherapy has been logically examined in both the adjuvant setting and in locally advanced inoperable patients. The neoadjuvant application of radiotherapy has also been investigated in several studies. In this setting, however, high level evidence comparing the role of radiotherapy in a head-to-head design to neoadjuvant chemotherapy is lacking. The true efficacy of radiotherapy on long term survival remains unclear, especially when combined with modern multiagent systemic treatments and surgical resection. Another concern in many radiotherapy studies is the heterogeneity of the treatment technique and dose used. For example, the techniques have evolved from conventional treatments to intensity modulated radiation therapy (IMRT) and stereotactic body radiation therapy (SBRT), more ablative approaches with adaptive planning platforms. Box 4 summarizes the characteristics of radiotherapy by types and doses. Table 3 summarizes the clinical studies of radiotherapy.

Characteristics of radiotherapy for pancreatic cancer by types and doses

3 dimensional conformal radiation therapy (3d-crt).

Using multiple beams shaped to conform to a tumor that is identified its size, shape, and location by 3D imaging (ie, CT, MRI)

Generally used dose:* 45.0-56.0 Gy in 1.75-2.20 Gy fractions

Image guided radiation therapy (IGRT)

An adjunctive technique to adjust the tumor location difference by using 3D imaging (ie, CT, MRI) performed immediately before each radiation treatment

Intensity modulated radiation therapy (IMRT)

Possible to adjust the irradiation intensity within a target volume

Possible to deliver a concentrated dose to a tumor and better spare the normal tissue

Stereotactic body radiotherapy (SBRT)

Accurately irradiate a tumor with high dose radiation in three dimensions from multiple directions

High local control rate, comparable toxicity 141

Generally used dose:* 30.0-40.0 Gy in 6.00-8.00 Gy fractions

*Based on the ASTRO clinical practice guideline. 142

Summary of key studies of radiotherapy for pancreatic cancer

Adjuvant radiotherapy

In theory, the purpose of adjuvant radiotherapy is to reduce the risk of local recurrence. NCCN guidelines recommend considering adjuvant chemoradiation treatment for patients with positive surgical margins. 67 However, prospective studies that support adjuvant radiotherapy are lacking, regardless of the surgical margin status. The aforementioned large randomized phase 3 trial (ESPAC-1) included 289 resected patients: 51 (17.6%) had positive resection margins. The results showed worse survival in the chemoradiotherapy arm (n=145) than in the non-radiotherapy arm (n=144) (median overall survival 15.9 v 17.9 months; hazard ratio 1.28; 95% confidence interval 0.99 to 1.66). 4 This study has discouraged further studies of adjuvant radiotherapy in Europe. However, the study had two major drawbacks. Firstly, the chemotherapy regimen was different in the chemotherapy arm (fluorouracil/leucovorin) and the chemoradiotherapy arm (fluorouracil). Secondly, the total dose of radiotherapy (20 Gy) did not reach 45 Gy, which represents the treatment dose of conventional, fractionated external beam radiotherapy. 67 Two randomized phase 2 studies investigated adjuvant gemcitabine plus radiotherapy for patients with negative resection margins. The first study administered 50.4 Gy in 28 fractions of radiotherapy, and found a lower local alone recurrence rate (11% v 24%), but did not show a difference in overall survival or disease free survival between the two arms (45 patients each). 143 The other small study (n=38) used a modern SBRT technique (25 Gy in five fractions), but showed no difference in any of the survival endpoints (recurrence free survival, locoregional recurrence free survival, or overall survival), even in the node positive subgroup. 144 An older systematic review included five randomized controlled trials (1985-2005) of adjuvant chemoradiotherapy consisting of fluorouracil based chemotherapy plus conventional radiotherapy, and showed no survival benefit of chemoradiation (pooled hazard ratio 1.09; 95% confidence interval 0.89 to 1.32). 145 The subgroup analysis in this study showed a possible efficacy of adjuvant chemoradiotherapy in patients with positive resection margins.

The RTOG0848 trial is a randomized phase 2/3 study that enrolled 322 resected patients. The ongoing phase 3 of this trial assesses the survival benefit of added radiotherapy (50.4 Gy) after six cycles of adjuvant gemcitabine based chemotherapy. However, because the standard of care regimen of adjuvant chemotherapy has changed to FOLFIRINOX, the results of this study might have a limited impact on clinical practice. Ultimately, the role of adjuvant radiotherapy is still ambiguous.

Neoadjuvant radiotherapy

One of the primary goals of neoadjuvant radiotherapy is to reduce the rate of positive margin resection, which is a risk factor for local recurrence. Two single arm phase 2 studies showed the tolerability and feasibility of concurrent radiotherapy combined with fluorouracil plus cisplatin 146 (n=41) and gemcitabine (n=41). 147 However, the evidence on the efficacy of neoadjuvant radiotherapy is inconsistent. A meta-analysis of three randomized controlled trials (n=189) that investigated chemoradiotherapy (fluorouracil based chemotherapy with a radiotherapy dose of 45-50.4 Gy) did not show any difference in overall survival between neoadjuvant chemoradiotherapy and adjuvant chemoradiotherapy (hazard ratio 0.93; 95% confidence interval 0.69 to 1.25). 148 The aforementioned PREOPANC-1 phase 3 trial, which showed a survival benefit of neoadjuvant chemoradiation for borderline resectable disease, did not evaluate effects with and without radiation. 110 Regarding neoadjuvant chemoradiotherapy with FOLFIRINOX, a phase 2 trial (n=48) showed that neoadjuvant FOLFIRINOX plus chemoradiotherapy in borderline resectable disease showed a high rate of margin negative resection, and prolonged median progression free survival and even median overall survival. 149 By contrast, a randomized phase 2 trial (ALLIANCE-A021501) showed worse survival in the patients with borderline resectable disease who were allocated to the neoadjuvant mFOLFIRINOX plus radiotherapy (SBRT or hypofractionated image guided radiotherapy) arm (n=56) compared with those who allocated to the neoadjuvant mFOLFIRINOX alone arm (n=70) (median overall survival 17.1 v 29.8 months; median event free survival 10.2 v 15.0 months). 150 However, the number of patients was modest, and the dropout rates were high in both the chemotherapy arm (71.4%) and the chemoradiation arm (82.1%). A meta-analysis comprising 15 studies (512 patients) of neoadjuvant FOLFIRINOX with or without radiotherapy for resectable and borderline resectable disease showed a better rate of margin negative resection in the chemoradiotherapy group (97.6% v 88.0%). 151 No differences were observed in resection rate, overall survival, or pathological outcomes. The PANDAS-PRODIGE 44 study, a randomized phase 2 study, assigned 130 patients with borderline resectable diseases to mFOLFIRINOX or mFOLFIRINOX plus conformal external radiation (50.4 Gy). This ongoing study aims to evaluate the histological negative margin resection rate as the primary endpoint.

Radiation for locally advanced disease

For locally advanced pancreatic cancer, radiation is used as the primary modality for local control and, on rare occasions, to facilitate margin negative resection in select patients who achieve good responses to treatment. 67 Trials for locally advanced diseases have reported various levels of efficacy. A randomized trial assigned 37 patients to receive chemoradiotherapy (gemcitabine, 50.4 Gy) and 34 patients to receive gemcitabine alone. The trial showed improved overall survival in the chemoradiotherapy group (11.1 v 9.2 months). 152 Progression free survival was not different, but the sample size was notably small. The LAP07 trial was a large randomized phase 3 trial that aimed to investigate the survival benefit of adding radiotherapy to chemotherapy (54 Gy plus capecitabine) compared with chemotherapy (gemcitabine or gemcitabine plus erlotinib) after four months of gemcitabine based induction chemotherapy. 153 The results showed no differences in overall (median 15.2 v 16.5 months; hazard ratio 1.03; 95% confidence interval 0.79 to 1.34) or progression free survival (9.9 v 8.4 months; 0.78; 0.61 to 1.01) between the chemoradiotherapy group (n=133) and the chemotherapy group (n=136). An older randomized phase 3 trial (2000-01 FFCD/SFRO) also compared gemcitabine chemotherapy (n=60) to chemoradiotherapy with fluorouracil and cisplatin (60 Gy) (n=59), 154 and showed worse overall survival (median 8.6 v 13.0 months) and progression free survival in the chemoradiotherapy group. 154 The study, however, suffered from major inconsistencies in the proportion of patients who received at least 75% of the planned dose of induction chemotherapy, being only 42.4% in the chemoradiotherapy group compared with 73.3% in the chemotherapy group.

Given that conventional fractionated radiotherapy techniques combined with gemcitabine based chemotherapy have failed to show a significant survival advantage, the focus of research has moved to SBRT and FOLFIRINOX. A meta-analysis of 1147 patients from 21 studies including randomized controlled trials (2002-2014) compared conventional external beam techniques to SBRT. 141 The estimated two year overall survival was higher in the SBRT group (26.9% v 13.7%), with less acute grade 3/4 toxicity (5.6% v 37.7%) and similar late grade 3/4 toxicity (9.0% v 10.1%). A phase 2 trial (LAPC-1) enrolled 50 patients to receive eight cycles of FOLFIRINOX followed by SBRT (40 Gy in five fractions). 155 In total, 39 patients underwent SBRT (78.0%) and seven (14.0%) patients underwent surgical resection; all had negative margins and pathological N0 stage. The overall survival in the resected patients was longer than in the unresected patients (median 24 v 15 months; three year survival rate 43% v 6.5%). A systematic review including 2446 patients from 28 phase 2/3 studies also showed a similar resection rate of 12.1% (95% confidence interval 10.0% to 14.5%). Therefore, this newest chemoradiotherapy approach could give the best chance of curative intent surgery, and achieve long term survival in a highly selected subgroup of patients.

Four phase 2/3 trials are ongoing. The CONKO-007 trial is a large randomized phase 3 trial enrolling 525 patients to evaluate chemoradiotherapy (50.4 Gy with gemcitabine) after induction chemotherapy with FOLFIRINOX (n=402) or gemcitabine (n=93) for three months; the primary endpoint was margin negative resection rate. The first results came out in 2022, and showed a higher rate of margin negative resection (resection and circumferential resection margin) (9.0% v 19.6%) in the chemoradiation arm (n=168, 61 underwent surgery) compared with the chemotherapy arm, which was continuing FOLFIRINOX or gemcitabine (n=167, 60 underwent surgery). 156 However, the total surgical resection margin negativity rate and survival did not reach statistical significance. The publication is pending. The other three trials are phase 2 trials and are still recruiting patients (SCALOP-2, 157 MASTERPLAN, 158 and GABRINOX-ART 159 ). These studies could provide more data about gemcitabine/nab-paclitaxel and SBRT for locally advanced pancreatic cancer. However, we are unable to draw a conclusion without well designed phase 3 trials using the latest technology and chemotherapy regimen.

Supportive care and palliative care

Weight loss is seen in more than half of patients at diagnosis of pancreatic cancer 11 ; as a result, the rates of malnutrition 160 161 (33.7-70.6%) and sarcopenia 162 (up to 74%) are high. Malnutrition and sarcopenia have been reported to be associated with poor outcomes of surgical resection and chemotherapy. 163 Given that the majority of patients suffer from metastatic diseases, palliative care, including pain management and nutrition support, is essential to their quality of life, and even prognosis. Table 4 highlights major studies on these topics.

Summary of studies on supportive/palliative care for pancreatic cancer

Emerging diagnostic tools and treatments

Diagnostic tools.

Fibrosis, both chemoradiotherapy induced and cancer associated, has been reported to be associated with overall survival. An MRI probe targeting chemoradiotherapy induced collagen (type I collagen) can detect this change in fibrosis. 170 Radiolabeled fibroblast activation protein inhibitors (FAPI) can target the expression of fibroblast activation protein in cancer associated fibroblasts, which is abundant in pancreatic cancer. 171 A meta-analysis showed superior performance of FAPI PET over FDG PET/CT/MRI for the determination of tumor, node, metastases (TNM) classification and peritoneal carcinomatosis. 172 A phase 2 trial is recruiting patients to evaluate the efficacy of FAPI PET/CT in patients with locally advanced disease ( NCT05518903 ).

Radiomics using machine learning or deep learning (artificial intelligence) is a new field of research, driven by advances in computer systems. Theoretically, a computer can learn and identify features and differences that a human cannot. A systematic review showed that radiomics models of the primary tumors had good performance in predicting patient prognosis. 173 Further studies with larger sample sizes for training and validating models with risk factors, images, and biomarkers will yield more conclusive results in this regard.

In the era of neoadjuvant chemotherapy, a new question has emerged of how to manage patients who have tumor progression during neoadjuvant treatment. A phase 2 trial ( NCT03322995 ) is recruiting patients (n=125) with resectable and borderline resectable disease to evaluate the efficacy of adaptive modification of neoadjuvant treatment (four months). Based on the results of restaging after four cycles of FOLFIRINOX, a decision will be made to either continue the same regimen, or switch to a gemcitabine based regimen and chemoradiotherapy. For locally advanced pancreatic cancer, the NEOPAN phase 3 trial successfully enrolled 171 patients with locally advanced pancreatic cancer to compare the progression free survival of FOLFIRINOX (12 cycles) with gemcitabine (four cycles), with preliminary results expected soon. Few data exist on the comparison of FOLFIRINOX with gemcitabine/nab-paclitaxel for both localized and advanced cancer. A randomized phase 2 study (PASS-01) is recruiting patients (planned n=150) with metastatic disease to investigate the difference in progression free survival between the two regimens. Moreover, genomic factors and putative biomarkers will be explored using whole genome sequencing and RNA sequencing, and patient derived organoids.

Immunotherapy has been largely ineffective in pancreatic cancer, potentially owing to both tumor cell intrinsic and tumor microenvironment factors. Recent trials have taken a combined approach. CISPD3, a randomized phase 3 trial (n=110), showed an improved objective response rate (50.0% v 23.9%; P=0.010) by adding sintilimab (a monoclonal antibody against programmed cell death protein 1) to FOLFIRINOX for metastatic patients, 174 albeit without superior overall survival and progression free survival. The same group is conducting a phase 3 trial to evaluate the same regimen in patients with borderline resectable and locally advanced diseases ( NCT03983057 ). Given the results of basic research in pancreatic cancer showing that the extracellular matrix plays an essential role in the tumor microenvironment and progression, several new agents have been introduced. A phase 2 trial ( NCT03336216 ) combining an immune checkpoint inhibitor with chemotherapy (FOLFIRINOX or gemcitabine based regimen) and cabiralizumab (a colony stimulating factor 1 receptor inhibitor that suppresses the activities of tumor associated macrophages) has been conducted. However, a 2020 press release 175 176 announced that this study missed the primary endpoint of progression free survival.

Pamrevlumab, a recombinant human monoclonal antibody against connective tissue growth factor, has been investigated in a randomized phase 3 trial (LAPIS) combined with FOLFIRINOX or gemcitabine/nab-paclitaxel (up to six cycles) for locally advanced tumors. The study has completed recruitment (n=284) and is continuing to evaluate the primary endpoint of overall survival. Most recently, a phase 1 trial proposed a notable approach to stimulating cancer immunity in pancreatic cancer, with promising results. 177 The study adopted the messenger RNA (mRNA) vaccine technique to make a personalized mRNA vaccine encoding five or more neoantigens, which were bioinformatically predicted from the resected primary tumor. This adjuvant treatment consisted of one dose of atezolizumab (anti-PDL1 (programmed death ligand 1) antibody) and eight doses (one week) of mRNA neoantigen vaccines, followed by 12 cycles of mFOLFIRINOX. In total, 16 of 28 resected patients received personalized vaccines, and eight patients responded to the vaccines, with no recurrence among responders after a median follow-up of 18.0 months. Larger studies will help establish whether this is a breakthrough in immunotherapy for pancreatic cancer.

Treatment strategies targeting specific genomic alterations have been explored in various molecularly defined patient subsets. Given the positive results for metastatic cancer in the POLO trial, 93 olaparib is being studied in a randomized phase 2 trial (APOLLO) to evaluate the additional benefit of one year of treatment on recurrence free survival in patients with a pathogenic BRCA1, BRCA2, or PALB2 mutation, who have received at least three months of multi-agent chemotherapy after curative resection. KRAS is an attractive target owing to its high rate of mutation (90%) in pancreatic cancer. 178 Although KRAS G12C mutations are rare (1.6% of pancreatic ductal adenocarcinoma (PDAC) cases), the ability to create covalent G12C inhibitors led to FDA approval in non-small cell lung cancer, and promising initial results in PDAC. Sotorasib, a KRAS G12C inhibitor, showed a median progression free survival of four months, and an objective response rate of 21% in metastatic patients with KRAS G12C mutations who received at least two lines of chemotherapy in a phase 1/2 trial. 179 Another KRAS G12C inhibitor, adagrasib, showed a median progression free survival of 6.6 months, and an objective response rate of 50% (5/10 patients), in patients with advanced pancreatic cancer in a phase 1/2 trial (KRYSTAL). 180

By contrast to the low mutation rate in BRCA1 (1.08%), BRCA2 (1.48%), PALB2 (0.54%), and KRAS G12C (1-2%), other KRAS mutations are quite common, and pan-KRAS inhibitors are under investigation. Two phase 1 studies of pan-RAS inhibitors are recruiting patients ( NCT04678648 and NCT05379985 ). Further studies on other KRAS targeting approaches are expected.

Radiotherapy has been suggested to have synergistic effects on local and even distant tumors when combined with immunotherapy. 181 182 A large randomized phase 3 trial showed that chemoradiotherapy followed by durvalumab (PDL1 inhibitor) had significantly longer overall survival than placebo in locally advanced, non-small cell lung cancer. 183 Recently, a phase 2 trial (CheckPAC) assigned 84 patients with refractory metastatic pancreatic cancer to receive SBRT/nivolumab (n=41) or SBRT/nivolumab/ipilimumab (n=43). 184 The SBRT/nivolumab/ipilimumab arm had a higher disease control rate (37.2% v 17.1%). Further studies with an immunotherapy–SBRT backbone are anticipated in locally advanced and metastatic disease settings.

Figure 2 summarizes all the data discussed above, and gives perspective on the future of the management of pancreatic cancer.

Precision medicine for pancreatic cancer. PanIN=pancreatic intraepithelial neoplasm

Several national and international guidelines for the management of pancreatic cancer have been published. Recommendations of those guidelines are proposed considering the evidence and the healthcare system of each country. We reviewed two major guidelines of the US and Europe, and also included the recent 2022 updated Japanese guideline. 6 7 8 All recommendations of these guidelines are made based on the metastatic status and the anatomical resectability of the primary tumors. Regarding treatments for resectable diseases, the NCCN guidelines list neoadjuvant chemotherapy as an option for high risk patients, and the Japan Pancreas Society guidelines recommend neoadjuvant for all patients. The ESMO guidelines recommend only upfront surgery. The NCCN and ESMO guidelines recommend mFOLFIRINOX as the first option of adjuvant chemotherapy, although S-1 monotherapy is recommended by the Japan Pancreas Society guidelines. Conversion surgery for locally advanced disease is an option in the NCCN and Japan Pancreas Society guidelines. No recommendation is made for conversion surgery for metastatic disease in any of the three sets of guidelines. Radiotherapy is listed as an option for non-metastatic diseases in the NCCN guidelines, while the other guidelines do not recommend it for resectable diseases. The NCCN guidelines recommend genetic testing of inherited mutations for all patients with pancreatic cancer, but no clear recommendations are made in the other sets of guidelines.

Conclusions

In the US and Europe, the incidence of pancreatic cancer has been increasing consistently, and this trend is estimated to continue for several decades. Advances in the combination of cytotoxic drugs have resulted in improvements in survival for all stages of the disease, and are changing treatment algorithms. Further investigation into the role of immuno-oncology agents and radiation could help a subset of patients. In addition, extensive efforts need to focus on risk assessment, screening, and early detection.

Research questions

・In patients treated with upfront systemic treatment, what is the optimal duration of systemic treatment and patient selection for surgical resection?

・How can immuno-oncology and targeted treatment be made effective?

・What is the optimal combination and sequence of radiotherapy, and who are the ideal targets?

・What is the specific population that needs routine screening and what is an effective combination of tests to detect precancerous lesions?

Glossary of abbreviations

NCCN: National Comprehensive Cancer Network

ESMO: European Society for Medical Oncology

PanIN: pancreatic intraepithelial neoplasia

IPMN: intraductal papillary mucinous neoplasm

CAPS: International Cancer of the Pancreas Screening

USPSTF: United States Preventive Services Task Force

CA19-9: carbohydrate antigen 19-9

RECIST: response evaluation criteria in solid tumors

FOLFIRINOX: combined leucovorin calcium (folinic acid), fluorouracil, irinotecan, and oxaliplatin

NALIRIFOX: combined liposomal irinotecan, fluorouracil, folinic acid, and oxaliplatin

mFOLFIRINOX: modified FOLFIRINOX

PEFG regimen: cisplatin, epirubicin, fluorouracil, and gemcitabine

IMRT: intensity modulated radiation therapy

SBRT: stereotactic body radiation therapy

3D-CRT: 3 dimensional conformal radiation therapy

IGRT: image guided radiation therapy

FAPI: fibroblast activation protein inhibitors

PDAC: pancreatic ductal adenocarcinoma

PDL1: programmed death ligand 1

State of the Art Reviews are commissioned on the basis of their relevance to academics and specialists in the US and internationally. For this reason they are written predominantly by US authors.

Competing interests : We have read and understood the BMJ policy on declaration of interests and declare the following interests: MDC receives grants from Haemonetics, and is the primary investigator of a Boston Scientific sponsored study. TS does not have conflicts of interest to declare. SDK receives investigator initiated clinical trial funding from Genentech and AstraZeneca. She also receives preclinical research support from Roche and Amgen. WAM receives institutional clinical trial funding from Genentech, Beigene, Pfizer, NGM, Gossamer, ALX, Exelixis, EDDC/D3, Mirati, RasCal Therapeutics, and CanBAS. He is also a Data and Safety Monitoring Board member of QED, Amgen, and Zymeworks.

Funding: This study is supported by funding sources: R01 DE028529-01 (SDK), R01 DE028282-01 (SDK), 1R01CA284651-01 (SDK), 1P50CA261605-01 (SDK), and the V Foundation Translational Research Award. The funders had no role in considering the study design or in the collection, interpretation of data, writing of the manuscript, or decision to submit the article for publication.

Contributors: Authors MDC and TS are joint first authors. The design, literature search, review, and writing of this manuscript was led by MDC and TS, and supported by SDK and WAM. MDC is the guarantor. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

We thank Hiroyuki Ishida for his drawings in figure 2 , and Michael J Kirsch for his assistance in proofreading this manuscript.

Patient involvement: No patients were involved in the writing of this review.

Provenance and peer review: commissioned; externally peer reviewed.

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Hallmarks to improving pancreatic cancer therapy identified by UCI researchers

Cell study offers Insights offer hope for better outcomes

Irvine, Calif., April 13, 2023 — Scientists from the University of California, Irvine, the University of Michigan and the University of Texas MD Anderson Cancer Center have made a significant contribution to the field of pancreatic cancer research. Their new study presents several crucial themes in the biology of pancreatic cancer that can serve as hallmarks for pancreatic cancer therapy. These themes include genomic alterations, metabolism, the tumor microenvironment, immunotherapy and innovative clinical trial design. The study appears in the journal Cell .

(Link to study:  https://www.cell.com/cell/fulltext/S0092-8674(23)00142-3 )

Pancreatic ductal adenocarcinoma, which represents the vast majority of pancreatic cancers, is one of the most challenging and fatal forms of cancer. Despite the substantial progress made in understanding the biology of PDAC over the past few decades, clinical care for most patients has not seen a major breakthrough. However, the authors believe that combined progress in these areas they have defined as hallmarks will prove transformative to the treatment of this disease.

According to Christopher Halbrook, assistant professor of molecular biology & biochemistry at UCI and lead author, “Initial efforts to target PDAC vastly oversimplified the complexity of the disease. It has taken several decades of hard work during which we have been aided by technological breakthroughs in techniques to understand intricacies of pancreatic tumors to finally provide us with a roadmap for the development of better treatments for our patients.”

The authors emphasize the importance of approaching the disease from multiple angles, encompassing as many of the hallmarks as possible for the highest chance of success.

Their review summarizes the consensus models that have emerged underpinning the genetic development and path-wise progression of pancreatic tumorigenesis. It further highlights several exciting examples of ongoing research, including the development of investigational compounds and clinically deployed approaches to target the genetic and immunological features of PDAC, cancer metabolism and chemoresistance.

The authors also discuss how advances in single-cell analysis and high-dimensional spatial profiling techniques have revealed the diversity of cell populations dynamically interacting within pancreatic tumors and discuss how to begin disrupting these networks to improve response to treatment. These approaches will pair with exciting avenues of new therapeutic development, such as cancer vaccines and antibody-drug conjugates, which hold enormous potential for the future of pancreatic cancer therapy.

The authors also express their optimism about the future of pancreatic cancer research and treatment.

“The previous 10 years has already seen the 5-year survival rate of PDAC double after remaining stagnant for decades prior. We are confident that the collective efforts of the scientific community will continue this trend to transform PDAC from a recalcitrant disease to a manageable disease,” said Halbrook.

The authors hope that their findings will inspire further research and ultimately lead to improved treatments and outcomes for pancreatic cancer patients.

Costas Lyssiotis and Marina Pasca di Magliano from the University of Michigan, and Anirban Maitra from the University of Texas MD Anderson Cancer Center particiated in the study. Support for Halbrook was provided the Sky Foundation, the V Foundation, the UCI Anti-Cancer Challenge, the University of California Pancreatic Cancer Consortium, and the Chao Family Comprehensive Cancer Center.

About the University of California, Irvine: Founded in 1965, UCI is a member of the prestigious Association of American Universities and is ranked among the nation’s top 10 public universities by U.S. News & World Report . The campus has produced five Nobel laureates and is known for its academic achievement, premier research, innovation and anteater mascot. Led by Chancellor Howard Gillman, UCI has more than 36,000 students and offers 224 degree programs. It’s located in one of the world’s safest and most economically vibrant communities and is Orange County’s second-largest employer, contributing $7 billion annually to the local economy and $8 billion statewide. For more on UCI, visit www.uci.edu .

Media access: Radio programs/stations may, for a fee, use an on-campus ISDN line to interview UCI faculty and experts, subject to availability and university approval. For more UCI news, visit news.uci.edu . Additional resources for journalists may be found at communications.uci.edu/for-journalists .

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Pancreatic Cancer

• What Is Pancreatic Cancer?
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Research into the causes, diagnosis, and treatment of pancreatic cancer is underway in many medical centers throughout the world.

Early detection

Screening tests for pancreatic cancer are recommended for patients with high-risk features. These features are generally the presence of genetic predispositions (i.e., BRCA ) or with premalignant lesions (i.e., IPMN).  However, the majority of pancreatic adenocarcinomas are diagnosed when it’s already developed into late-stage cancer. The medical community continues to search for screening tests. Studies include:

• Understanding if certain gene mutations in pancreatic precancerous conditions (benign and precancerous growths in the pancreas) increases risk for cancer
• Understanding if certain proteins found in the blood can be used to find pancreatic cancer early when it is likely to be easier to treat
• Understanding if a blood test can be developed to test people with new-onset diabetes for possible pancreatic cancer   

A lot of research is focused on finding better treatments for pancreatic cancer. Improving surgery and radiation therapy are major goals, as is determining the best combination of treatments for people with certain stages of cancer.

Radiation therapy

Some studies are looking at different ways to give radiation to treat pancreatic cancer. These include intraoperative radiation therapy (in which a single large dose of radiation is given to the area of the cancer in the operating room at the time of surgery) and proton beam radiation (which uses a special type of radiation that might do less damage to nearby normal cells).

Chemotherapy

Many clinical trials are testing new combinations of chemotherapy drugs for pancreatic cancer. Other newer chemo drugs are also being tested, as are combinations of chemo drugs with newer types of drugs.

Targeted therapies

Targeted drugs work differently from standard chemotherapy drugs in that they attack only specific targets on cancer cells (or nearby cells). Targeted therapies may prove to be useful along with, or instead of, current treatments. In general, they seem to have different side effects than traditional chemo drugs. Looking for new targets to attack is an active area of cancer research.

Immunotherapy

Immune therapies  attempt to boost a person’s immune system or give them ready-made components of an immune system to attack cancer cells. Some studies of these treatments have shown promising results.

Monoclonal antibodies: One form of immune therapy uses injections of man-made monoclonal antibodies . These immune system proteins are made to hone in on a specific molecule, such as carcinoembryonic antigen (CEA), which is sometimes found on the surface of pancreatic cancer cells. Toxins or radioactive atoms can be attached to these antibodies, which bring them directly to the tumor cells. The hope is that they will destroy cancer cells while leaving normal cells alone. For use in pancreatic cancer, these types of treatments are available only in clinical trials at this time.

Cancer vaccines: Several types of vaccines for boosting the body’s immune response to pancreatic cancer cells are being tested in clinical trials. Unlike vaccines against infections like measles or mumps, these vaccines are designed to help treat, not prevent, pancreatic cancer. One possible advantage of these types of treatments is that they tend to have very limited side effects. At this time, vaccines are available only in clinical trials.

Drugs that target immune system checkpoints: The immune system normally keeps itself from attacking other normal cells in the body by using “checkpoints” – proteins on immune cells that need to be activated (or inactivated) to start an immune response. Cancer cells sometimes find ways to use these checkpoints to avoid being attacked by the immune system. Drugs that target these checkpoints have shown promise in treating some types of cancer. Some of these are now being studied for use in pancreatic cancer.

Individualization of therapy

Some drugs seem to work better if certain types of mutations can be found in the patient’s tumor. For example, olaparib may work better in patients whose tumors have a particular inherited change in the BRCA gene. This concept is an area of intense study. Identifying markers that can predict how well a drug will work before it is given is an important area of research in many types of cancer.

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Our team is made up of doctors and oncology certified nurses with deep knowledge of cancer care as well as editors and translators with extensive experience in medical writing.

Ansari D, Tingstedt B, Andersson B, Holmquist F, Sturesson C, Williamsson C, Sasor A, Borg D, Bauden M, Andersson R. Pancreatic cancer: yesterday, today and tomorrow. Future Oncol. 2016 Aug;12(16):1929-46. doi: 10.2217/fon-2016-0010. Epub 2016 Jun 1. PMID: 27246628.

Maemura K1 Mataki Y, Kurahara H, Kawasaki Y, Iino S, Sakoda M et al. Comparison of proton beam radiotherapy and hyper-fractionated accelerated chemoradiotherapy for locally advanced pancreatic cancer. Pancreatology. 2017 Sep - Oct;17(5):833-838. doi: 10.1016/j.pan.2017.07.191. Epub 2017 Jul 27.

Stoffel EM, Brand RE, Goggins M. Pancreatic Cancer: Changing Epidemiology and New Approaches to Risk Assessment, Early Detection, and Prevention. Gastroenterology. 2023 Apr;164(5):752-765. doi: 10.1053/j.gastro.2023.02.012. Epub 2023 Feb 18. PMID: 36804602; PMCID: PMC10243302.

Tempero MA. NCCN Guidelines Updates: Pancreatic Cancer. J Natl Compr Canc Netw. 2019 May 1;17(5.5):603-605. doi: 10.6004/jnccn.2019.5007. PMID: 31117041.

Last Revised: February 5, 2024

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Overcoming therapy resistance in pancreatic cancer: New insights and future directions

Affiliations.

• 1 Department of Diagnostic and Intervention, Umeå Universitet, Umeå, Sweden; Wallenberg Centre for Molecular Medicine, Umeå Universitet, Umeå, Sweden. Electronic address: [email protected].
• 2 Department of Diagnostic and Intervention, Umeå Universitet, Umeå, Sweden; Wallenberg Centre for Molecular Medicine, Umeå Universitet, Umeå, Sweden.
• 3 Department of Diagnostic and Intervention, Umeå Universitet, Umeå, Sweden.
• 4 Department of Diagnostic and Intervention, Umeå Universitet, Umeå, Sweden; Universitat de Barcelona, Barcelona, Spain.
• 5 Department of Diagnostic and Intervention, Umeå Universitet, Umeå, Sweden; Wallenberg Centre for Molecular Medicine, Umeå Universitet, Umeå, Sweden. Electronic address: [email protected].
• PMID: 39153553
• DOI: 10.1016/j.bcp.2024.116492

Pancreatic adenocarcinoma (PDAC) is predicted to become the second leading cause of cancer deaths by 2030 and this is mostly due to therapy failure. Limited treatment options and resistance to standard-of-care (SoC) therapies makes PDAC one of the cancer types with poorest prognosis and survival rates [1,2]. Pancreatic tumors are renowned for their poor response to therapeutic interventions including targeted therapies, chemotherapy and radiotherapy. Herein, we review hallmarks of therapy resistance in PDAC and current strategies aiming to tackle escape mechanisms and to re-sensitize cancer cells to therapy. We will further provide insights on recent advances in the field of drug discovery, nanomedicine, and disease models that are setting the ground for future research.

Keywords: Cancer-associated fibroblast; Pancreatic cancer; Therapy resistance; Tumor microenvironment.

Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.

PubMed Disclaimer

Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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• Chemoresistance in pancreatic ductal adenocarcinoma: Overcoming resistance to therapy. Bhoopathi P, Mannangatti P, Das SK, Fisher PB, Emdad L. Bhoopathi P, et al. Adv Cancer Res. 2023;159:285-341. doi: 10.1016/bs.acr.2023.02.010. Epub 2023 Apr 18. Adv Cancer Res. 2023. PMID: 37268399
• Immune Checkpoint Inhibition for Pancreatic Ductal Adenocarcinoma: Current Limitations and Future Options. Kabacaoglu D, Ciecielski KJ, Ruess DA, Algül H. Kabacaoglu D, et al. Front Immunol. 2018 Aug 15;9:1878. doi: 10.3389/fimmu.2018.01878. eCollection 2018. Front Immunol. 2018. PMID: 30158932 Free PMC article. Review.
• Combination, Modulation and Interplay of Modern Radiotherapy with the Tumor Microenvironment and Targeted Therapies in Pancreatic Cancer: Which Candidates to Boost Radiotherapy? Benkhaled S, Peters C, Jullian N, Arsenijevic T, Navez J, Van Gestel D, Moretti L, Van Laethem JL, Bouchart C. Benkhaled S, et al. Cancers (Basel). 2023 Jan 26;15(3):768. doi: 10.3390/cancers15030768. Cancers (Basel). 2023. PMID: 36765726 Free PMC article. Review.
• Overcoming the Tumor Microenvironmental Barriers of Pancreatic Ductal Adenocarcinomas for Achieving Better Treatment Outcomes. Alzhrani R, Alsaab HO, Vanamal K, Bhise K, Tatiparti K, Barari A, Sau S, Iyer AK. Alzhrani R, et al. Adv Ther (Weinh). 2021 Jun;4(6):2000262. doi: 10.1002/adtp.202000262. Epub 2021 Apr 24. Adv Ther (Weinh). 2021. PMID: 34212073 Free PMC article.
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• Mayo Clinic pancreatic cancer research is changing the paradigm for neoadjuvant therapy

March 31, 2023

Although pancreatic cancer accounts for only 3% of new cancer diagnoses, it is projected to become the second most common cause of cancer-related death in the United States by 2030, according to the National Cancer Institute. Surgery is the only known cure for patients without obvious metastases. Patients whose tumors involve critical blood vessels, also called borderline resectable or locally advanced, are often treated with neoadjuvant therapy including systemic chemotherapy followed by consolidative chemoradiation, with some patients being considered for complex surgical resection afterward.

Traditional cross-sectional imaging such as CT and MRI poorly predicts response to this neoadjuvant therapy, and National Comprehensive Cancer Network guidelines don't currently include radiologic response as a metric. PET imaging has been used in many other types of cancer but is not typically used for patients with pancreatic cancer.

Although a blood-based tumor marker, CA 19-9, does exist to monitor the impact of neoadjuvant therapy, it has limited sensitivity. Furthermore, 10% of patients do not have measurable levels, called nonsecretors, and up to one-third of patients present with normal levels of CA 19-9. For the 60% of patients who would exhibit a CA 19-9 level useful to their care plans, there is disagreement in the field about the optimal decrease of that marker to indicate the best possible surgical outcomes.

Physicians at Mayo Clinic, however, have been using FDG- PET imaging to measure treatment response and predict surgical outcomes for several years to address this unmet need.

"The PET scan adds to all the different things we monitor to help patients make the most informed decisions," says Mark J. Truty, M.D., M.S. , a surgical oncologist at Mayo Clinic Comprehensive Cancer Center in Rochester, Minnesota.

A retrospective analysis of Dr. Truty and his colleagues' use of PET imaging for patients with pancreatic cancer was published in the Journal of the National Comprehensive Cancer Network in September 2022. This research has the potential to change treatment response guidelines for all patients with pancreatic cancer throughout the country.

Retrospective review of PET imaging cohort

PET scan for pancreatic cancer

PET scan shows pancreatic lesions before and after chemotherapy.

The final cohort reviewed included 202 patients with a mean age of 64.7 years at the time of surgery. Women accounted for 42% of the cohort. All patients received first line neoadjuvant chemotherapy, and 94 patients underwent chemotherapy switch. Nearly all patients (91%) had preoperative chemoradiation following neoadjuvant therapy.

Of the initial cohort, 46 patients had normal CA 19-9 levels at diagnosis and 21 patients were nonsecretors. Only 67% of patients presented with an elevated CA 19-9 level at diagnosis, and half of those patients' levels had normalized following neoadjuvant therapy.

All patients had at least one FDG- PET scan following neoadjuvant therapy and before surgical resection, and 90.1% of patients had two or more.

PET imaging results correlate with surgical outcomes

There is a significant association between neoadjuvant therapy pathologic response and patient survival. However, researchers only know the results of pathologic response after surgery. Dr. Truty and his colleagues assessed preoperative factors using biochemical response measured with CA 19-9 level and metabolic response measured with FDG- PET . Both were compared with neoadjuvant pathologic response.

Major pathologic response was more likely in patients with optimal CA 19-9 levels, major CA 19-9 response and major metabolic response. Without the presence of major metabolic response, biochemical response did not correlate with major pathologic response. On the contrary, major metabolic response was highly associated with major pathologic response regardless of biochemical response. When both biochemical and metabolic factors were observed, pathologic response was even more predictive.

"The most rewarding part of this is that we are able to have more-informed discussions with our patients," said Ajit H. Goenka, M.D. , a radiologist with Mayo Clinic Comprehensive Cancer Center in Rochester, Minnesota. "We can have shared decision-making with them."

The future of pancreatic cancer care

Drs. Truty and Goenka developed this concept in a true testament to Mayo Clinic's multidisciplinary model of care.

"It all started as a hallway conversation," says Dr. Goenka. "We have this cross-pollination of ideas and thoughts about problems. The culture of Mayo Clinic helps people from different disciplines come together to solve problems."

Research is underway to evaluate new imaging tracers. In the meantime, FDG- PET imaging is something all practitioners can do for their patients with pancreatic cancer.

"We can actually consider taking patients to the operating room for more-complex operations because we can highly predict whether or not they received effective chemotherapy, and we can change things if the chemotherapy isn't effective," says Dr. Truty. "The real future is not just to make sure that there are better drugs but also to prove the drugs we're giving are beneficial."

Dr. Truty, Dr. Goenka and their colleagues in the field discussed this research and other pancreatic cancer care optimizations in a webinar in December 2022 .

For more information

Annual report to the nation 2022: Overall cancer statistics. National Cancer Institute.

Abdelrahman AM, et al. FDG- PET predicts neoadjuvant therapy response and survival in borderline resectable/locally advanced pancreatic adenocarcinoma. Journal of the National Comprehensive Cancer Network. 2022;20:1023.

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July 4, 2024

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Target discovered for the treatment of pancreatic cancer

by Kiel University

A team at the Institute of Biochemistry at Kiel University has found a way to inhibit the function of the tumor-causing protein MYC. This can be used to develop new drugs.

MYC genes and the resulting proteins are the key drivers of many types of cancer. "It really is one of the most important, if not the most important oncogene in humans," said Professor Elmar Wolf, Director of the Institute of Biochemistry of the Faculty of Medicine at Kiel University (CAU).

This is why researchers across the globe are looking for possible ways to switch off this cancer gene in order to develop new approaches to cancer treatments. However, no inhibitor has yet reached clinical application.

As it is difficult to target MYC directly, Wolf's working group is pursuing an indirect approach via the necessary binding partners. This is because the cancer-promoting function of MYC is conveyed through binding to other proteins. Wolf and his team have identified one of these essential binding partners in cell culture and animal models for pancreatic cancer.

The work, which was published in the journal Gut , demonstrates that only very few MYC binding partners are important for the progression of pancreatic cancer. One of these is the protein RUVBL1.

"The absence of this protein restricted the tumor growth of pancreatic cancer cells the most compared to the other binding partners investigated," explained first author Markus Vogt, a doctoral candidate in Wolf's working group. Switching off RUVBL1 led to a significant reduction in the size of the tumors in the pancreas and to the migration of immune cells into the tumor.

The oncogene MYC requires the protein RUVBL1 for its cancer-promoting function

This discovery was preceded by extensive work. Firstly, mass spectrometry was used to determine which proteins bind to MYC. The result was 90 proteins.

Each of these 90 binding partners was then investigated to determine which one is important for tumor growth. To this end, the researchers constructed systems in which one of these proteins was genetically switched off.

This screen was carried out both in cultured cancer cells and in the animal model for pancreatic cancer (PDAC). The study in the animal model was decisive.

"This is because many MYC binding partners proved important to cultured PDAC cells, but not in vivo," Vogt stressed. The best hit was the protein RUVBL1, said Vogt. This was then analyzed more closely in cell culture.

Subsequently, animal models were used to test whether switching off RUVBL1 actually slows tumor growth or whether existing tumors even regressed.

"We mainly used genetic methods to prevent the production of this protein. And that had a therapeutic effect. The tumors regressed and the immune system was activated," explained Wolf.

He suspects that the effectiveness is based on the fact that immune cells migrate into the tumor. Pancreatic tumors in mice, as in humans, contain only a few immune cells and are therefore considered immunologically "cold."

Accordingly, most patients with pancreatic cancer do not benefit from immunotherapies. Wolf said, "We suspect that drugs that target the MYC-RUVBL1 axis could make pancreatic tumors susceptible to immunotherapy."

Switching off RUBVL1 causes tumor to shrink

Data from human tumors confirm the importance of the protein in pancreatic cancer. According to this data, RUVBL1 protein levels are increased in tumors compared to normal, healthy tissue. And it follows the expression level of MYC.

"There are tumors that have comparatively little RUVBL1, and at the same time they also have little MYC. Tumors that have a lot of RUVBL1 also have a lot of MYC." In addition, RUVBL1 appears to be an indicator of the aggressiveness of the tumor, as mortality is higher in tumors with a lot of RUVBL1 than in tumors with little RUVBL1.

The scientists are convinced that RUVBL1 is a good target for drugs against pancreatic cancer . In the Collaborative Research Center/Transregio 387 "Functionalisation of the Ubiquitin System against Cancer—UbiQancer," which has just been approved by the German Research Foundation (DFG), they will drive forward the development of active substances.

New Collaborative Research Center involving the Institute of Biochemistry at Kiel University

The aim of the research is to facilitate the development of fundamentally new drugs against cancer. The focus is on the protein ubiquitin and the processes associated with ubiquitin. Ubiquitin is characterized by the fact that it can be attached to other target proteins, for example RUVBL1, in multiple ways and modify it in different ways.

This enables ubiquitin to fulfill various functions, for example in protein degradation, in the regulation of the cell cycle, in cellular protein transport or in the activation and inactivation of enzymes. Prof Elmar Wolf heads two sub-projects of the SFB/TRR 387.

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Pancreatic Cancer Could Be Detected Sooner with Nanoprobe-Based Blood Test

Credit: Science Photo Library - SCIEPRO/Getty Images

Pancreatic cancer (PC) is one of the most lethal forms of cancer, primarily because it is usually diagnosed very late. Current markers are too insensitive and unspecific for early detection screenings. An international research team has now reported on the development of a new pancreatic cancer test that uses nanoparticle probes to selectively detect tumor associated autoantibodies against mucin-1 (MUC1) in blood sera. The team, headed by Roberto Fiammengo, PhD, and Giovanni Malerba, PhD, at the University of Verona, together with Alfredo Martínez, PhD, at the Center for Biomedical Research of La Rioja, and Francisco Corzana, PhD, at the Universidad de La Rioja, reported in Angewandte Chemie on development of the new assay, and the results of tests on blood samples from pancreatic cancer patients. The team suggests their test strategy could lead to significantly more precise and reliable pancreatic cancer diagnosis.

In their published paper, titled “ Detection of Tumor-Associated Autoantibodies in the Sera of Pancreatic Cancer Patients Using Engineered MUC1 Glycopeptide Nanoparticle Probes ,” the investigators wrote, “The autoantibodies detected by this probe show significantly better true and false positive rates for PC identification than current clinical biomarkers and are suggested as an independent biomarker that could improve disease diagnosis.”

Pancreatic cancer is the seventh leading cause of cancer-related deaths worldwide, and its high lethality is a consequence of late detection, the authors commented. While the five-year survival rate can be 40% for localized-stage disease at diagnosis, five-year survival is only about 3% for distant-stage disease at diagnosis. “The 5-year relative survival rate according to the latest statistical data in the US is only 11% for all disease stages combined,” the team continued, “These dismaying numbers highlight the importance for early detection of PC as the most effective way to improve survival.”

The biomarker CA-19-9, is considered a good diagnostic biomarker in symptomatic patients, and may be used for monitoring benign pancreatic diseases and screening high PC risk individuals, the team stated, but to date no biomarker or panel of biomarkers with sufficient diagnostic accuracy has been approved for the early diagnosis of PC. “Therefore, finding alternative, possibly more sensitive and specific, biomarkers is crucial to improve early detection, allowing for prompt medical intervention and higher patient survival rates.”

One potential and “appealing” possibility is to exploit circulating tumor-associated autoantibodies that can be detected readily in serum samples. Tumors produce certain tumor-associated antigens that draw the attention of the body’s constantly patrolling immune system and trigger an immune response. As a consequence, antibodies directed against the tumors—tumor-associated autoantibodies—are formed, circulating in the blood at very early stages of the disease—which makes them useful for early detection. “Tumor-associated autoantibodies effectively represent a natural amplification mechanism and can be identified at a very early stage of the disease before tumor-associated antigens can be detected, thus being ideally suited for early diagnosis.”

The new pancreatic cancer diagnostic approach developed by Fiammengo, Malerba and colleagues is based on the detection of tumor-associated autoantibodies directed against the tumor-associated form of mucin-1 (TA-MUC1). Mucin-1 is a heavily glycosylated protein that occurs, for example, in glandular tissue. In many types of tumors, including pancreatic cancer, it is found in significantly elevated concentrations. In addition, the pattern of glycosylation is different from that of the normal form. The team’s goal was to detect autoantibodies that are directed specifically against TA-MUC1 and are a clear indicator of pancreatic cancer.

Based on structural analyses and computer simulations of known antibodies against TA-MUC1 (SM3 and 5E5), the team designed a collection of synthetic glycopeptides that mimic different segments (epitopes) of TA-MUC1. “We used a structure-guided approach to develop unnatural glycopeptides as model antigens for tumor-associated MUC1,” they wrote. They also made unnatural modifications to increase the chances of identifying autoantibody subgroups indicative of the disease. The team immobilized these model antigens on gold nanoparticles (AuNPs) to create probes suitable for a serological assay (dot-blot assay).

The diagnostic assay was validated with real samples from patients with pancreatic cancer and a healthy control group. The team found that some of the nanoparticle probes could differentiate very well between samples from diseased and healthy individuals, demonstrating they detected tumor associated autoantibodies. Notably, these specific autoantibodies displayed significantly better correct positive/false positive ratios than current clinical biomarkers for pancreatic cancer. “Our work shows that it is possible to exploit structurally engineered unnatural glycopeptides to develop a nanoparticle-based diagnostic assay that detects subsets of autoantibodies associated with the tumoral state,” they commented.

Probes with smaller glycopeptide antigens that correspond to only a single epitope gave better results than larger probes that mimic multiple epitopes—an advantage for easier synthetic production. A short glycopeptide with an unnatural modification to its sugar component was found to be particularly effective for the detection of discriminating autoantibodies. This new structure-based approach could help in the selection of autoantibody subgroups with higher tumor specificity. “… our approach has allowed the development of TA-MUC1 model antigens that are short and simple glycopeptides significantly reducing the synthetic effort and increasing their attractivity for clinical diagnostic applications,” the team further stated. “Future work is focused on the development of more selective glycopeptide nanoparticle probes and on the application of our diagnostic assay in suitable validation cohorts.”

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Pancreatic Cancer

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Jeffrey Drebin, Chair of the Department of Surgery, is one of MSK’s many experts in diagnosing and treating pancreatic cancer.

This guide from Memorial Sloan Kettering (MSK) can help answer your questions about pancreatic cancer. It’s based on MSK’s strong expertise in treating pancreatic cancer and our credentials as a National Pancreas Foundation Center of Excellence .  

You may have just learned you have pancreatic cancer, or are worried you have it. It’s common to have questions. How do you know if you have pancreatic cancer? What causes pancreatic cancer? What’s the best hospital for treating pancreatic cancer? 

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About MSK’s guide to pancreatic cancer

This guide can support you and your loved ones as you learn more about this disease. We share expert information about pancreatic cancer symptoms and the latest treatments. We have information about pancreatic cancer research studies, also known as clinical trials , that you may be able to join.

Who is this disease guide for? 

• You’re waiting to learn if you have cancer    This guide gives you information about pancreatic cancer so you’re better prepared. If you want to know right away if you have cancer, we have information about MSK’s rapid diagnosis program . 
• You want a second opinion    This guide explains new treatments for pancreatic cancer. Learning about them can help you decide if you want a second opinion . MSK’s experts offer second opinions about both diagnosis and treatment options, no matter where you live.  
• You’re worried about your current treatment plan    This guide can help you learn about other treatment options. MSK experts only use the latest treatments for pancreatic cancer, some only offered at MSK and very few other hospitals.  
• You’re worried about your genetic risk for cancer    This guide can help you learn about your risk for pancreatic cancer. We offer cancer genetic risk assessments to see if you’re at higher risk for some cancers. About 10 out of every 100 cases of pancreatic cancer are from inherited genes passed on from parents to children.
• You’re a caregiver to someone who has cancer    We have information about how to support a loved one who has cancer , even if they’re not an MSK patient. At MSK, supporting caregivers is as important as caring for people with cancer. 

Where is the pancreas and what does it do?

What the pancreas looks like and its anatomy in your body 

The pancreas is a small gland. It’s located in your abdomen (belly) between your stomach and intestines.

The main job of the pancreas is to make enzymes, a kind of protein that helps you digest food. These enzymes are made by a type of cell called an exocrine cell. Most of your pancreas is made up of exocrine cells.  

A very small part of the pancreas is made of endocrine cells. These cells make hormones, including insulin, that control the level of sugar in your blood. 

Pancreatic tumors start in either exocrine or endocrine cells. Most pancreatic cancers are exocrine tumors, not neuroendocrine tumors. 

Types of pancreatic tumors 

There are about 20 different types of tumors that can grow in the pancreas. Exocrine pancreatic cancer tumors are the most common. More than 9 out of every 10 cases of pancreatic cancer are exocrine tumors.  

The most common kind is adenocarcinoma. Others are: 

• Acinar cell carcinoma 
• Intraductal papillary-mucinous neoplasm (IPMN) 
• Mucinous cystic neoplasm  

Neuroendocrine pancreatic cancer tumors are less common. Fewer than 1 out of every 10 cases of pancreatic cancer are neuroendocrine tumors. They include pancreatic neuroendocrine (islet cell) tumors .  

What makes pancreatic cancer so hard to treat and deadly?  

How pancreatic cancer spreads .

The pancreas is deep in the body. That makes it harder for your healthcare provider to see or feel a tumor during regular exams.  

There often are no  symptoms of early pancreatic cancer. Tumors can grow large and spread to healthy organs before there are signs of the disease.  

As a pancreatic tumor grows, it can spread to nearby organs, such as the bile duct, intestines, or stomach. It also can spread to nearby blood vessels.  

Pancreatic tumor cells also can break away. These cells can spread to the lymph nodes, liver, or somewhere else in the abdomen (belly). 

Pancreatic cancer is not the most common cancer, but it’s deadly 

Pancreatic cancer is not that common, with about 64,000 cases diagnosed each year in the United States. The number of new cases is rising. 

There are no recommended screening tests for people at average risk for pancreatic cancer. That makes it harder to catch this cancer early, before it spreads. 

Pancreatic cancer is hard to cure. 

The 5-year survival rate for pancreatic cancer has improved in recent years because of better treatments and diagnosis. But it’s still low at around 12%. That means out of every 100 people who get pancreatic cancer, only 12 will be alive 5 years later.  

The disease rarely causes  symptoms  in its early stages. It’s often diagnosed only after it metastasized (spread) from the pancreas to other parts of the body. After it spreads it’s much harder to treat. 

Why should I choose Memorial Sloan Kettering to treat pancreatic cancer? 

Msk’s team of pancreatic cancer experts .

MSK’s team of pancreatic cancer experts is among the nation’s largest. We’re a leading hospital for pancreatic cancer care and research.  

Our surgeons operate on about 350 people with pancreatic cancer a year. Our oncologists (cancer doctors) and other subspecialists treat about 850 people a year. That’s among the highest volumes of pancreatic cancer cases in both New York City and the country. 

MSK is home to the David M. Rubenstein Center for Pancreatic Cancer Research (CPCR). Its mission is to offer the latest pancreatic cancer treatments and resources while supporting your physical and emotional well-being. 

Research excellence 

The David M. Rubenstein Center of Pancreatic Research is finding new ways to treat pancreatic cancer through research studies, also known as clinical trials . We led the first clinical trial to test mRNA vaccines as a possible new treatment for pancreatic cancer. The vaccine trains the body to protect itself against its own cancer cells. 

National center of excellence 

As a National Pancreas Foundation Centers of Excellence , MSK offers the best possible treatment results to give you a better quality of life.  

Being named a NPF Center of Excellence means MSK: 

• Passed a very strict review of our doctors.  
• Offers many programs to support people who have pancreatic cancer. This includes pain management and symptom control, counseling , nutrition, integrative medicine , rehabilitation , pre-habilitation, and other services. 
• Shows excellence in our clinical trials as we test new treatments for pancreatic cancer. 

Pancreatic cyst surveillance

MSK’s Pancreatic Cyst Surveillance Program is one of the largest in the country . It monitors pancreatic cysts and has provided treatment for pancreatic cysts for more than 5,000 people.  Each year, MSK sees more than 300 new patients who have cysts in their pancreas.

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Ritchie School Professor Dali Sun Talks His Career and Groundbreaking Pancreatic Research

Owyn cooper.

Communications and Events Specialist

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303-871-4218

Biosensing Engineering Professor discusses his groundbreaking engineering research with cancer through collaboration across many STEM fields

Dr. Dali Sun, professor in biosensor technology, MATLAB, instrumentation and data acquisition at the Ritchie School of Engineering and Computer Science, recently published a research paper titled “ Integrated proteomic profiling identifies amino acids selectively cytotoxic to pancreatic cancer cells .” 

As explained in the paper’s abstract, “Pancreatic adenocarcinoma (PDAC) is one of the most deadly   cancers, characterized by extremely limited therapeutic options and a poor prognosis, as it is often diagnosed during late disease stages. Through proteomics analysis of extracellular vesicles, we discovered an imbalanced distribution of amino acids secreted by PDAC tumor cells.” 

With Dr. Sun’s focus in biosensing technology and bioinstrumentation, he was excited to put his engineering research to work in advancing clinical tools. 

“Because we are engineers, we do tools to help clinicians or to help researchers to study disease,” said Dr. Sun. “While we study these tools, we found some phenomena that can be divided into three domains or detection algorithms. We then dive into those new masters we developed and try to find a solution.”

As part of the endeavor to find a cure for cancer, the research process also works to ensure that the patient is not suffering during the healing process. “In order to decrease the suffering from the patient, we want to find a solution that does not introduce a lot of side effects,” Dr. Sun said.

In a Q+A with the Ritchie School, he delved into his background and experience in biosensing engineering. 

1. How did you get into biosensing engineering?

I got into biosensing engineering because of my fascination with the intersection of biology and technology. With a multidisciplinary background in Biology, Computer Science, Electrical Engineering, and Biomedical Engineering, I have been able to understand how engineering principles can solve complex biological problems. This unique blend of education and industry experience inspired me to pursue graduate studies focused on biosensing technologies. 

I wanted to develop innovative solutions for detecting and monitoring various biological processes. The potential to make a significant impact on healthcare by creating devices that enable early disease detection and real-time monitoring truly solidified my passion for this field.

2. What inspired you to study and research pancreatic cancer treatment?

One of the inspirations is  the high mortality rate and the lack of effective therapies for this aggressive disease. Pancreatic cancer often presents at an advanced stage, making it difficult to treat. Another source of inspiration for me is that this is the first cancer where I have observed something remarkable through my multidisciplinary approach—an insight that could aid in the detection of this cancer. 

In scientific research, both inspiration and luck play crucial roles. This initial observation, combined with the urgent need for new therapeutic strategies, has driven me to focus my research in this area. Witnessing many patients suffer from severe side effects, and my personal experiences with loved ones affected by cancer, has only heightened my commitment to finding innovative solutions that can improve patient outcomes and quality of life.

3. With pancreatic cancer treatment, how did the multidisciplinary approach come to be?

Our multidisciplinary approach to treating pancreatic cancer arose from recognizing that addressing this complex disease requires expertise from various fields. Initially, our strategy was inspired by data analysis methods grounded in my computer science background. Based on proteomics result, we processed data and found promising leads. To validate these leads, we employed biochemistry and bioengineering techniques, conducting in vitro assays and confirming the concept in vivo with mice. 

By merging the strengths of bioengineering, molecular biology, and clinical research, we have been able to develop comprehensive treatment strategies. Collaboration with experts in these fields has allowed us to design novel therapeutic agents and gain a deeper understanding of the disease's underlying mechanisms. This holistic approach has been pivotal in advancing our research and moving us closer to effective treatments.

4. What is a rewarding aspect of teaching engineering to Ritchie School students?

My teaching philosophy centers on connecting real-world problems to what students are learning. It's incredibly rewarding to see students applying the knowledge from my class directly to their job hunting and future careers. While some engineering concepts can be quite abstract, I strive to make them as easy to understand as possible. 

I firmly believe that no knowledge is too difficult to learn. In my class, students don’t need to know everything to start learning. As a proponent of multidisciplinary education, I encourage students not to be afraid of exploring new fields.

Regardless of your background, come to my class and let me guide you through the learning process. One of the most fulfilling aspects of teaching engineering at Ritchie School is witnessing students grow and develop as they master complex concepts and apply them creatively. Seeing students develop critical thinking skills, innovate, and solve real-world problems is incredibly satisfying. 

5. What was it like to collaborate with other professors at the Ritchie School?

Collaboration is crucial to our scientific success. The Ritchie School has created an environment that strongly supports this. 

As part of the Knoebel Institute of Healthy Aging, I have access to excellent lab resources and facilities. It's easy to connect with other professors in the same building and collaborate with students from different labs, whether for collaboration, suggestions, or quick questions. The diverse expertise and perspectives of my colleagues have significantly enhanced our research projects, leading to innovative solutions. This collaborative atmosphere fosters continuous learning and mutual support, allowing ideas to be freely exchanged and refined. Working with such talented and dedicated colleagues has been both inspiring and essential in advancing our collective research goals.

6. What was it like to collaborate with Ritchie School students on the article?

The first author of the paper, my top student Alfred Akinlalu is exceptionally smart, motivated, and diligent. I am very proud that he has won the DU doctoral fellowship. All my students are highly motivated, excellent and come from diverse backgrounds. It is an honor to be their mentor, and I strive to guide them through the learning process.

7. What is something you’d like the Ritchie School community to know about your research?

Cancer patients still endure severe side effects from treatments and face significant economic burdens because many cancer therapies are very costly. Our lab aims to address these issues from an engineering perspective to work on low-cost cancer detection and treatment solution. Don’t rely on the pharmaceutical industry to focus on these lower-profit therapies; we need your support to continue our research. Our lab is deeply committed to advancing research that has a tangible impact on patient care and health outcomes.

“There’s no really good solution for cancer yet. Patients suffer a lot, and then the current treatment may introduce more side effects. We want to find a mastered solution that does not introduce a lot of side effects that will lower the risk (of suffering) for a patient.” 

If you’re interested in exploring more of the research at the Ritchie School,  please check out our page on Research and Innovation . Students can learn from Dr. Dali Sun in courses such as Biosensing Technology (ENGR-3/4450), Instrumentation and Data Acquisition (ENER-3/4100), and Applied MATLAB Programming (ENGR-1572).

Related Articles

Researcher Uses Engineering Methods to Reveal Promising Pancreatic Cancer Treatment

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• Open access
• Published: 24 August 2024

Complicated role of ALKBH5 in gastrointestinal cancer: an updated review

• Weitong Shu 1 , 2   na1 ,
• Qianying Huang 1 , 2   na1 ,
• Rui Chen 1 , 2   na1 ,
• Huatao Lan 1 , 2 ,
• Luxin Yu 1 , 2 ,
• Kai Cui 1 , 2 ,
• Wanjun He 1 , 2 ,
• Songshan Zhu 1 , 2 ,
• Mei Chen 1 , 2 ,
• Li Li 1 , 2 ,
• Dan Jiang 1 , 2 &
• Guangxian Xu 1 , 2  

Cancer Cell International volume  24 , Article number:  298 ( 2024 ) Cite this article

Metrics details

Gastrointestinal cancer is the most common malignancy in humans, often accompanied by poor prognosis. N6-methyladenosine (m6A) modification is widely present in eukaryotic cells as the most abundant RNA modification. It plays a crucial role in RNA splicing and processing, nuclear export, translation, and stability. Human AlkB homolog 5 (ALKBH5) is a type of RNA demethylase exhibiting abnormal expression in various gastrointestinal cancers.It is closely related to the tumorigenesis, proliferation, migration, and other biological functions of gastrointestinal cancer. However, recent studies indicated that the role and mechanism of ALKBH5 in gastrointestinal cancer are complicated and even controversial. Thus, this review summarizes recent advances in elucidating the role of ALKBH5 as a tumor suppressor or promoter in gastrointestinal cancer. It examines the biological functions of ALKBH5 and its potential as a therapeutic target, providing new perspectives and insights for gastrointestinal cancer research.

Gastrointestinal cancer is among the most common and deadly tumors worldwide, accounting for approximately one-fourth of the global cancer incidence and a mortality rate as high as one-third [ 1 ]. Although current conventional treatments, such as surgical resection, chemotherapy, and radiotherapy, are used for treating gastrointestinal cancer, the risks of cancer recurrence and drug resistance remain high. Precision targeting of tumors holds great promise in cancer therapy, leading to more in-depth research and analysis of cancer.

Epigenetic modifications are alterations independent of the DNA sequence [ 2 ], primarily regulating gene expression at the transcriptional level. Discoveries have been made in various aspects, including DNA and RNA methylation [ 3 , 4 ], histone modifications [ 5 ], transcriptional control [ 6 ], chromatin remodeling [ 7 ], non-coding RNA [ 8 ], and cancer immunotherapy [ 9 ]. Recent research indicated that cancer cells are often regulated by relevant epigenetic proteins, which are essential for maintaining normal cell growth, inducing differentiation, and initiating, sustaining, and propagating disease and abnormal cell states [ 10 ]. There is growing evidence indicating that epigenetic modifications, especially RNA modifications play a crucial role in tumorigenesis [ 11 , 12 ].

With the development of high-throughput sequencing technologies, over 170 RNA modifications have been identified, and m6A modification is one of the most prevalent types [ 13 ]. Transcriptome sequencing reveals that m6A binding sites are found within the RRACH sequence (R = A/G, H = A/C/U), predominantly enriched in the 3’ untranslated regions (UTRs) near the termination codon of mRNA exons [ 14 , 15 ]. M6A modification participates in various RNA metabolism processes, including splicing, nuclear export, translation, decay, processing, and RNA-protein interactions. Additionally, it plays a crucial role in embryonic stem cell differentiation, meiosis, tissue development, circadian rhythm, and tumor occurrence[ 16 , 17 , 18 , 19 , 20 ]. M6A modification is a dynamic and reversible process, which is primarily led by methyltransferases (Writers), demethylases (Erasers), and identified and promoted by some specific RNA-binding proteins (Readers)[ 21 ](Fig.  1 ).

Up to now, methyltransferase-like 3 (METTL3), methyltransferase-like 14 (METTL14), methyltransferase-like 16 (METTL16), Wilms tumor 1 associated protein (WTAP), zinc finger CCCH-type containing 13 (ZC3H13) proteins, RNA-binding motif protein 15 (RBM15), Vir-like m6 A methyltransferase-associated (VIRMA/KIAA1429), Cbl proto-oncogene like1 (CBLL1/Hakai), and Fl(2)d-associated complex component (Flacc) were regarded as Writers, and they can interact with each other to form a stable methyltransferase complex (MTC), or plays a supporting role in catalyzing the heterodimeric methyltransferase activity [ 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 ](Fig.  1 ). Erasers, including Fat mass and obesity-associated protein (FTO) and ALKBH5, are central to the removal of m6A modifications [ 32 , 33 ]. They are part of the alpha-ketoglutarate-dependent dioxygenase family, mediating the reverse process of m6A methylation under the action of Fe(II) and α-ketoglutarate[ 34 ]. FTO is involved in the regulation of the cell cycle, cell differentiation, splicing, cancer development, immunotherapy, and various other biological functions [ 35 , 36 , 37 , 38 ]. Importantly, ALKBH5, as another member of the α-ketoglutarate-dependent dioxygenase family, was found that knocking out ALKBH5 not only increases the m6A levels of RNA inside cells but also enhances the export of these RNAs from the nucleus to the cytoplasm [ 33 ]. Readers mainly include the YT521-B homology (YTH) domain family, IGF2 mRNA binding protein (IGF2BPs), and heterogeneous nuclear ribonucleoproteins (HNRNPs)[ 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 ]. And they mainly play a role in post-transcriptional regulation by identifying and binding to m6A-targeted genes, regulating downstream functions (Fig.  1 ).

Molecular mechanism of m6A modification. M6A is mediated by writers, erasers and readers, the details are as follows. METTL14 binds to METTL3 and forms a stable MTC. WTAP recruits MTC and localizes it in the nuclear speckle, performing a function that aids in catalyzing the activity of methyltransferases. ZC3H13, RBM15, and VIRMA act on the MTC to regulate the occurrence of m6A methylation. Hakai serves as a core component of the m6A writer and interacts with other writers. METTL16, which is a conserved U6 snRNA methyltransferase, controls the homeostasis of S-adenosylmethionine (SAM) by post-transcriptionally regulating the expression of SAM synthase genes. FTO and ALKBH5 belong to the family of ketoglutarate-dependent dioxygenases, mediating the reverse process of m6A methylation under the action of Fe(II) and α-ketoglutarate. YTHDF2 is the first discovered m6A reader protein, regulating the degradation of mRNA. YTHDF1 can promote the translation of m6A-modified mRNAs by binding to m6A sites and regulating translation factors. YTHDF3 can act on YTHDF1 to enhance the translation of mRNAs, and it can also act on YTHDF2 to regulate the degradation of mRNAs. YTHDC1 regulates the splicing function of mRNAs by recruiting splicing factors, and it also mediates m6A-dependent nuclear export. YTHDC2, as an RNA helicase, can enhance the translation efficiency of mRNAs while reducing their RNA abundance. IGF2BPs recognize the GG(m6A)C sequence and promote the stability, translation, and storage of targeted mRNAs. HNRNPs regulate the processing, and maturation of miRNAs and the abundance and splicing of mRNAs in an m6A-dependent manner. (figure was created with Biorender.com)

Among these regulators, ALKBH5, which was first discovered in 2013 as a demethylase for m6A, is becoming a hub in the research of epigenetic regulation of the development of cancer cells. The complicated biological functions of ALKBH5 have been widely found to be involved in various gastrointestinal cancers, including gastric cancer (GC), colorectal cancer (CRC), liver cancer (LC), pancreatic cancer (PC), and esophageal squamous cell carcinoma (ESCC). This review will focus on the role of ALKBH5 in gastrointestinal cancer and discuss directions for future research and potential clinical application of ALKBH5 for gastrointestinal cancer.

The structure and role of ALKBH5

ALKBH5 is a member of the AlkB family, a 2-oxoglutarate and ferrous acid-dependent nucleic acid oxygenase. It is located on human chromosome 17p11.2. Human ALKBH5 has a full length of 394 amino acids and its catalytic core contains features of a double-stranded β-helix fold (DSBH). Aik W et al. suggested that the DSBH fold of ALKBH5 is composed of eight reverse parallel β-strands, with the major β-sheet consisting of β6, β8, β11, and β13, and the minor β-sheet being formed by β7, β9, β10, and β12 [ 48 ]. However, Feng C et al. suggested that the DSBH fold of ALKBH5 does not have the typical eight reverse parallel β-strands, where β4, β5, β8, and β9 form the major sheet while β6, β7, and a short α-helix (α7) plus a long loop (C1) form the minor sheet [ 49 ]. The unique structural feature of ALKBH5 that plays an important role in substrate recognition and catalysis is the nucleotide recognition caps called “Flip1” and “Flip2” outside the DSBH fold. In addition, a disulfide bond formed between Cys-230 and Cys-267 has been identified in ALKBH5, and this structure is believed to underlie the selectivity of ALKBH5 for single-stranded substrates [ 48 , 49 ].

Normally, ALKBH5 is highly expressed in the testis, and it has been found that increased m6A expression in ALKBH5-deficient male mice affects apoptosis in mid-meiotic spermatocytes, leading to impaired fertility [ 33 , 50 ]. In addition to the fact that ALKBH5 can affect the spermatogenesis process, Pollard PJ et al. discovered that ALKBH5 is directly regulated by hypoxia-inducible factor 1α (HIF-1α), an oxygenase dependensst on 2-oxoglutarate (2OG) that is induced under hypoxic conditions. [ 51 ]. It has also shown that ALKBH5 can affect osteogenesis in ligamentum flavum cells through the protein kinase B (AKT) signaling pathway [ 52 ], as well as the osteogenic process through the NF-κB (nuclear factor-κB) signaling pathway [ 53 ].

The role of ALKBH5 in gastrointestinal cancer

Increasing evidence suggests that the m6A demethylase ALKBH5 is aberrantly expressed in various gastrointestinal cancers, closely associated with tumorigenesis, tumor proliferation, migration, invasion, and more (Table  1 ), making it a potential novel target for cancer treatment (Fig.  2 ). In the following section, we discuss the expression of ALKBH5 in gastrointestinal cancer and the mechanisms involved.

Biological functions of ALKBH5 in gastrointestinal cancer. ALKBH5 regulates tumor cell proliferation, migration, and invasion. ALKBH5 also controls monocyte recruitment and M2 polarization, as well as cellular autophagy. ALKBH5 also plays a role in tumor immune infiltration, hot/cold tumor transition, and the enhancement or attenuation of tumor radiosensitivity. It can also regulate epithelial-mesenchymal transition, stemness maintenance, glycolysis, and RNA degradation. (figure was created with Biorender.com)

Colorectal cancer

CRC is the third deadliest cancer in the world, ranking consistently among the top three in both incidence and mortality rates among all cancer types. It accounts for approximately 10% of all cancer-related deaths each year [ 54 ]. Despite increasing research and treatment efforts dedicated to colorectal cancer each year, many molecular mechanisms remain unclear. There is growing evidence that m6A modification plays a crucial role in the molecular regulation of CRC (Fig.  3 ).

Bioinformatics results revealed a decreased expression of ALKBH5 in CRC. Its expression is strongly correlated with survival prognosis, staging, distant metastasis, and the American Joint Committee on Cancer (AJCC) stage, establishing it as one of the independent prognostic indicators for CRC. Immune checkpoint inhibitor therapy, as one of the mature approaches in current cancer treatment, is often less effective due to the low immunogenicity of cold tumors. ALKBH5, in collaboration with YTHDF1, can impact the immune environment, promoting the transformation of colon adenocarcinoma (COAD) patients from the cold tumor type to the hot tumor type [ 55 , 56 ], greatly enhancing the effectiveness of immunotherapy. ALKBH5 can bind to the Wnt pathway inhibitor AXIN2, inducing its degradation, thereby activating Wnt/β-catenin and its associated protein Dickkopf-related protein 1 (DKK1). This process induces DKK1 to recruit inhibitory cells derived from the bone marrow, driving immune suppression in CRC [ 57 ]. Overexpression of ALKBH5 suppresses CRC cell proliferation, migration, and invasion. It alleviates the malignant progression of CRC by promoting CD8(+) T cell infiltration in the tumor microenvironment through the NF-κB (nuclear factor-κB)-CCL5(C-C motif chemokine ligand 5) axis [ 58 ]. Furthermore, related studies suggest that ALKBH5 is downregulated in CRC and is associated with poor prognosis in CRC patients. ALKBH5 can suppress the occurrence and development of CRC by removing the methylation modification of its downstream target gene plant homeodomain finger protein 20 (PHF20), thereby reducing the mRNA stability of PHF20 [ 59 ]. Wu and colleagues discovered that improving the identification and delivery system for CRC treatment can effectively alleviate the development of CRC. They confirmed the effectiveness of this approach in mitigating CRC development by synthesizing folate-modified exosome-liposome hybrid nanoparticles loaded with ALKBH5 mRNA and utilizing nano therapy to modulate the ALKBH5/JMXD8/PKM2 (Pyruvate kinase M2) axis and suppress glycolysis [ 60 ].

It is worth noted that experimental results from some scholars indicate that ALKBH5 can act as an oncogene, promoting the occurrence and development of CRC. That suggests that ALKBH5 may have a dual regulatory role in CRC. Shen et al. discovered that ALKBH5 can function as an upstream target of a Rab GTPase family protein (RAB5A), and through m6A-YTHDF2-dependent mechanisms, reduce the mRNA degradation efficiency of RAB5A, increasing the expression of RAB5A, thereby promoting the progression of CRC [ 61 ]. The regulation of CRC by ALKBH5 in non-coding RNA has also been reported. The ALKBH5-LncRNA NEAT1 (lncRNA nuclear paraspeckle assembly transcript 1) axis may serve as a potential therapeutic target for CRC. NEAT1 is upregulated in CRC and is associated with poor prognosis, and ALKBH5 promotes the progression of COAD by reducing the methylation of lncRNA NEAT1 [ 62 ]. ALKBH5 can decrease the m6A modification of Forkhead box O3 (FOXO3), and enhance the RNA stability of FOXO3. Thus, it targets miR-21 through FOXO3 and increases sprouty2 (SPRY2) expression, forming the FOXO3/miR-21/SPRY2 axis to regulate the progression of CRC [ 63 ]. Research indicates that CircRNA AFF2 is highly expressed in radiation-sensitive colorectal cancer patients, and those with high expression have a better prognosis. Its regulation is closely associated with the ALKBH5/YTHDF2 m6A-dependent pathway. CircAFF2 can reverse the radiation sensitivity induced by ALKBH5 or YTHDF2 and may serve as a potential target for radiotherapy in CRC [ 64 ]. Luo et al. discovered that ALKBH5 is downregulated in CRC. ALKBH5 removes m6A modification on the mRNA of solute carrier family 7 members 11 (SLC7A11), reducing mRNA stability, thereby decreasing SLC7A11 transcription and expression, promoting ferroptosis in CRC cells [ 65 ].

In summary, these studies confirm the close association of ALKBH5 with the progression of CRC, suggesting that ALKBH5 may hold significant clinical significance as a target for drug therapy in CRC.

Liver cancer

LC is the sixth most common cancer globally, ranking fourth in mortality among all cancers [ 66 ]. Studies suggest that ALKBH5 is highly expressed in hepatocellular carcinoma (HCC) and correlates with poor prognosis in HCC patients. Tumor-associated macrophages (TAMs) play a critical role in establishing the tumor microenvironment. ALKBH5, through an m6A-dependent mechanism, regulates the expression of mitogen-activated protein kinase kinase kinase 8 (MAP3K8), mediating the activation of downstream c-Jun N-terminal kinase (JNK) and extracellular regulated kinase (ERK) pathways, and promoting HCC cell proliferation, migration, and the recruitment of programmed death-ligand 1 (PD-L1) + macrophages [ 67 ]. Related studies have reported interactions of ALKBH5 with PD-L1 mRNA in intrahepatic cholangiocarcinoma (ICC). Through the ALKBH5-PD-L1 axis, it maintains the expression of PD-L1 in tumor cells, suppressing T-cell proliferation and cytotoxicity, and regulating the occurrence of ICC [ 68 ]. Liver cancer stem cells (LCSCs) are closely associated with the treatment and recurrence of LC. ALKBH5 regulates the expression of SRY-related HMG box (SOX4) through demethylation, thereby activating the sonic hedgehog (SHH) signaling pathway and promoting the progression of LCSCs [ 69 ]. Extracellular vesicles (EVs) play a crucial role in the intercellular transfer of various bioactive substances that promote tumor proliferation, migration, invasion, and development. Han et al. discovered that bone-metastasized HCC-derived EVs (BM-EVs) can promote the progression of HCC by transferring miR-3190 targeting ALKBH5 [ 70 ]. Recently, Zhang et al. found that LINC02551 serves as a target of ALKBH5, disrupting the combination between DEAD-box RNA helicase (DDX24) and E3 ubiquitin ligase tripartite motif-containing 27 (TRIM27) to reduce the ubiquitination of DDX24 and subsequent degradation, ultimately promoting HCC growth and metastasis [ 71 ].

Some studies suggest that ALKBH5 is downregulated in HCC compared to normal liver cells and may act as a tumor suppressor to inhibit cancer development processes such as proliferation, migration, and invasion in HCC. Therefore, further exploration of the role of ALKBH5 in HCC is warranted. Wang et al. found that ALKBH5 is downregulated in HCC, through interaction with the m6A reader protein IGF2BP1, downregulates the expression of its target gene AdipoQ Receptor 4 (PAQR4) at the transcriptional and translational levels, thereby inhibiting the activation of the PI3K/AKT pathway and the growth of LC [ 72 ]. Research indicates that LY6/PLAUR Domain Containing 1 (LYPD1) can act as an oncogene to promote the occurrence and development of HCC. ALKBH5, through an m6A-dependent mechanism, diminishes the expression of LYPD1 and strengthens the inhibitory effect of ALKBH5 on LYPD1 under the recognition and stabilization of IGF2BP1[ 73 ]. Hepatic stellate cells (HSCs) can induce radiation-induced liver fibrosis (RILF) under radiotherapy for HCC. ALKBH5 can regulate the hepatic microenvironment and serve as a radiosensitization target for HCC, providing new insights into the radiotherapy and prognosis of HCC [ 74 ] (Fig.  3 ).

Overall, the role of ALKBH5 expression in LC is complex and diverse. It can either promote or inhibit LC progression, and these contradictory findings may be due to different pathways regulated by ALKBH5.

Pancreatic cancer

PC is a prevalent malignancy of the digestive tract, marked by challenging early diagnosis, concealed symptoms, and high mortality, with a 5-year survival rate of less than 10% [ 75 ]. Research suggests that ALKBH5 is downregulated in PC. Kaplan-Meier survival analysis demonstrates a significant correlation between low ALKBH5 expression and overall survival in PC patients. ALKBH5 interacts with the YTHDF2 reading protein to upregulate the expression of the period circadian regulator 1 (PER1) gene in an m6A-dependent manner. The upregulation of PER1 activates the P53-related signaling pathway, suppressing the growth of PC cells [ 76 ]. Antisense LncRNA is closely linked to tumor development. He et al. discovered that Potassium two pore domain channel subfamily K member 15 and WISP2 antisense RNA 1 (KCNK15-AS1) is downregulated in PC cells and tissues, leading to the suppression of migration and invasion in PC cells. Mechanistically, ALKBH5 enhances the expression of KCNK15-AS1 by demethylating m6A modification. It recruits the proto-oncogene mouse double minute 2 (MDM2) to facilitate the ubiquitination of RE1-silencing transcription factor (REST), leading to the transcriptional upregulation of phosphatase and tension homolog (PTEN) to deactivate the AKT signaling pathway [ 77 , 78 ]. Iron metabolism plays a crucial role in multiple aspects of cancer cells, including DNA synthesis, mitochondrial respiration, cell proliferation, and the tumor microenvironment. In pancreatic ductal adenocarcinoma (PDAC), ALKBH5 regulates the stability of F-box and leucine-rich repeat protein 5 (FBXL5) RNA. Overexpression of ALKBH5 results in a marked decrease in intracellular iron levels, along with reduced cell migration and invasion capabilities. FBXL5, through the regulation of iron proteins such as iron regulatory protein 2 (IRP2), contributes to the control of PDAC occurrence and progression [ 79 ]. Tang and colleagues discovered that overexpression of ALKBH5 enhances the sensitivity of PDAC cells to chemotherapy. Reduced levels of ALKBH5 are linked to poor prognosis in PDAC and various other cancers. ALKBH5 can impact the Wnt signaling pathway, decrease RNA methylation of Wnt inhibitory factor 1 (WIF-1), and inhibit PC tumorigenesis [ 80 ]. Studies suggest that ALKBH5-mediated m6A modification results in the upregulation of DNA damage-inducible transcript 4 (DDIT4-AS1) expression in PDAC. DDIT-AS1, by stabilizing DDIT4 and activating the mechanistic target of the rapamycin (mTOR) pathway, enhances cancer stem cells and inhibits chemosensitivity to gemcitabine (GEM) [ 81 ]. M6A methylation is closely associated with the tumor hypoxic microenvironment. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) results reveal that histone deacetylase type 4 (HDAC4) is an m6A-targeted gene in the tumor-hypoxic environment, and it modulates the tumor-hypoxic microenvironment through the ALKBH5/HDAC4 /HIF1α pathway [ 82 ] (Fig.  3 ). In summary, ALKBH5 is downregulated in PC, and could influence the growth, migration, invasion, and chemotherapy sensitivity of PC cells through multiple mechanisms.

Gastric cancer

GC is presently among the most common cancers, ranking fifth in the incidence of various cancers [ 54 ]. Significant attention should be given to the diagnosis and treatment of GC. Experimental evidence from in vivo and in vitro studies indicates that ALKBH5 is upregulated in GC and correlates with clinical poor prognosis and low survival rates. LINC00659 facilitates the binding and upregulation of ALKBH5 with Janus kinase 1 (JAK1) mRNA in a m6A-YTHDF2-dependent manner, thereby promoting the development of GC [ 83 ]. Wang and colleagues discovered that lncRNA NRON is highly expressed in GC and promotes the occurrence and development of GC by binding with demethylase ALKHB5 to mediate Nanog (homeobox domain transcription factor) mRNA decay. It is anticipated to be a prognostic factor and potential therapeutic target for GC patients [ 84 ]. Studies suggest a close association between lncRNA NEAT1 and ALKBH5. MeRIP experiments and rescue experiments confirm that ALKBH5 can bind to lncRNA NEAT1, mediating the demethylation process of NEAT1 in an m6A-dependent manner. This process influences the expression of EZH2 (a subunit of the polycomb repressive complex) and contributes to the invasion and metastasis of GC [ 85 ]. Bioinformatics results indicate that ALKBH5 acts as an upstream target of Protein kinase, membrane-associated tyrosine/threonine 1 (PKMYT1), negatively regulating PKMYT1 expression. In collaboration with the reading protein IGF2BP3, PKMYT1’s mRNA stability is increased. Depletion of ALKBH5 results in the upregulation of PKMYT1 expression, consequently promoting the invasion and migration of GC [ 86 ](Fig.  3 ). In conclusion, the expression of ALKBH5 is upregulated in GC. ALKBH5 promotes the invasion and metastasis of GC cells through various mechanisms, and is associated with poor prognosis and low survival rates of GC patients.

Esophageal squamous cell carcinoma

ESCC is the seventh most common cancer globally, and it stands as the sixth most common cause of cancer-related deaths. Notably, ESCC exhibits high recurrence rates, leading to an unfavorable prognosis over the long term [ 87 ]. Xiao et al. discovered reduced expression of ALKBH5 in ESCC. The overexpression of ALKBH5 suppresses the proliferation, migration, and invasion of ESCC cells. Simultaneously, it induces a certain degree of G1 phase arrest in ESCC cells, suggesting that the deficiency in ALKBH5 expression is one of the contributing factors to the malignancy of ESCC tumors. In vivo, experiments confirm that the loss of ALKBH5 significantly inhibits the tumor growth of ESCC cells transplanted subcutaneously in BALB/c nude mice. ALKBH5 acts as an independent prognostic factor for patient survival and is correlated with poor prognosis in ESCC patients [ 88 ].

Currently, research on ALKBH5 in ESCC is relatively scarce, and more substantial research is needed for making the role and mechanism clearer.

ALKBH5 promotes or inhibits the progression of gastrointestinal cancer by targeting related molecules in concert with reader proteins. ( A ) ALKBH5 regulates the molecular mechanism of CRC. ( B ) ALKBH5 regulates the molecular mechanism of HCC, ICC, and LCSCs. ( C ) ALKBH5 regulates the molecular mechanism of PC and PDAC. ( D ) ALKBH5 regulates the molecular mechanism of GC. (figure was created with Biorender.com)

Future perspectives

In recent years, with the confirmed demethylase activity of ALKBH5 and the rapid development of high-throughput sequencing for m6A methylation, research on the demethylase ALKBH5 has steadily advanced worldwide. The dysregulation of m6A demethylase ALKBH5 is observed in various gastrointestinal cancers and can directly or indirectly function as a regulatory gene in multiple cancers, regulating processes such as tumor cell proliferation, migration, invasion, metastasis, and drug resistance, thereby influencing the progression of cancer. However, it is worth noting that ALKBH5 plays a dual role in inhibiting or promoting cancer development in certain digestive tract tumors. For example, in CRC, ALKBH5 inhibits CRC development by reducing the mRNA stability of PHF20 [ 54 ], while lncRNA NEAT1 promotes CRC progression under the demethylation effect of ALKBH5 [ 57 ]. This may be related to the heterogeneity of tumors, differences in the clinical samples collected by researchers, differences in research models, and so on. Therefore, further in-depth research and analysis of the genes regulated by ALKBH5 in specific cancers are needed. Additionally, multiple studies indicate that in the process of regulating the occurrence and development of cancer through downstream target genes, reader proteins often play an auxiliary modifying role. Reader proteins enhance the binding ability between ALKBH5 and target genes by regulating the stability of downstream gene mRNA, mediating the demethylation process of target genes. This provides a new direction for the research on the regulatory mechanism of ALKBH5 in cancer and the development of targeted therapeutic drugs that affect tumor progression through the m6A-dependent regulation of related genes.

Conclusions

ALKBH5 has emerged as an important regulator and promising therapeutic target for the treatment of gastrointestinal cancer. However, the current research on the mechanism of ALKBH5 in gastrointestinal cancer is still in the preliminary stage, and there is a significant gap that needs to be filled in understanding the mechanisms of ALKBH5 in regulating metabolism, angiogenesis, and related signaling pathways, which may be the causes of the dual or controversial role of ALKBH5 in gastrointestinal cancer. More efforts in advanced studies will hold great potential and promote our understanding of the role of ALKBH5 in gastrointestinal cancer as well as lead to the development of more effective and personalized treatments for patients with gastrointestinal cancer.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

N6-methyladenosine

Untranslated regions

AlkB homolog 5

Methyltransferase-like 3

Methyltransferase-like 14

Methyltransferase-like 16

Wilms tumor 1 associated protein

Zinc finger CCCH-type containing 13

RNA-binding motif protein 15

Vir-like m6 A methyltransferase-associated

Cbl proto-oncogene like1

Fl(2)d-associated complex component

Fat mass and obesity-associated protein

YT521-B homology

YTH N6-methyladenosine RNA binding protein 1/2/3

YT521-B homology-domain-containing protein 1/2

IGF2 mRNA binding protein

Insulin-like growth factor 2 mRNA binding protein 1/2

Heterogeneous nuclear ribonucleoproteins

Pancreatic ductal adenocarcinoma

Colon adenocarcinoma

Hepatocellular carcinoma

Intrahepatic cholangiocarcinoma

Liver cancer stem cells

Hepatic stellate cells

Double-stranded β-helix fold

Hypoxia-inducible factor 1α

American Joint Committee on Cancer

Protein kinase B

Nuclear factor-κB

Dickkopf-related protein 1

C-C motif chemokine ligand 5

Plant homeodomain finger protein 20

Pyruvate kinase M2

A Rab GTPase family protein

Nuclear paraspeckle assembly transcript 1

Forkhead box O3

Solute carrier family 7 members 11

Tumor-associated macrophages

Mitogen-activated protein kinase kinase kinase 8

C-Jun N-terminal kinase

Extracellular regulated kinase

Programmed death-ligand 1

SRY-related HMG box

Sonic hedgehog

Extracellular vesicles

Bone-metastasized HCC-derived EVs

DEAD-box RNA helicase

E3 ubiquitin ligase tripartite motif-containing 27

AdipoQ Receptor 4

Phosphatidylinositol 3-kinase

LY6/PLAUR Domain Containing 1

Radiation-induced liver fibrosis

Period circadian regulator 1

K member 15 and WISP2 antisense RNA 1

Mouse double minute 2

RE1-silencing transcription factor

Phosphatase and tension homolog

F-box and leucine-rich repeat protein 5

Iron regulatory protein 2

Wnt inhibitory factor 1

DNA damage-inducible transcript 4

Mechanistic target of rapamycin

Gemcitabine

Methylated RNA immunoprecipitation sequencing

Histone deacetylase type 4

Janus kinase 1

Protein kinase, membrane associated tyrosine/threonine 1

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High-level Talent Research Funding Program of the First Dongguan Affiliated Hospital of Guangdong Medical University (GCC2023004); Doctoral Initial Funding of Guangdong Medical University (4SG23190G, GDMU2022030); Dongguan Social Development Science and Technology Project (20231800940642); Discipline Construction Project of Guangdong Medical University (2051K20220006); GuangDong Basic and Applied Basic Research Foundation (2023A1515140148).

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Weitong Shu, Qianying Huang and Rui Chen contributed equally to this work.

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Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, The First Dongguan Affiliated Hospital, School of Medical Technology, Guangdong Medical University, Dongguan, China

Weitong Shu, Qianying Huang, Rui Chen, Huatao Lan, Luxin Yu, Kai Cui, Wanjun He, Songshan Zhu, Mei Chen, Li Li, Dan Jiang & Guangxian Xu

Dongguan Key Laboratory of Molecular Immunology and Cell Therapy, Dongguan, China

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XG and JD contributed to the background, future prospects, conclusion, and the finalization of the manuscript. SW, HQ and LH were responsible for part of the role of ALKBH5 in gastrointestinal cancers. YL, CR, ZS, CK, HW, LL and CM provided revisions to the manuscript. All authors have read and approved the final manuscript.

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Correspondence to Dan Jiang or Guangxian Xu .

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Shu, W., Huang, Q., Chen, R. et al. Complicated role of ALKBH5 in gastrointestinal cancer: an updated review. Cancer Cell Int 24 , 298 (2024). https://doi.org/10.1186/s12935-024-03480-5

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Fasting and ketogenic diet reveal new vulnerability of pancreatic tumors to existing cancer drug

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In a recent study published in Nature , researchers examine the role of fasting and ketogenesis in regulating protein synthesis and its potential implications for cancer therapy.

Health benefits of fasting

Fasting has been historically recommended for its health benefits, with records dating back to ancient Greece.

The health benefits associated with fasting can be attributed to ‘metabolic rewiring,’ during which the body utilizes ketone bodies for energy instead of glucose. This stimulates weight loss, reduces inflammation, improves brain function, and may protect against cancer. Fasting may also support gut health by promoting a healthier and more diverse microbiome , support the regulation of key hormones including human growth hormone (HGH), leptin, and ghrelin, as well as increase longevity through its anti-aging effects.

Fasting, a high-fat low-carbohydrate diet, and exercise can induce ketogenesis, which is involved in various cellular signaling pathways. Despite extensive research on the biological mechanisms that may be responsible for the health benefits of fasting, it remains unclear how this dietary approach alters the proteome.

Effects of fasting on protein translation

During fasting, fatty acid levels rise due to the breakdown of fats, thereby providing an alternative source for energy production.

Fasting also inhibits the mammalian target of rapamycin (mTOR) pathway, which is a kinase that is traditionally involved in the synthesis and translation of proteins. The reduced activity of mTOR during fasting subsequently leads to reduced protein synthesis, particularly in the liver.

However, the synthesis of certain liver proteins increases during fasting, an effect that is mediated by phosphorylation of the eukaryotic translation initiation factor 4E (P-eIF4E). P-eIF4E plays a crucial role in regulating the translation of various proteins that are crucial for ketone production.

What is P-eIF4E?

Long-chain fatty acids produced during ketogenesis bind to adenosine monophosphate (AMP)-activated protein kinase (AMPK), which activates glucose and increases the uptake of fatty acids during low energy states. AMPK activity also activates mitogen-activated protein kinase (MAPK)-interacting protein kinase (MNK), which phosphorylates eIF4E; therefore, AMPK is key a regulator of ketogenesis through P-eIF4E.

This pathway, which is otherwise referred to as the AMPK-MNK-eIF4E axis, is a crucial aspect of selective protein translation that occurs during ketogenic states like fasting. Rising P-eIF4E levels during fasting leads to increased translation of specific messenger ribonucleic acids (mRNAs) involved in lipid catabolism and ketone body production. The binding of P-eIF4E to translation regulatory elements in the 5’ untranslated regions (5’ UTRs) upregulates these genes.

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• Diet-derived molecules identified as main drivers of young-onset colorectal cancer risk

Cancer metabolism and the AMPK-MNK-eIF4E axis

Certain cancers, especially those that originate in the pancreas, can adapt to low-glucose environments by converting their energy source to ketone bodies. During this form of metabolism, cancerous cells may rely on P-eIF4E for their growth and metastasis .

In an effort to elucidate the role of ketogenesis in cancer cell survival and proliferation, the researchers of the current study explored the potential anticancer effects of the P-eIF4E inhibitor tomivosertib. To this end, tomivosertib treatment led to a significant reduction in P-eIF4E levels and ketogenesis in mice; however, no significant effects on body weight or blood glycerol and fatty acid levels were observed.

Thus, P-eIF4E inhibition leads to the reduced translation of mRNAs involved in ketogenesis, which subsequently prevents ketone production and affects the metabolism of lipids involved in cancer cell growth.

Conclusions

The current study demonstrates the crucial role of the AMPK-MNK-eIF4E axis in linking lipid metabolism with selective protein translation during fasting and ketogenesis. Through this pathway, P-eIF4E supports homeostasis within the liver by facilitating the production and release of ketone bodies as an alternative energy source when glucose is not available.

In the future, the researchers of the current study anticipate that combining a ketogenic diet with P-eIF4E inhibitor treatment has the potential to treat pancreatic cancer. Although the current study only examined the role of ketogenesis and P-eIF4E in the context of pancreatic cancer, additional research is needed to explore whether this type of translational regulation extends to other cancers and tissue types than liver cells.

Our findings unveil a new fatty acid-induced signalling pathway that activates selective translation, which underlies ketogenesis and provides a tailored diet intervention therapy for cancer .”

• Yang, H., Zingaro, V. A., Lincoff, J., et al. (2024). Remodelling of the translatome controls diet and its impact on tumorigenesis. Nature .  doi:10.1038/s41586-024-07781-7 .

Posted in: Medical Science News | Medical Research News | Medical Condition News | Healthcare News

Tags: Adenosine , Aging , Blood , Brain , Cancer , Cancer Therapy , Carbohydrate , Cell , Diet , Exercise , Fasting , Fatty Acids , Genes , Ghrelin , Glucose , Growth Hormone , Hormone , Inflammation , Ketogenic Diet , Kinase , Leptin , Lipids , Liver , Metabolism , Metastasis , Microbiome , Pancreas , Pancreatic Cancer , Phosphorylation , Proliferation , Protein , Protein Synthesis , Proteome , Rapamycin , Research , Translation , Tumorigenesis , Weight Loss

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.

Please use one of the following formats to cite this article in your essay, paper or report:

Thomas, Liji. (2024, August 21). Fasting and ketogenic diet reveal new vulnerability of pancreatic tumors to existing cancer drug. News-Medical. Retrieved on August 24, 2024 from https://www.news-medical.net/news/20240821/Fasting-and-ketogenic-diet-reveal-new-vulnerability-of-pancreatic-tumors-to-existing-cancer-drug.aspx.

Thomas, Liji. "Fasting and ketogenic diet reveal new vulnerability of pancreatic tumors to existing cancer drug". News-Medical . 24 August 2024. <https://www.news-medical.net/news/20240821/Fasting-and-ketogenic-diet-reveal-new-vulnerability-of-pancreatic-tumors-to-existing-cancer-drug.aspx>.

Thomas, Liji. "Fasting and ketogenic diet reveal new vulnerability of pancreatic tumors to existing cancer drug". News-Medical. https://www.news-medical.net/news/20240821/Fasting-and-ketogenic-diet-reveal-new-vulnerability-of-pancreatic-tumors-to-existing-cancer-drug.aspx. (accessed August 24, 2024).

Thomas, Liji. 2024. Fasting and ketogenic diet reveal new vulnerability of pancreatic tumors to existing cancer drug . News-Medical, viewed 24 August 2024, https://www.news-medical.net/news/20240821/Fasting-and-ketogenic-diet-reveal-new-vulnerability-of-pancreatic-tumors-to-existing-cancer-drug.aspx.

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