research topics in cancer metastasis

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Review Article
Published: 24 March 2021

Emerging strategies for treating metastasis

Mark Esposito ORCID: orcid.org/0000-0002-5724-4087 1 ,
Shridar Ganesan 2 , 3 , 4 &
Yibin Kang ORCID: orcid.org/0000-0002-1626-6730 1 , 2 , 5

Nature Cancer volume 2 , pages 258–270 ( 2021 ) Cite this article

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Cancer therapy

The systemic spread of tumor cells is the ultimate cause of the majority of deaths from cancer, yet few successful therapeutic strategies have emerged to specifically target metastasis. Here we discuss recent advances in our understanding of tumor-intrinsic pathways driving metastatic colonization and therapeutic resistance, as well as immune-activating strategies to target metastatic disease. We focus on therapeutically exploitable mechanisms, promising strategies in preclinical and clinical development, and emerging areas with potential to become innovative treatments.

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Targeting metastatic cancer

Mechanism insights and therapeutic intervention of tumor metastasis: latest developments and perspectives

Cancer progression and the invisible phase of metastatic colonization

Data availability.

The human cancer mortality data in Fig. 1 were derived from the SEER database with 2017 as the most recently annotated 5-year survival date: https://seer.cancer.gov/data/ . Source data are provided with this paper. All other data are available from the corresponding author on reasonable request.

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Acknowledgements

We thank the members of our laboratory for helpful discussions. We also apologize to the many investigators whose important studies could not be cited directly here owing to space limitations. The work in the authors’ laboratories is supported by grants from the Brewster Foundation, the American Cancer Society, the Susan G. Komen Foundation, the Breast Cancer Research Foundation, the NIH and the US Department of Defense to Y.K. S.G. is supported by grants from the NCI, the US Department of Defense, the Breast Cancer Research Foundation, Hugs for Brady, AHEPA, the Val Skinner Foundation and the Gertrude Fogarty Trust.

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Department of Molecular Biology, Princeton University, Princeton, NJ, USA

Mark Esposito & Yibin Kang

Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA

Shridar Ganesan & Yibin Kang

Center for Systems and Computational Biology, Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ, USA

Shridar Ganesan

Department of Medicine, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA

Ludwig Institute for Cancer Research, Princeton University, Princeton, NJ, USA

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Correspondence to Yibin Kang .

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M.E. holds equity interest and a management position in KayoThera, a company developing cancer therapeutics. Y.K. holds equity interest in KayoThera and Firebrand Therapeutics and is a member of the scientific advisory boards of KayoThera, Firebrand Therapeutics and Cytocares. Y.K. has consulted for Merck, Amgen and Ono Pharma and has previously received funding support from Merck, Amgen, Johnson & Johnson, Janssen, Glycomimetics and Ono Pharma. S.G. has consulted for Merck, Roche, Foundation Medicine, Foghorn Therapeutics, Novartis, Silagene, EQRX and Inspirata, has received research funding from M2GEN and has equity interest in Inspirata and Silagene.

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Fig. 1 5-year survival rates for the select cancers shown in Fig. 1 extracted from the SEER database (2020).

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Esposito, M., Ganesan, S. & Kang, Y. Emerging strategies for treating metastasis. Nat Cancer 2 , 258–270 (2021). https://doi.org/10.1038/s43018-021-00181-0

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Mechanisms of cancer metastasis

Affiliations.

1 Translational Molecular Pathology, MD Anderson Cancer Center, Houston, TX 77030, USA.
2 Translational Molecular Pathology, MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Pathology and Lab Medicine, Brown University, Providence, RI 02912, USA; Legoretta Cancer Center, Brown University, Providence, RI 021912, USA.
3 Molecular & Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: [email protected].
4 Translational Molecular Pathology, MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Pathology and Lab Medicine, Brown University, Providence, RI 02912, USA; Legoretta Cancer Center, Brown University, Providence, RI 021912, USA. Electronic address: [email protected].
PMID: 36354098
DOI: 10.1016/j.semcancer.2022.10.006

Metastatic cancer is almost always terminal, and more than 90% of cancer deaths result from metastatic disease. Combating cancer metastasis and post-therapeutic recurrence successfully requires understanding each step of metastatic progression. This review describes the current state of knowledge of the etiology and mechanism of cancer progression from primary tumor growth to the formation of new tumors in other parts of the body. Open questions, avenues for future research, and therapeutic approaches with the potential to prevent or inhibit metastasis through personalization to each patient's mutation and/or immune profile are also highlighted.

Keywords: Cancer metastasis; Epithelial-mesenchymal plasticity; Epithelial-mesenchymal transition; Extravasation; Invasion.

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Stopping the spread: A revolution in how we think about metastasis

18 October 2022

When a cancer spreads from a primary tumour, the place where it first started to grow, to another area of the body, this is referred to as metastasis .

To spread, some cells from a primary tumour need to break away and travel to another place in the body via the bloodstream. These cells then form another tumour, called a secondary tumour, in another organ.

For example, breast cancer cells may travel to the lungs and form a secondary tumour there.

Metastasis is associated with very poor prognosis, and despite being the main cause of death in people with cancer, it has remained incredibly difficult to prevent and treat. This is largely because we haven’t been able to identify key drivers of this process that could act as therapeutic targets. Until now.

Ground-breaking research from scientists at our Cambridge Institute, recently published in Nature Genetics , has identified a protein in our cells, called NALCN, as a key regulator of metastasis.

What’s more, their findings show us that metastasis isn’t a process unique to cancer cells. Instead, cancer cells exploit a process that healthy tissues use to shed cells and move around the body, revolutionising the way we think about metastasis.

These findings are among the most important to have come out of my lab for three decades. Not only have we identified one of the elusive drivers of metastasis, but we have also turned a commonly held understanding of this on its head, showing how cancer hijacks this process in healthy cells for its own gains. Professor Richard Gilbertson

Finding the right channel

In their previous research, the team had identified a gene that was ‘turned off’ when a normal stem cell became a malignant stem cell in stomach cancers.

That gene makes the protein NALCN, which is a channel in the membrane of our cells that lets tiny molecules of salt pass in and out of them. The mutations caused the channel to be blocked off so it can’t perform its usual function.

This was unexpected, as the normal function of NALCN seemed to have no bearing otherwise on cancer development or progression.

So, in their most recent study they tested the effect of switching off this gene in mice with gastrointestinal cancers.

What they found was that losing the function of this gene had no effect on the primary tumour, but it caused the cancer to become extremely metastatic.

To investigate this phenomenon further, they switched the gene off in mice without cancer. And that’s where things got more interesting.

In these mice that had no NALCN, they found that healthy cells were metastasising around the body at a level similar to that of tumour cells in the mice with cancer.

Crucially, when these circulating cells reached another organ, they formed normal tissue in that organ. For example, if cells that had shed from the stomach had moved to the kidney, they turned into normal kidney cells.

“Traditionally, we think about our organs a bit like houses in a street, and those houses never share bricks with each other throughout life,” says Professor Richard Gilbertson, senior group leader at our Cambridge Institute.

“What this opens the possibility for is that organs can actually share their cells with each other.

“In fact, we see this at low rates going on all the time, even when we don’t delete this channel, suggesting that organs actually are much more fluid than we used to think.”

It may be that the body is therefore using this process as a repair mechanism. If some of the cells in one organ are damaged, cells from other organs can be mobilised to replace them.

This is the first time it’s been shown that metastasis is in fact a normal process, and it’s not only cancer cells that can spread around the body, a belief that’s been held for decades.

Solving the mysteries

In addition to elucidating the mechanism of metastasis, these findings might help to explain other current mysteries surrounding metastasis. For example, secondary tumours can appear in a person that had their primary tumour removed many years earlier or, in very rare cases, never had a primary tumour.

In these cases, it may be that healthy cells acquired some cancer-causing mutations but did not develop into cancer at their primary location. These ‘normal’ cells then shed from their original site, and move to other organs, where they formed normal tissue.

These cells then go on to become cancerous in the future after accumulating more mutations, creating metastases even though a primary tumour has been removed, or never formed in the tissue they originally came from.

And on the flipside, it provides an explanation as to why, for many years, dormant circulating tumour cells (CTCs) have been observed in people with cancer that have not gone on to form secondary tumours, which raised the question of why some CTCs form tumours and others don’t.

It’s because these circulating cells aren’t actually tumour cells, they’re cells from healthy tissues, we just didn’t know they could circulate before now.

“We’ve been tied to the concept that this has to be abnormal, therefore, they have to be cancer cells,” says Gilbertson. “But now we know that isn’t the case. They’re not tumour cells, they’re actually part of this normal process.”

Opening the possibilities

Having identified the driver of metastasis, we now have a potential therapeutic target for preventing it, which has huge implications for cancer survival.

The team are therefore looking into ways to restore the function of NALCN in cancer cells to prevent metastasis from occurring.

This might be tricky, as drugs that target this type of channel usually aim to block them, rather than hold them open. However, it has been achieved before in drugs used to treat other conditions like cystic fibrosis, and the team are investigating whether there are existing drugs that could be repurposed to prevent metastasis.

But that isn’t the only implication of this research.

“We’ve got lots of different avenues to explore,” says Dr Eric Rahrmann, lead researcher on the study and senior research associate at our Cambridge Institute.

“Can we use the mutations in this gene as a diagnostic marker? Like an early detection approach. Can we make predictions on whether people will have metastatic disease?

“We’re also looking at regenerative therapy medicines. If we enhance dissemination of cells from one organ to go into another organ to repair it, can we use this more as a truly reparative mechanism?”

This discovery has the potential to truly change the research landscape, both in the field of cancer research and beyond.

“If you could stop metastasis,” Gilbertson concludes. “Or significantly suppress it, you’re getting towards managing cancer for the long term, and that’s the Holy Grail.”

This is such an amazing discovery and really great news. I do so enjoy reading about the fantasic work being done by CRUK and associated research groups.

I have been reading your observations which clearly show great strides in your work which show great advancement in your research.

Keep up the good work so eventually you will develop enough experience gained from trials with mice to start trials in humans .

I am thrilled beyond words with this progress albeit nearly 8 years too late for my beloved husband

I hope and pray that this study can be fast tracked. If meds for Covid came so fast I truly hope this can too. Think of the lives that could be saved. As I’m living with MBC and also living with HOPE.

They need to realize time is critical. My young daughter has mtnbc and will likely never make it as “oversight” agencies spend years and years dragging things out. They will never convince me this is necessary for something absolutely lethal…

As someone living with MBC I am hopeful and thankful to all who are working to eradicate this horrible disease. A lot of these discoveries may not come to fruition in time for me with human trials but I am thankful that they may save so many lives.

Excellent news and as a stage IV breast cancer patient some inspirational news. Let’s have the drug available sooner than later please.

Amazing news about metastatic cancer Hopefully one day it can be treated and controlled, if not cured

An extremely exciting decision development!

This is fantastic research, congratulations to the team. Any chance we can get it fast tracked so that we are not waiting at least 10 years before it can save lives, either through repurposed drugs or novel drugs. We need urgent action now to save life and end the terrible suffering currently taking place with this disease.

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Cancer Control
v.28; Jan-Dec 2021

Cancer Biology, Epidemiology, and Treatment in the 21st Century: Current Status and Future Challenges From a Biomedical Perspective

Patricia piña-sánchez.

1 Oncology Research Unit, Oncology Hospital, Mexican Institute of Social Security, Mexico

Antonieta Chávez-González

Martha ruiz-tachiquín, eduardo vadillo, alberto monroy-garcía, juan josé montesinos, rocío grajales.

2 Department of Medical Oncology, Oncology Hospital, Mexican Institute of Social Security, Mexico

Marcos Gutiérrez de la Barrera

3 Clinical Research Division, Oncology Hospital, Mexican Institute of Social Security, Mexico

Hector Mayani

Since the second half of the 20th century, our knowledge about the biology of cancer has made extraordinary progress. Today, we understand cancer at the genomic and epigenomic levels, and we have identified the cell that starts neoplastic transformation and characterized the mechanisms for the invasion of other tissues. This knowledge has allowed novel drugs to be designed that act on specific molecular targets, the immune system to be trained and manipulated to increase its efficiency, and ever more effective therapeutic strategies to be developed. Nevertheless, we are still far from winning the war against cancer, and thus biomedical research in oncology must continue to be a global priority. Likewise, there is a need to reduce unequal access to medical services and improve prevention programs, especially in countries with a low human development index.

Introduction

During the last one hundred years, our understanding of the biology of cancer increased in an extraordinary way. 1 - 4 Such a progress has been particularly prompted during the last few decades because of technological and conceptual progress in a variety of fields, including massive next-generation sequencing, inclusion of “omic” sciences, high-resolution microscopy, molecular immunology, flow cytometry, analysis and sequencing of individual cells, new cell culture techniques, and the development of animal models, among others. Nevertheless, there are many questions yet to be answered and many problems to be solved regarding this disease. As a consequence, oncological research must be considered imperative.

Currently, cancer is one of the illnesses that causes more deaths worldwide. 5 According to data reported in 2020 by the World Health Organization (WHO), cancer is the second cause of death throughout the world, with 10 million deaths. 6 Clearly, cancer is still a leading problem worldwide. With this in mind, the objective of this article is to present a multidisciplinary and comprehensive overview of the disease. We will begin by analyzing cancer as a process, focusing on the current state of our knowledge on 4 specific aspects of its biology. Then, we will look at cancer as a global health problem, considering some epidemiological aspects, and discussing treatment, with a special focus on novel therapies. Finally, we present our vision on some of the challenges and perspectives of cancer in the 21 st century.

The Biology of Cancer

Cancer is a disease that begins with genetic and epigenetic alterations occurring in specific cells, some of which can spread and migrate to other tissues. 4 Although the biological processes affected in carcinogenesis and the evolution of neoplasms are many and widely different, we will focus on 4 aspects that are particularly relevant in tumor biology: genomic and epigenomic alterations that lead to cell transformation, the cells where these changes occur, and the processes of invasion and metastasis that, to an important degree, determine tumor aggressiveness.

Cancer Genomics

The genomics of cancer can be defined as the study of the complete sequence of DNA and its expression in tumor cells. Evidently, this study only becomes meaningful when compared to normal cells. The sequencing of the human genome, completed in 2003, was not only groundbreaking with respect to the knowledge of our gene pool, but also changed the way we study cancer. In the post-genomic era, various worldwide endeavors, such as the Human Cancer Genome Project , the Cancer Genome ATLAS (TCGA), the International Cancer Genome Consortium, and the Pan-Cancer Analysis Working Group (PCAWG), have contributed to the characterization of thousands of primary tumors from different neoplasias, generating more than 2.5 petabytes (10 15 ) of genomic, epigenomic, and proteomic information. This has led to the building of databases and analytical tools that are available for the study of cancer from an “omic” perspective, 7 , 8 and it has helped to modify classification and treatment of various neoplasms.

Studies in the past decade, including the work by the PCAWG, have shown that cancer generally begins with a small number of driving mutations (4 or 5 mutations) in particular genes, including oncogenes and tumor-suppressor genes. Mutations in TP53, a tumor-suppressor gene, for example, are found in more than half of all cancer types as an early event, and they are a hallmark of precancerous lesions. 9 - 12 From that point on, the evolution of tumors may take decades, throughout which the mutational spectrum of tumor cells changes significantly. Mutational analysis of more than 19 000 exomes revealed a collection of genomic signatures, some associated with defects in the mechanism of DNA repair. These studies also revealed the importance of alterations in non-coding regions of DNA. Thus, for example, it has been observed that various pathways of cell proliferation and chromatin remodeling are altered by mutations in coding regions, while pathways, such as WNT and NOTCH, can be disrupted by coding and non-coding mutations. To the present date, 19 955 genes that codify for proteins and 25 511 genes for non-coding RNAs have been identified ( https://www.gencodegenes.org/human/stats.html ). Based on this genomic catalogue, the COSMIC (Catalogue Of Somatic Mutations In Cancer) repository, the most robust database to date, has registered 37 288 077 coding mutations, 19 396 fusions, 1 207 190 copy number variants, and 15 642 672 non-coding variants reported up to August 2020 (v92) ( https://cosmic-blog.sanger.ac.uk/cosmic-release-v92/ ).

The genomic approach has accelerated the development of new cancer drugs. Indeed, two of the most relevant initiatives in recent years are ATOM (Accelerating Therapeutics for Opportunities in Medicine), which groups industry, government and academia, with the objective of accelerating the identification of drugs, 13 and the Connectivity Map (CMAP), a collection of transcriptional data obtained from cell lines treated with drugs for the discovery of functional connections between genes, diseases, and drugs. The CMAP 1.0 covered 1300 small molecules and more than 6000 signatures; meanwhile, the CMAP 2.0 with L1000 assay profiled more than 1.3 million samples and approximately 400 000 signatures. 14

The genomic study of tumors has had 2 fundamental contributions. On the one hand, it has allowed the confirmation and expansion of the concept of intratumor heterogeneity 15 , 16 ; and on the other, it has given rise to new classification systems for cancer. Based on the molecular classification developed by expression profiles, together with mutational and epigenomic profiles, a variety of molecular signatures have been identified, leading to the production of various commercial multigene panels. In breast cancer, for example, different panels have been developed, such as Pam50/Prosigna , Blue Print , OncotypeDX , MammaPrint , Prosigna , Endopredict , Breast Cancer Index , Mammostrat, and IHC4 . 17

Currently, the genomic/molecular study of cancer is more closely integrated with clinical practice, from the classification of neoplasms, as in tumors of the nervous system, 18 to its use in prediction, as in breast cancer. 17 Improvement in molecular methods and techniques has allowed the use of smaller amounts of biological material, as well as paraffin-embedded samples for genomic studies, both of which provide a wealth of information. 19 In addition, non-invasive methods, such as liquid biopsies, represent a great opportunity not only for the diagnosis of cancer, but also for follow-up, especially for unresectable tumors. 20

Research for the production of genomic information on cancer is presently dominated by several consortia, which has allowed the generation of a great quantity of data. However, most of these consortia and studies are performed in countries with a high human development index (HDI), and countries with a low HDI are not well represented in these large genomic studies. This is why initiatives such as Human Heredity and Health in Africa (H3Africa) for genomic research in Africa are essential. 21 Generation of new information and technological developments, such as third-generation sequencing, will undoubtedly continue to move forward in a multidisciplinary and complex systems context. However, the existing disparities in access to genomic tools for diagnosis, prognosis, and treatment of cancer will continue to be a pressing challenge at regional and social levels.

Cancer Epigenetics

Epigenetics studies the molecular mechanisms that produce hereditable changes in gene expression, without causing alterations in the DNA sequence. Epigenetic events are of 3 types: methylation of DNA and RNA, histone modification (acetylation, methylation, and phosphorylation), and the expression of non-coding RNA. Epigenetic aberrations can drive carcinogenesis when they alter chromosome conformation and the access to transcriptional machinery and to various regulatory elements (promoters, enhancers, and anchors for interaction with chromatin, for example). These changes may activate oncogenesis and silence tumor-suppressor mechanisms when they modulate coding and non-coding sequences (such as micro-RNAs and long-RNAs). This can then lead to uncontrolled growth, as well as the invasion and metastasis of cancer cells.

While genetic mutations are stable and irreversible, epigenetic alterations are dynamic and reversible; that is, there are several epigenomes, determined by space and time, which cause heterogeneity of the “epigenetic status” of tumors during their development and make them susceptible to environmental stimuli or chemotherapeutic treatment. 22 Epigenomic variability creates differences between cells, and this creates the need to analyze cells at the individual level. In the past, epigenetic analyses measured “average states” of cell populations. These studies revealed general mechanisms, such as the role of epigenetic marks on active or repressed transcriptional states, and established maps of epigenetic composition in a variety of cell types in normal and cancerous tissue. However, these approaches are difficult to use to examine events occurring in heterogeneous cell populations or in uncommon cell types. This has led to the development of new techniques that permit marking of a sequence on the epigenome and improvement in the recovery yield of epigenetic material from individual cells. This has helped to determine changes in DNA, RNA, and histones, chromatin accessibility, and chromosome conformation in a variety of neoplasms. 23 , 24

In cancer, DNA hypomethylation occurs on a global scale, while hypermethylation occurs in specific genomic loci, associated with abnormal nucleosome positioning and chromatin modifications. This information has allowed epigenomic profiles to be established in different types of neoplasms. In turn, these profiles have served as the basis to identify new neoplasm subgroups. For example, in triple negative breast cancer (TNBC), 25 and in hepatocellular carcinoma, 26 DNA methylation profiles have helped to the identification of distinct subgroups with clinical relevance. Epigenetic approaches have also helped to the development of prognostic tests to assess the sensitivity of cancer cells to specific drugs. 27

Epigenetic traits could be used to characterize intratumoral heterogeneity and determine the relevance of such a heterogeneity in clonal evolution and sensitivity to drugs. However, it is clear that heterogeneity is not only determined by genetic and epigenetic diversity resulting from clonal evolution of tumor cells, but also by the various cell populations that form the tumor microenvironment (TME). 28 Consequently, the epigenome of cancer cells is continually remodeled throughout tumorigenesis, during resistance to the activity of drugs, and in metastasis. 29 This makes therapeutic action based on epigenomic profiles difficult, although significant advances in this area have been reported. 30

During carcinogenesis and tumor progression, epigenetic modifications are categorized by their mechanisms of regulation ( Figure 1A ) and the various levels of structural complexity ( Figure 1B ). In addition, the epigenome can be modified by environmental stimuli, stochastic events, and genetic variations that impact the phenotype ( Figure 1C ). 31 , 32 The molecules that take part in these mechanisms/events/variations are therapeutic targets of interest with potential impact on clinical practice. There are studies on a wide variety of epidrugs, either alone or in combination, which improve antitumor efficacy. 33 However, the problems with these drugs must not be underestimated. For a considerable number of epigenetic compounds still being under study, the main challenge is to translate in vitro efficacy of nanomolar (nM) concentrations into well-tolerated and efficient clinical use. 34 The mechanisms of action of epidrugs may not be sufficiently controlled and could lead to diversion of the therapeutic target. 35 It is known that certain epidrugs, such as valproic acid, produce unwanted epigenetic changes 36 ; thus the need for a well-established safety profile before these drugs can be used in clinical therapy. Finally, resistance to certain epidrugs is another relevant problem. 37 , 38

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Epigenetics of cancer. (A) Molecular mechanisms. (B) Structural hierarchy of epigenomics. (C) Factors affecting the epigenome. Modified from Refs. 31 and 32 .

As we learn about the epigenome of specific cell populations in cancer patients, a door opens to the evaluation of sensitivity tests and the search for new molecular markers for detection, prognosis, follow-up, and/or response to treatment at various levels of molecular regulation. Likewise, the horizon expands for therapeutic alternatives in oncology with the use of epidrugs, such as pharmacoepigenomic modulators for genes and key pathways, including methylation of promoters and regulation of micro-RNAs involved in chemoresponse and immune response in cancer. 39 There is no doubt that integrated approaches identifying stable pharmagenomic and epigenomic patterns and their relation with expression profiles and genetic functions will be more and more valuable in our fight against cancer.

Cancer Stem Cells

Tumors consist of different populations of neoplastic cells and a variety of elements that form part of the TME, including stromal cells and molecules of the extracellular matrix. 40 Such intratumoral heterogeneity becomes even more complex during clonal variation of transformed cells, as well as influence the elements of the TME have on these cells throughout specific times and places. 41 To explain the origin of cancer cell heterogeneity, 2 models have been put forward. The first proposes that mutations occur at random during development of the tumor in individual neoplastic cells, and this promotes the production of various tumor populations, which acquire specific growth and survival traits that lead them to evolve according to intratumor mechanisms of natural selection. 42 The second model proposes that each tumor begins as a single cell that possess 2 functional properties: it can self-renew and it can produce several types of terminal cells. As these 2 properties are characteristics of somatic stem cells, 43 the cells have been called cancer stem cells (CSCs). 44 According to this model, tumors must have a hierarchical organization, where self-renewing stem cells produce highly proliferating progenitor cells, unable to self-renew but with a high proliferation potential. The latter, in turn, give rise to terminal cells. 45 Current evidence indicates that both models may coexist in tumor progression. In agreement with this idea, new subclones could be produced as a result of a lack of genetic stability and mutational changes, in addition to the heterogeneity derived from the initial CSC and its descendants. Thus, in each tumor, a set of neoplastic cells with different genetic and epigenetic traits may be found, which would provide different phenotypic properties. 46

The CSC concept was originally presented in a model of acute myeloid leukemia. 47 The presence of CSCs was later proved in chronic myeloid leukemia, breast cancer, tumors of the central nervous system, lung cancer, colon cancer, liver cancer, prostate cancer, pancreatic cancer, melanoma, and cancer of the head and neck, amongst others. In all of these cases, detection of CSCs was based on separation of several cell populations according to expression of specific surface markers, such as CD133, CD44, CD24, CD117, and CD15. 48 It is noteworthy that in some solid tumors, and even in some hematopoietic ones, a combination of specific markers that allow the isolation of CSCs has not been found. Interestingly, in such tumors, a high percentage of cells with the capacity to start secondary tumors has been observed; thus, the terms Tumor Initiating Cells (TIC) or Leukemia Initiating Cells (LIC) have been adopted. 46

A relevant aspect of the biology of CSCs is that, just like normal stem cells, they can self-renew. Such self-renewal guarantees the maintenance or expansion of the tumor stem cell population. Another trait CSCs share with normal stem cells is their quiescence, first described in chronic myeloid leukemia. 49 The persistence of quiescent CSCs in solid tumors has been recently described in colorectal cancer, where quiescent clones can become dominant after therapy with oxaliplatin. 50 In non-hierarchical tumors, such as melanoma, the existence of slow-cycling cells that are resistant to antimitogenic agents has also been proved. 51 Such experimental evidence supports the idea that quiescent CSCs or TICs are responsible for both tumor resistance to antineoplastic drugs and clinical relapse after initial therapeutic success.

In addition to quiescence, CSCs use other mechanisms to resist the action of chemotherapeutic drugs. One of these is their increased numbers: upon diagnosis, a high number of CSCs are observed in most analyzed tumors, making treatment unable to destroy all of them. On the other hand, CSCs have a high number of molecular pumps that expulse drugs, as well as high numbers of antiapoptotic molecules. In addition, they have very efficient mechanisms to repair DNA damage. In general, these cells show changes in a variety of signaling pathways involved in proliferation, survival, differentiation, and self-renewal. It is worth highlighting that in recent years, many of these pathways have become potential therapeutic targets in the elimination of CSCs. 52 Another aspect that is highly relevant in understanding the biological behavior of CSCs is that they require a specific site for their development within the tissue where they are found that can provide whatever is needed for their survival and growth. These sites, known as niches, are made of various cells, both tumor and non-tumor, as well as a variety of non-cellular elements (extracellular matrix [ECM], soluble cytokines, ion concentration gradients, etc.), capable of regulating the physiology of CSCs in order to promote their expansion, the invasion of adjacent tissues, and metastasis. 53

It is important to consider that although a large number of surface markers have been identified that allow us to enrich and prospectively follow tumor stem cell populations, to this day there is no combination of markers that allows us to find these populations in all tumors, and it is yet unclear if all tumors present them. In this regard, it is necessary to develop new purification strategies based on the gene expression profiles of these cells, so that tumor heterogeneity is taken into account, as it is evident that a tumor can include multiple clones of CSCs that, in spite of being functional, are genetically different, and that these clones can vary throughout space (occupying different microenvironments and niches) and time (during the progression of a range of tumor stages). Such strategies, in addition to new in vitro and in vivo assays, will allow the development of new and improved CSC elimination strategies. This will certainly have an impact on the development of more efficient therapeutic alternatives.

Invasion and Metastasis

Nearly 90% of the mortality associated with cancer is related to metastasis. 54 This consists of a cascade of events ( Figure 2 ) that begins with the local invasion of a tumor into surrounding tissues, followed by intravasation of tumor cells into the blood stream or lymphatic circulation. Extravasation of neoplastic cells in areas distant from the primary tumor then leads to the formation of one or more micrometastatic lesions which subsequently proliferate to form clinically detectable lesions. 4 The cells that are able to produce metastasis must acquire migratory characteristics, which occur by a process known as epithelial–mesenchymal transition (EMT), that is, the partial loss of epithelial characteristics and the acquirement of mesenchymal traits. 55

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Invasion and metastasis cascade. Invasion and metastasis can occur early or late during tumor progression. In either case, invasion to adjacent tissues is driven by stem-like cells (cancer stem cells) that acquire the epithelial–mesenchymal transition (EMT) (1). Once they reach sites adjacent to blood vessels, tumor cells (individually or in clusters) enter the blood (2). Tumor cells in circulation can adhere to endothelium and extravasation takes place (3). Other mechanisms alternative to extravasation can exist, such as angiopelosis, in which clusters of tumor cells are internalized by the endothelium. Furthermore, at certain sites, tumor cells can obstruct microvasculature and initiate a metastatic lesion right there. Sometimes, a tumor cells that has just exit circulation goes into an MET in order to become quiescent (4). Inflammatory signals can activate quiescent metastatic cells that will proliferate and generate a clinically detectable lesion (5).

Although several of the factors involved in this process are currently known, many issues are still unsolved. For instance, it has not yet been possible to monitor in vivo the specific moment when it occurs 54 ; the microenvironmental factors of the primary tumor that promote such a transition are not known with precision; and the exact moment during tumor evolution in which one cell or a cluster of cells begin to migrate to distant areas, is also unknown. The wide range of possibilities offered by intra- and inter-tumoral heterogeneity 56 stands in the way of suggesting a generalized strategy that could resolve this complication.

It was previously believed that metastasis was only produced in late stages of tumor progression; however, recent studies indicate that EMT and metastasis can occur during the early course of the disease. In pancreatic cancer, for example, cells going through EMT are able to colonize and form metastatic lesions in the liver in the first stages of the disease. 52 , 57 Metastatic cell clusters circulating in peripheral blood (PB) are prone to generate a metastatic site, compared to individual tumor cells. 58 , 59 In this regard, novel strategies, such as the use of micro-RNAs, are being assessed in order to diminish induction of EMT. 60 It must be mentioned, however, that the metastatic process seems to be even more complex, with alternative pathways that do not involve EMT. 61 , 62

A crucial stage in the process of metastasis is the intravasation of tumor cells (alone or in clusters) towards the blood stream and/or lymphatic circulation. 63 These mechanisms are also under intensive research because blocking them could allow the control of spreading of the primary tumor. In PB or lymphatic circulation, tumor cells travel to distant parts for the potential formation of a metastatic lesion. During their journey, these cells must stand the pressure of blood flow and escape interaction with natural killer (NK) cells . 64 To avoid them, tumor cells often cover themselves with thrombocytes and also produce factors such as VEGF, angiopoietin-2, angiopoietin-4, and CCL2 that are involved in the induction of vascular permeability. 54 , 65 Neutrophils also contribute to lung metastasis in the bloodstream by secreting IL-1β and metalloproteases to facilitate extravasation of tumor cells. 64

The next step in the process of metastasis is extravasation, for which tumor cells, alone or in clusters, can use various mechanisms, including a recently described process known as angiopellosis that involves restructuring the endothelial barrier to internalize one or several cells into a tissue. 66 The study of leukocyte extravasation has contributed to a more detailed knowledge of this process, in such a way that some of the proposed strategies to avoid extravasation include the use of integrin inhibitors, molecules that are vital for rolling, adhesion, and extravasation of tumor cells. 67 , 68 Another strategy that has therapeutic potential is the use of antibodies that strengthen vascular integrity to obstruct transendothelial migration of tumor cells and aid in their destruction in PB. 69

Following extravasation, tumor cells can return to an epithelial phenotype, a process known as mesenchymal–epithelial transition and may remain inactive for several years. They do this by competing for specialized niches, like those in the bone marrow, brain, and intestinal mucosa, which provide signals through the Notch and Wnt pathways. 70 Through the action of the Wnt pathway, tumor cells enter a slow state of the cell cycle and induce the expression of molecules that inhibit the cytotoxic function of NK cells. 71 The extravasated tumor cell that is in a quiescent state must comply with 2 traits typical of stem cells: they must have the capacity to self-renew and to generate all of the cells that form the secondary tumor.

There are still several questions regarding the metastatic process. One of the persisting debates at present is if EMT is essential for metastasis or if it plays a more important role in chemoresistance. 61 , 62 It is equally important to know if there is a pattern in each tumor for the production of cells with the capacity to carry out EMT. In order to control metastasis, it is fundamental to know what triggers acquisition of the migratory phenotype and the intrinsic factors determining this transition. Furthermore, it is essential to know if mutations associated with the primary tumor or the variety of epigenetic changes are involved in this process. 55 It is clear that metastatic cells have affinity for certain tissues, depending on the nature of the primary tumor (seed and soil hypothesis). This may be caused by factors such as the location and the direction of the bloodstream or lymphatic fluid, but also by conditioning of premetastatic niches at a distance (due to the large number of soluble factors secreted by the tumor and the recruitment of cells of the immune system to those sites). 72 We have yet to identify and characterize all of the elements that participate in this process. Deciphering them will be of upmost importance from a therapeutic point of view.

Epidemiology of Cancer

Cancer is the second cause of death worldwide; today one of every 6 deaths is due to a type of cancer. According to the International Agency for Research on Cancer (IARC), in 2020 there were approximately 19.3 million new cases of cancer, and 10 million deaths by this disease, 6 while 23.8 million cases and 13.0 million deaths are projected to occur by 2030. 73 In this regard, it is clear the increasing role that environmental factors—including environmental pollutants and processed food—play as cancer inducers and promoters. 74 The types of cancer that produce the greatest numbers of cases and deaths worldwide are indicated in Table 1 . 6

Total Numbers of Cancer Cases and Deaths Worldwide in 2020 by Cancer Type (According to the Global Cancer Observatory, IARC).

	Cases
Both sexes	Women	Men
Breast (2.26 million)	Breast (2.26 million)	Lung (1.43 million)
Lung (2.20 million)	Colorectal (865 000)	Prostate (1.41 million)
Colorectal (1.93 million)	Lung (770 000)	Colorectal (1.06 million)
Prostate (1.41 million)	Cervical (604 000)	Stomach (719 000)
Stomach (1.08 million)	Thyroid (448 000)	Liver (632 000)

	Deaths
Both sexes	Women	Men
Lung (1.79 million)	Breast (684 000)	Lung (1.18 million)
Colorectal (935 000)	Lung (607 000)	Liver (577 000)
Liver (830 000)	Colorectal (419 000)	Colorectal (515 000)
Stomach (768 000)	Cervical (341 000)	Stomach (502 000)
Breast (684 000)	Stomach (266 000)	Prostate (375 000)

Data presented on this table were obtained from Ref. 6.

As shown in Figure 3 , lung, breast, prostate, and colorectal cancer are the most common throughout the world, and they are mostly concentrated in countries of high to very high human development index (HDI). Although breast, prostate, and colorectal cancer have a high incidence, the number of deaths they cause is proportionally low, mostly reflecting the great progress made in their control. However, these data also reveal the types of cancer that require further effort in prevention, precise early detection avoiding overdiagnosis, and efficient treatment. This is the case of liver, lung, esophageal, and pancreatic cancer, where the difference between the number of cases and deaths is smaller ( Figure 3B ). Social and economic transition in several countries has had an impact on reducing the incidence of neoplasms associated with infection and simultaneously produced an increase in the types related to reproductive, dietary, and hormonal factors. 75

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Incidence and mortality for some types of cancer in the world. (A) Estimated number of cases and deaths in 2020 for the most frequent cancer types worldwide. (B) Incidence and mortality rates, normalized according to age, for the most frequent cancer types in countries with very high/& high (VH&H; blue) and/low and middle (L&M; red) Human Development Index (HDI). Data include both genders and all ages. Data according to https://gco.iarc.fr/today , as of June 10, 2021.

In the past 3 decades, cancer mortality rates have fallen in high HDI countries, with the exception of pancreatic cancer, and lung cancer in women. Nevertheless, changes in the incidence of cancer do not show the same consistency, possibly due to variables such as the possibility of early detection, exposure to risk factors, or genetic predisposition. 76 , 77 Countries such as Australia, Canada, Denmark, Ireland, New Zealand, Norway, and the United Kingdom have reported a reduction in incidence and mortality in cancer of the stomach, colon, lung, and ovary, as well as an increase in survival. 78 Changes in modifiable risk factors, such as the use of tobacco, have played an important role in prevention. In this respect, it has been estimated that decline in tobacco use can explain between 35% and 45% of the reduction in cancer mortality rates, 79 while the fall in incidence and mortality due to stomach cancer can be attributed partly to the control of Helicobacter pylori infection. 80 Another key factor in the fall of mortality rates in developed countries has been an increase in early detection as a result of screening programs, as in breast and prostate cancer, which have had their mortality rates decreased dramatically in spite of an increase in their incidence. 76

Another important improvement observed in recent decades is the increase in survival rates, particularly in high HDI countries. In the USA, for example, survival rates for patients with prostate cancer at 5 years after initial diagnosis was 28% during 1947–1951; 69% during 1975–1977, and 100% during 2003–2009. Something similar occurred with breast cancer, with a 5-year survival rate of 54% in 1947–1951, 75% in 1975–1977, and 90% in 2003–2009. 81 In the CONCORD 3 version, age-standardize 5-year survival for patients with breast cancer in the USA during 2010–2014 was 90%, and 97% for prostate cancer patients. 82 Importantly, even among high HDI countries, significant differences have been identified in survival rates, being stage of disease at diagnosis, time for access to effective treatment, and comorbidities, the main factors influencing survival in these nations. 78 Unfortunately, survival rates in low HDI countries are significantly lower due to several factors, including lack of information, deficient screening and early detection programs, limited access to treatment, and suboptimal cancer registration. 82 It should be noted that in countries with low to middle HDI, neoplasms with the greatest incidence are those affecting women (breast and cervical cancer), which reflects not only a problem with access to health services, but also a serious inequality issue that involves social, cultural, and even religious obstacles. 83

Up to 42% of incident cases and 47% of deaths by cancer in the USA are due to potentially modifiable risk factors such as use of tobacco, physical activity, diet, and infection. 84 It has been calculated that 2.4 million deaths by cancer, mostly of the lung, can be attributed to tobacco. 73 In 2020, the incidence rate of lung cancer in Western Africa was 2.2, whereas in Polynesia and Eastern Asia was 37.3 and 34.4, respectively. 6 In contrast, the global burden of cancer associated with infection was 15.4%, but in Sub-Saharan Africa it was 30%. 85 Likewise, the incidence of cervical cancer in Eastern Africa was 40.1, in contrast with the USA and Canada that have a rate of 6.2. This makes it clear that one of the challenges we face is the reduction of the risk factors that are potentially modifiable and associated with specific types of cancer.

Improvement of survival rates and its disparities worldwide are also important challenges. Five-year survival for breast cancer—diagnosed during 2010-2014— in the USA, for example, was 90%, whereas in countries like South Africa it was 40%. 82 Childhood leukemia in the USA and several European countries shows a 5-year survival of 90%, while in Latin-American countries it is 50–76%. 86 Interestingly, there are neoplasms, such as pancreatic cancer, for which there has been no significant increase in survival, which remains low (5–15%) both in developed and developing countries. 82

Although data reported on global incidence and mortality gives a general overview on the epidemiology of cancer, it is important to note that there are great differences in coverage of cancer registries worldwide. To date, only 1 out of every 3 countries reports high quality data on the incidence of cancer. 87 For the past 50 years, the IARC has supported population-based cancer registries; however, more than one-third of the countries belonging to the WHO, mainly countries of low and middle income (LMIC), have no data on more than half of the 18 indicators of sustainable development goals. 88 High quality cancer registries only cover 4% of the population in Africa, 8% in Asia, and 7% in Latin America, contrasting with 83% in the USA and Canada, and 33% in Europe. 89 In response to this situation, the Global Initiative for Cancer Registry Development was created in 2012 to generate improved infrastructure to permit greater coverage and better quality registries, especially in countries with low and middle HDI. 88 It is expected that initiatives of this sort in the coming years will allow more and better information to guide strategies for the control of cancer worldwide, especially in developing regions. This will enable survival to be measured over longer periods of time (10, 15, or 20 years), as an effective measure in the control of cancer. The WHO has established as a target for 2025 to reduce deaths by cancer and other non-transmissible diseases by 25% in the population between the ages of 30–69; such an effort requires not only effective prevention measures to reduce incidence, but also more efficient health systems to diminish mortality and increase survival. At the moment, it is an even greater challenge because of the effects of the COVID-19 pandemic which has negatively impacted cancer prevention and health services. 90

Oncologic Treatments

A general perspective.

At the beginning of the 20th century, cancer treatment, specifically treatment of solid tumors, was based fundamentally on surgical resection of tumors, which together with other methods for local control, such as cauterization, had been used since ancient times. 91 At that time, there was an ongoing burst of clinical observations along with interventions sustained on fundamental knowledge about physics, chemistry, and biology. In the final years of the 19 th century and the first half of the 20th, these technological developments gave rise to radiotherapy, hormone therapy, and chemotherapy. 92 - 94 Simultaneously, immunotherapy was also developed, although usually on a smaller scale, in light of the overwhelming progress of chemotherapy and radiotherapy. 95

Thus began the development and expansion of disciplines based on these approaches (surgery, radiotherapy, chemotherapy, hormone therapy, and immunotherapy), with their application evolving ever more rapidly up to their current uses. Today, there is a wide range of therapeutic tools for the care of cancer patients. These include elements that emerged empirically, arising from observations of their effects in various medical fields, as well as drugs that were designed to block processes and pathways that form part of the physiopathology of one or more neoplasms according to knowledge of specific molecular alterations. A classic example of the first sort of tool is mustard gas, originally used as a weapon in war, 96 but when applied for medical purposes, marked the beginning of the use of chemicals in the treatment of malignant neoplasms, that is, chemotherapy. 94 A clear example of the second case is imatinib, designed specifically to selectively inhibit a molecular alteration in chronic myeloid leukemia: the Bcr-Abl oncoprotein. 97

It is on this foundation that today the 5 areas mentioned previously coexist and complement one another. The general framework that motivates this amalgam and guides its development is precision medicine, founded on the interaction of basic and clinical science. In the forecasts for development in each of these fields, surgery is expected to continue to be the fundamental approach for primary tumors in the foreseeable future, as well as when neoplastic disease in the patient is limited, or can be limited by applying systemic or regional elements, before and/or after surgical resection, and it can be reasonably anticipated for the patient to have a significant period free from disease or even to be cured. With regards to technology, intensive exploration of robotic surgery is contemplated. 98

The technological possibilities for radiotherapy have progressed in such a way that it is now possible to radiate neoplastic tissue with an extraordinary level of precision, and therefore avoid damage to healthy tissue. 99 This allows administration of large doses of ionizing radiation in one or a few fractions, what is known as “radiosurgery.” The greatest challenges to the efficacy of this approach are related to radio-resistance in certain neoplasms. Most efforts regarding research in this field are concentrated on understanding the underlying biological mechanisms of the phenomenon and their potential control through radiosensitizers. 100

“Traditional” chemotherapy, based on the use of compounds obtained from plants and other natural products, acting in a non-specific manner on both neoplastic and healthy tissues with a high proliferation rate, continues to prevail. 101 The family of chemotherapeutic drugs currently includes alkylating agents, antimetabolites, anti-topoisomerase agents, and anti-microtubules. Within the pharmacologic perspective, the objective is to attain a high concentration or activity of such molecules in specific tissues while avoiding their accumulation in others, in order to achieve an increase in effectiveness and a reduction in toxicity. This has been possible with the use of viral vectors, for example, that are able to limit their replication in neoplastic tissues, and activate prodrugs of normally nonspecific agents, like cyclophosphamide, exclusively in those specific areas. 102 More broadly, chemotherapy also includes a subgroup of substances, known as molecular targeted therapy, that affect processes in a more direct and specific manner, which will be mentioned later.

There is no doubt that immunotherapy—to be explored next—is one of the therapeutic fields where development has been greatest in recent decades and one that has produced enormous expectation in cancer treatment. 103 Likewise, cell therapy, based on the use of immune cells or stem cells, has come to complement the oncologic therapeutic arsenal. 43 Each and every one of the therapeutic fields that have arisen in oncology to this day continue to prevail and evolve. Interestingly, the foreseeable future for the development of cancer treatment contemplates these approaches in a joint and complementary manner, within the general framework of precision medicine, 104 and sustained by knowledge of the biological mechanisms involved in the appearance and progression of neoplasms. 105 , 106

Immunotherapy

Stimulating the immune system to treat cancer patients has been a historical objective in the field of oncology. Since the early work of William Coley 107 to the achievements reached at the end of the 20 th century, scientific findings and technological developments paved the way to searching for new immunotherapeutic strategies. Recombinant DNA technology allowed the synthesis of cytokines, such as interferon-alpha (IFN-α) and interleukin 2 (IL-2), which were authorized by the US Food and Drug Administration (FDA) for the treatment of hairy cell leukemia in 1986, 108 as well as kidney cancer and metastatic melanoma in 1992 and 1998, respectively. 109

The first therapeutic vaccine against cancer, based on the use of autologous dendritic cells (DCs), was approved by the FDA against prostate cancer in 2010. However, progress in the field of immunotherapy against cancer was stalled in the first decade of the present century, mostly due to failure of several vaccines in clinical trials. In many cases, application of these vaccines was detained by the complexity and cost involved in their production. Nevertheless, with the coming of the concept of immune checkpoint control, and the demonstration of the relevance of molecules such as cytotoxic T-lymphocyte antigen 4 (CTLA-4), and programmed cell death molecule-1 (PD-1), immunotherapy against cancer recovered its global relevance. In 2011, the monoclonal antibody (mAb) ipilimumab, specific to the CTLA-4 molecule, was the first checkpoint inhibitor (CPI) approved for the treatment of advanced melanoma. 110 Later, inhibitory mAbs for PD-1, or for the PD-1 ligand (PD-L1), 111 as well as the production of T cells with chimeric receptors for antigen recognition (CAR-T), 112 which have been approved to treat various types of cancer, including melanoma, non-small cell lung cancer (NSCLC), head and neck cancer, bladder cancer, renal cell carcinoma (RCC), and hepatocellular carcinoma, among others, have changed the paradigm of cancer treatment.

In spite of the current use of anti-CTLA-4 and anti-PD-L1 mAbs, only a subgroup of patients has responded favorably to these CPIs, and the number of patients achieving clinical benefit is still small. It has been estimated that more than 70% of patients with solid tumors do not respond to CPI immunotherapy because either they show primary resistance, or after responding favorably, develop resistance to treatment. 113 In this regard, it is important to mention that in recent years very important steps have been taken to identify the intrinsic and extrinsic mechanisms that mediate resistance to CPI immunotherapy. 114 Intrinsic mechanisms include changes in the antitumor immune response pathways, such as faulty processing and presentation of antigens by APCs, activation of T cells for tumor cell destruction, and changes in tumor cells that lead to an immunosuppressive TME. Extrinsic factors include the presence of immunosuppressive cells in the local TME, such as regulatory T cells, myeloid-derived suppressor cells (MDSC), mesenchymal stem/stromal cells (MSCs), and type 2 macrophages (M2), in addition to immunosuppressive cytokines.

On the other hand, classification of solid tumors as “hot,” “cold,” or “excluded,” depending on T cell infiltrates and the contact of such infiltrates with tumor cells, as well as those that present high tumor mutation burden (TMB), have redirected immunotherapy towards 3 main strategies 115 ( Table 2 ): (1) Making T-cell antitumor response more effective, using checkpoint inhibitors complementary to anti-CTLA-4 and anti-PD-L1, such as LAG3, Tim-3, and TIGT, as well as using CAR-T cells against tumor antigens. (2) Activating tumor-associated myeloid cells including monocytes, granulocytes, macrophages, and DC lineages, found at several frequencies within human solid tumors. (3) Regulating the biochemical pathways in TME that produce high concentrations of immunosuppressive molecules, such as kynurenine, a product of tryptophan metabolism, through the activity of indoleamine 2,3 dioxygenase; or adenosine, a product of ATP hydrolysis by the activity of the enzyme 5’nucleotidase (CD73). 116

Current Strategies to Stimulate the Immune Response for Antitumor Immunotherapy.

Strategies	T cells	Myeloid cells	TME
Lymph node	Anti-CTLA4	TNF-α
To improve tumor antigen presentation by APCs	Anti-CD137	IFN-α
To optimize effector T-cell activation	Anti-OX40	IL-1
	Anti-CD27/CD70	GM-CSF
	HVEM	CD40L/CD40
	GITR	CDN
	L-2	ATP
	IL-12	HMGB1
		TLR
		STING
		RIG-1/MDA-5
Blood vessel	CX3CL1
To improve T-cell traffic to tumors	CXCL9
To favor T-cell infiltration into tumors	CXCL10
Transference of T cells bearing antigen-specific receptor	CCL5
	LFA1/ICAM1
	Selectins
	CAR-T cell
	TCR-T cell
Tumor	Anti-PD-L1	Anti-CSF1/CSF1R	Anti-VEGF
To improve tumor antigen uptake by APCs	Anti-CTLA-4	Anti-CCR2	Inhibitors of IDO anti-CD73
To improve recognition and killing of tumor cells by T cells	Anti-LAG-3	PI3Kγ	ARs antagonists
	Anti-TIM-3
	Anti-TIGIT
	TNFR-agonists
	IL-2
	IL-10

Abbreviations: TME, tumor microenvironment; IL, interleukin; TNF, Tumor Necrosis Factor; TNFR, TNF-receptor; CD137, receptor–co-stimulator of the TNFR family; OX40, member number 4 of the TNFR superfamily; CD27/CD70, member of the TNFR superfamily; CD40/CD40L, antigen-presenting cells (APC) co-stimulator and its ligand; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; STING, IFN genes-stimulator; RIG-I, retinoic acid inducible gene-I; MDA5, melanoma differentiation-associated protein 5; CDN, cyclic dinucleotide; ATP, adenosine triphosphate; HMGB1, high mobility group B1 protein; TLR, Toll-like receptor; HVEM, Herpes virus entry mediator; GITR, glucocorticoid-induced TNFR family-related gene; CTLA4, cytotoxic T lymphocyte antigen 4; PD-L1, programmed death ligand-1; TIGIT, T-cell immunoreceptor with immunoglobulin and tyrosine-based inhibition motives; CSF1/CSF1R, colony-stimulating factor-1 and its receptor; CCR2, Type 2 chemokine receptor; PI3Kγ, Phosphoinositide 3-Kinase γ; CXCL/CCL, chemokine ligands; LFA1, lymphocyte function-associated antigen 1; ICAM1, intercellular adhesion molecule 1; VEGF, vascular endothelial growth factor; IDO, indolamine 2,3-dioxigenase; TGF, transforming growth factor; LAG-3, lymphocyte-activation gene 3 protein; TIM-3, T-cell immunoglobulin and mucin-domain containing-3; CD73, 5´nucleotidase; ARs, adenosine receptors; Selectins, cell adhesion molecules; CAR-T, chimeric antigen receptor T cell; TCR-T, T-cell receptor engineered T cell.

Apart from the problems associated with its efficacy (only a small group of patients respond to it), immunotherapy faces several challenges related to its safety. In other words, immunotherapy can induce adverse events in patients, such as autoimmunity, where healthy tissues are attacked, or cytokine release syndrome and vascular leak syndrome, as observed with the use of IL-2, both of which lead to serious hypotension, fever, renal failure, and other adverse events that are potentially lethal. The main challenges to be faced by immunotherapy in the future will require the combined efforts of basic and clinical scientists, with the objective of accelerating the understanding of the complex interactions between cancer and the immune system, and improve treatment options for patients. Better comprehension of immune phenotypes in tumors, beyond the state of PD-L1 and TME, will be relevant to increase immunotherapy efficacy. In this context, the identification of precise tumor antigenicity biomarkers by means of new technologies, such as complete genome sequencing, single cell sequencing, and epigenetic analysis to identify sites or subclones typical in drug resistance, as well as activation, traffic and infiltration of effector cells of the immune response, and regulation of TME mechanisms, may help define patient populations that are good candidates for specific therapies and therapeutic combinations. 117 , 118 Likewise, the use of agents that can induce specific activation and modulation of the response of T cells in tumor tissue, will help improve efficacy and safety profiles that can lead to better clinical results.

Molecular Targeted Therapy

For over 30 years, and based on the progress in our knowledge of tumor biology and its mechanisms, there has been a search for therapeutic alternatives that would allow spread and growth of tumors to be slowed down by blocking specific molecules. This approach is known as molecular targeted therapy. 119 Among the elements generally used as molecular targets there are transcription factors, cytokines, membrane receptors, molecules involved in a variety of signaling pathways, apoptosis modulators, promoters of angiogenesis, and cell cycle regulators. 120

Imatinib, a tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia, became the first targeted therapy in the final years of the 1990s. 97 From then on, new drugs have been developed by design, and today more than 60 targeted therapies have been approved by the FDA for the treatment of a variety of cancers ( Table 3 ). 121 This has had a significant impact on progression-free survival and global survival in neoplasms such as non-small cell lung cancer, breast cancer, renal cancer, and melanoma.

FDA Approved Molecular Targeted Therapies for the Treatment of Solid Tumors.

Drug	Therapeutic target	Indications	Biomarkers
Abemaciclib	CDK4/6 inhibitor	Breast cancer	ER+/PR+
Abiraterone	Anti-androgen	Prostate cancer	AR+
Afatinib	TKI anti-ErbB, EGFR (ErbB1), HER2 (ErbB2), ErbB3, ErbB4	NSCLC	EGFR mutated
			Deletion of exon 19
			Substitution in exon 21 (L858R)
Aflibercept	Anti-VEGF fusion protein	Colorectal cancer
Alectinib	Anti-ALK TKI	NSCLC	ALK+
Alpelisib	PI3K inhibitor	Breast cancer	PI3K mutated
Apalutamide	Anti-androgen	Prostate cancer	AR+
Atezolizumab	Anti-PD-L1 mAb	Breast cancer	PD-L1
		Hepatocellular carcinoma
		NSCLC
		Bladder cancer
Avapritinib	Kinase inhibitor	GIST	PDGFRA mutated in exon 18 (D842V)
Avelumab	Anti-PD-L1 mAb	Renal cancer	PD-L1
		Bladder cancer
		Neuroendocrine tumors
Axitinib	Anti-VEGF TKI	Renal cancer
Bevacizumab	Anti-VEGF mAb	CNS tumors
		Ovarian cancer
		Cervical cancer
		Colorectal cancer
		Hepatocellular carcinoma
		NSCLC
		Renal cancer
Brigatinib	Anti-ALK TKI	NSCLC	ALK+
Cabozantinib	TKR inhibitor: anti-MET, anti-VEGF, anti-RET, ROS1, MER, KIT	Renal cancer
		Hepatocellular carcinoma
		Thyroid cancer
Ceritinib	Anti-ALK TKI	NSCLC	ALK+
Cetuximab	Anti-EGFR mAb	Colorectal cancer	KRAS
		Head and Neck cancer	EGFR+
Crizotinib	Anti-ALK TKI	NSCLC	ALK+, ROS1+
Dabrafenib	BRAF inhibitor	NSCLC	BRAF-V600E, V600K
		Thyroid cancer
		Melanoma
Dacomitinib	Anti-EGFR TKI	NSCLC	EGFR+
Darolutamide	Anti-androgen	Prostate cancer	AR+
Durvalumab	Anti-PD-L1 mAb	NSCLC	PD-L1
		Bladder cancer
Encorafenib	BRAF inhibitor	Colorectal cancer	BRAF-V600E
		Melanoma
Entrectinib	Anti-ROS1 TKI	NSCLC	ROS1+
Enzalutamide	Anti-androgen	Prostate cancer	AR+
Erdafitinib	Anti-FGFR-1 TKI	Bladder cancer
Erlotinib	Anti-EGFR TKI	NSCLC	EGFR mutated
		Pancreatic caner	Deletion of exon 19
			Substitution in exon 21 (L858R)
Everolimus	mTOR inhibitor	CNS tumors
		Pancreatic cancer
		Breast cancer
		Renal cancer
Fulvestrant	ER antagonist	Breast cancer	ER+/PR+
Gefitinib	Anti-EGFR TKI	NSCLC	EGFR mutated
			Deletion of exon 19
			Substitution in exon 21 (L858R)
Imatinib	Anti-KIT TKI	GIST	KIT+
		Dermatofibroma protuberans
Ipilimumab	Anti-CTLA-4 mAb	Colorectal cancer
		Hepatocellular carcinoma
		NSCLC
		Melanoma
		Renal cancer
Lapatinib	TKI: anti-EGFR, anti-HER2	Breast cancer	ERBB2 over-expression or amplification
Lenvatinib	TKR: anti-VEGF, VEGFR1 (FLT1), VEGFR2 (KDR) y VEGFR3 (FLT4); (FGF) FGFR1, 2, 3 y 4, PDGF, PDGFRA, KIT, RET	Endometrial cancer
		Hepatocellular carcinoma
		Renal cancer
		Thyroid cancer
Lorlatinib	TKI: anti-ALK, anti-ROS2	NSCLC	ALK+, ROS1+
Necitumumab	Anti-EGFR mAb	NSCLC	EGFR+
Neratinib	Anti-HER2 TKI
Anti-EGFR	Breast cancer	ERBB2 over-expression or amplification
Niraparib	PARP inhibitor	Ovarian cancer	BRCA1/2 mutations
		Fallopian tube cancer	Homologous recombination deficiency
		Peritoneal cancer
Nivolumab	Anti-PD-1 mAb	Colorectal cancer	PD-1
		Esophageal cancer
		Hepatocellular carcinoma
		NSCLC
		Melanoma
		Renal cancer
		Bladder cancer
		Head and Neck cancer
Olparib	PARP inhibitor	Breast cancer	BRCA1/2 mutations
		Ovarian cancer
		Pancreatic cancer
		Prostate cancer
Osimertinib	Anti-EGFR TKI	NSCLC	EGFR-T790M
Palbociclib	CDK4/6 inhibitor	Breast cancer	RE+/RP+
Pantitumumab	Anti-EGFR mAb	Colorectal cancer	KRAS
			EGFR+
Pazopanib	TKI: Anti-VEGF, anti-PDGFR, anti-FGFR, anti-cKIT	Renal cancer
		Soft tissues sarcoma
Pembrolizumab	PD-1 inhibitor	Cervical cancer	PD-1
		Endometrial cancer
		Esophageal cancer
		Gastric cancer
		Hepatocellular carcinoma
		NSCLC
		Bladder cancer
		Head and Neck cancer
Pertuzumab	Anti-HER2 mAb	Breast cancer	ERBB2 over-expression or amplification
Ramucirumab	Anti-VEGF mAb	Colorectal cancer
		Esophageal cancer
		Gastric cancer
		Hepatocellular carcinoma
		NSCLC
Regorafenib	Anti-cKIT TKI	Colorectal cancer	KIT+
		Hepatocellular carcinoma
		GIST
Ribociclib	CDK4/6 inhibitor	Breast cancer	ER+/PR+
Ripretinib	TKI: anti-KIT, anti-PDGFR	GIST	KIT+
Rucaparib	PARP inhibitor	Prostate cancer	BRCA1/2 mutations
		Ovarian cancer
		Fallopian tube cancer
		Peritoneal cancer
Sacituzumab-Govitecan	Conjugated Ab anti-trop-2	Breast cancer	RE- RP- HER2-
Selpercatinib	Kinase inhibitor	NSCLC	RET+
		Thyroid cancer
Sorafenib	Multi-kinase inhibitor: anti-PDGFR, VEGFR, cKIT, TKR	Renal cancer
		Hepatocellular carcinoma
		Thyroid cancer
Sunitinib	Multi-kinase inhibitor: anti-PDGFR, VEGFR, cKIT, TKR	Renal cancer
		Pancreatic cancer
		GIST
Tamoxifeno	SERM	Breast cancer	ER+/PR+
Talazoparib	PARP inhibitor	Breast cancer	BRCA1/2 mutations
Temsirolimus	mTOR inhibitor	Renal cancer
Trametinib	BRAF inhibitor	NSCLC	BRAF-V600E, V600K
		Thyroid cancer
		Melanoma
Trastuzumab	Anti-HER2 mAb	Gastric cancer	ERBB2 over-expression of amplification
		Gastro-esophageal junction cancer
		Breast cancer
Trastuzumab-Deruxtecan	Anti-HER2 conjugated Ab	Breast cancer	ERBB2 over-expression of amplification
Trastuzumab-Emtansine	Anti-HER2 conjugated Ab	Breast cancer	ERBB2 over-expression of amplification
Tucatinib	Anti-HER2 TKI	Breast cancer	ERBB2 over-expression of amplification
Vandetanib	TKI: anti-VEGF, anti-EGFR	Thyroid cancer	EGFR+
Vemurafenib	BRAF inhibitor	Melanoma	BRAF-V600E

Abbreviations: mAb, monoclonal antibody; ALK, anaplastic lymphoma kinase; CDK, cyclin-dependent kinase; CTLA-4, cytotoxic lymphocyte antigen-4; EGFR, epidermal growth factor receptor; FGFR, fibroblast growth factor receptor; GIST, gastrointestinal stroma tumor; mTOR, target of rapamycine in mammal cells; NSCLC, non-small cell lung carcinoma; PARP, poli (ADP-ribose) polimerase; PD-1, programmed death protein-1; PDGFR, platelet-derived growth factor receptor; PD-L1, programmed death ligand-1; ER, estrogen receptor; PR, progesterone receptor; TKR, tyrosine kinase receptors; SERM, selective estrogen receptor modulator; TKI, tyrosine kinase inhibitor; VEGFR, vascular endothelial growth factor receptor. Modified from Ref. [ 127 ].

Most drugs classified as targeted therapies form part of 2 large groups: small molecules and mAbs. The former are defined as compounds of low molecular weight (<900 Daltons) that act upon entering the cell. 120 Targets of these compounds are cell cycle regulatory proteins, proapoptotic proteins, or DNA repair proteins. These drugs are indicated based on histological diagnosis, as well as molecular tests. In this group there are multi-kinase inhibitors (RTKs) and tyrosine kinase inhibitors (TKIs), like sunitinib, sorafenib, and imatinib; cyclin-dependent kinase (CDK) inhibitors, such as palbociclib, ribociclib and abemaciclib; poli (ADP-ribose) polimerase inhibitors (PARPs), like olaparib and talazoparib; and selective small-molecule inhibitors, like ALK and ROS1. 122

As for mAbs, they are protein molecules that act on membrane receptors or extracellular proteins by interrupting the interaction between ligands and receptors, in such a way that they reduce cell replication and induce cytostasis. Among the most widely used mAbs in oncology we have: trastuzumab, a drug directed against the receptor for human epidermal growth factor-2 (HER2), which is overexpressed in a subgroup of patients with breast and gastric cancer; and bevacizumab, that blocks vascular endothelial growth factor and is used in patients with colorectal cancer, cervical cancer, and ovarian cancer. Other mAbs approved by the FDA include pembolizumab, atezolizumab, nivolumab, avelumab, ipilimumab, durvalumab, and cemiplimab. These drugs require expression of response biomarkers, such as PD-1 and PD-L1, and must also have several resistance biomarkers, such as the expression of EGFR, the loss of PTEN, and alterations in beta-catenin. 123

Because cancer is such a diverse disease, it is fundamental to have precise diagnostic methods that allow us to identify the most adequate therapy. Currently, basic immunohistochemistry is complemented with neoplastic molecular profiles to determine a more accurate diagnosis, and it is probable that in the near future cancer treatments will be based exclusively on molecular profiles. In this regard, it is worth mentioning that the use of targeted therapy depends on the existence of specific biomarkers that indicate if the patient will be susceptible to the effects of the drug or not. Thus, the importance of underlining that not all patients are susceptible to receive targeted therapy. In certain neoplasms, therapeutic targets are expressed in less than 5% of the diagnosed population, hindering a more extended use of certain drugs.

The identification of biomarkers and the use of new generation sequencing on tumor cells has shown predictive and prognostic relevance. Likewise, mutation analysis has allowed monitoring of tumor clone evolution, providing information on changes in canonic gene sequences, such as TP53, GATA3, PIK3CA, AKT1, and ERBB2; infrequent somatic mutations developed after primary treatments, like SWI-SNF and JAK2-STAT3; or acquired drug resistance mutations such as ESR1. 124 The study of mutations is vital; in fact, many of them already have specific therapeutic indications, which have helped select adequate treatments. 125

There is no doubt that molecular targeted therapy is one of the main pillars of precision medicine. However, it faces significant problems that often hinder obtaining better results. Among these, there is intratumor heterogeneity and differences between the primary tumor and metastatic sites, as well as intrinsic and acquired resistance to these therapies, the mechanisms of which include the presence of heterogeneous subclones, DNA hypermethylation, histone acetylation, and interruption of mRNA degradation and translation processes. 126 Nonetheless, beyond the obstacles facing molecular targeted therapy from a biological and methodological point of view, in the real world, access to genomic testing and specific drugs continues to be an enormous limitation, in such a way that strategies must be designed in the future for precision medicine to be possible on a global scale.

Cell Therapy

Another improvement in cancer treatment is the use of cell therapy, that is, the use of specific cells as therapeutic agents. This clinical procedure has 2 modalities: the first consists of replacing and regenerating functional cells in a specific tissue by means of stem/progenitor cells of a certain kind, 43 while the second uses immune cells as effectors to eliminate malignant cells. 127

Regarding the first type, we must emphasize the development of cell therapy based on hematopoietic stem and progenitor cells. 128 For over 50 years, hematopoietic cell transplants have been used to treat a variety of hematologic neoplasms (different forms of leukemia and lymphoma). Today, it is one of the most successful examples of cell therapy, including innovative modalities, such as haploidentical transplants, 129 as well as application of stem cells expanded ex vivo . 130 There are also therapies that have used immature cells that form part of the TME, such as MSCs. The replication potential and cytokine secretion capacity of these cells make them an excellent option for this type of treatment. 131 Neural stem cells can also be manipulated to produce and secrete apoptotic factors, and when these cells are incorporated into primary neural tumors, they cause a certain degree of regression. They can even be transfected with genes that encode for oncolytic enzymes capable of inducing regression of glioblastomas. 132

With respect to cell therapy using immune cells, several research groups have manipulated cells associated with tumors to make them effector cells and thus improve the efficacy and specificity of the antitumor treatment. PB leckocytes cultured in the presence of IL-2 to obtain activated lymphocytes, in combination with IL-2 administration, have been used in antitumor clinical protocols. Similarly, infiltrating lymphocytes from tumors with antitumor activity have been used and can be expanded ex vivo with IL-2. These lymphocyte populations have been used in immunomodulatory therapies in melanoma, and pancreatic and kidney tumors, producing a favorable response in treated patients. 133 NK cells and macrophages have also been used in immunotherapy, although with limited results. 134 , 135

One of the cell therapies with better projection today is the use of CAR-T cells. This strategy combines 2 forms of advanced therapy: cell therapy and gene therapy. It involves the extraction of T cells from the cancer patient, which are genetically modified in vitro to express cell surface receptors that will recognize antigens on the surface of tumor cells. The modified T cells are then reintroduced in the patient to aid in an exacerbated immune response that leads to eradication of the tumor cells ( Figure 4 ). Therapy with CAR-T cells has been used successfully in the treatment of some types of leukemia, lymphoma, and myeloma, producing complete responses in patients. 136

An external file that holds a picture, illustration, etc.
Object name is 10.1177_10732748211038735-fig4.jpg

CAR-T cell therapy. (A) T lymphocytes obtained from cancer patients are genetically manipulated to produce CAR-T cells that recognize tumor cells in a very specific manner. (B) Interaction between CAR molecule and tumor antigen. CAR molecule is a receptor that results from the fusion between single-chain variable fragments (scFv) from a monoclonal antibody and one or more intracellular signaling domains from the T-cell receptor. CD3ζ, CD28 and 4-1BB correspond to signaling domains on the CAR molecule.

Undoubtedly, CAR-T cell therapy has been truly efficient in the treatment of various types of neoplasms. However, this therapeutic strategy can also have serious side effects, such as release of cytokines into the bloodstream, which can cause different symptoms, from high fever to multiorgan failure, and even neurotoxicity, leading to cerebral edema in many cases. 137 Adequate control of these side effects is an important medical challenge. Several research groups are trying to improve CAR-T cell therapy through various approaches, including production of CAR-T cells directed against a wider variety of tumor cell-specific antigens that are able to attack different types of tumors, and the identification of more efficient types of T lymphocytes. Furthermore, producing CAR-T cells from a single donor that may be used in the treatment of several patients would reduce the cost of this sort of personalized cell therapy. 136

Achieving wider use of cell therapy in oncologic diseases is an important challenge that requires solving various issues. 138 One is intratumor cell heterogeneity, including malignant subclones and the various components of the TME, which results in a wide profile of membrane protein expression that complicates finding an ideal tumor antigen that allows specific identification (and elimination) of malignant cells. Likewise, structural organization of the TME challenges the use of cell therapy, as administration of cell vehicles capable of recognizing malignant cells might not be able to infiltrate the tumor. This results from low expression of chemokines in tumors and the presence of a dense fibrotic matrix that compacts the inner tumor mass and avoids antitumor cells from infiltrating and finding malignant target cells.

Further Challenges in the 21st Century

Beyond the challenges regarding oncologic biomedical research, the 21 st century is facing important issues that must be solved as soon as possible if we truly wish to gain significant ground in our fight against cancer. Three of the most important have to do with prevention, early diagnosis, and access to oncologic medication and treatment.

Prevention and Early Diagnosis

Prevention is the most cost-effective strategy in the long term, both in low and high HDI nations. Data from countries like the USA indicate that between 40-50% of all types of cancer are preventable through potentially modifiable factors (primary prevention), such as use of tobacco and alcohol, diet, physical activity, exposure to ionizing radiation, as well as prevention of infection through access to vaccination, and by reducing exposure to environmental pollutants, such as pesticides, diesel exhaust particles, solvents, etc. 74 , 84 Screening, on the other hand, has shown great effectiveness as secondary prevention. Once population-based screening programs are implemented, there is generally an initial increase in incidence; however, in the long term, a significant reduction occurs not only in incidence rates, but also in mortality rates due to detection of early lesions and timely and adequate treatment.

A good example is colon cancer. There are several options for colon cancer screening, such as detection of fecal occult blood, fecal immunohistochemistry, flexible sigmoidoscopy, and colonoscopy, 139 , 140 which identify precursor lesions (polyp adenomas) and allow their removal. Such screening has allowed us to observe 3 patterns of incidence and mortality for colon cancer between the years 2000 and 2010: on one hand, an increase in incidence and mortality in countries with low to middle HDI, mainly countries in Asia, South America, and Eastern Europe; on the other hand, an increase in incidence and a fall in mortality in countries with very high HDI, such as Canada, the United Kingdom, Denmark, and Singapore; and finally a fall in incidence and mortality in countries like the USA, Japan, and France. The situation in South America and Asia seems to reflect limitations in medical infrastructure and a lack of access to early detection, 141 while the patterns observed in developed countries reveal the success, even if it may be partial, of that which can be achieved by well-structured prevention programs.

Another example of success, but also of strong contrast, is cervical cancer. The discovery of the human papilloma virus (HPV) as the causal agent of cervical cancer brought about the development of vaccines and tests to detect oncogenic genotypes, which modified screening recommendations and guidelines, and allowed several developed countries to include the HPV vaccine in their national vaccination programs. Nevertheless, the outlook is quite different in other areas of the world. Eighty percent of the deaths by cervical cancer reported in 2018 occurred in low-income nations. This reveals the urgency of guaranteeing access to primary and secondary prevention (vaccination and screening, respectively) in these countries, or else it will continue to be a serious public health problem in spite of its preventability.

Screening programs for other neoplasms, such as breast, prostate, lung, and thyroid cancer have shown outlooks that differ from those just described, because, among other reasons, these neoplasms are highly diverse both biologically and clinically. Another relevant issue is the overdiagnosis of these neoplasms, that is, the diagnosis of disease that would not cause symptoms or death in the patient. 142 It has been calculated that 25% of breast cancer (determined by mammogram), 50–60% of prostate cancer (determined by PSA), and 13–25% of lung cancer (determined by CT) are overdiagnosed. 142 Thus, it is necessary to improve the sensitivity and specificity of screening tests. In this respect, knowledge provided by the biology of cancer and “omic” sciences offers a great opportunity to improve screening and prevention strategies. All of the above shows that prevention and early diagnosis are the foundations in the fight against cancer, and it is essential to continue to implement broader screening programs and better detection methods.

Global Equity in Oncologic Treatment

Progress in cancer treatment has considerably increased the number of cancer survivors. Nevertheless, this tendency is evident only in countries with a very solid economy. Indeed, during the past 30 years, cancer mortality rates have increased 30% worldwide. 143 Global studies indicate that close to 70% of cancer deaths in the world occur in nations of low to middle income. But even in high-income countries, there are sectors of society that are more vulnerable and have less access to cancer treatments. 144 Cancer continues to be a disease of great social inequality.

In Europe, the differences in access to cancer treatment are highly marked. These treatments are more accessible in Western Europe than in its Eastern counterpart. 145 Furthermore, highly noticeable differences between high-income countries have been detected in the cost of cancer drugs. 146 It is interesting to note that in many of these cases, treatment is too costly and the clinical benefit only marginal. Thus, the importance of these problems being approached by competent national, regional, and global authorities, because if these new drugs and therapeutic programs are not accessible to the majority, progress in biomedical, clinical and epidemiological research will have a limited impact in our fight against cancer. We must not forget that health is a universal right, from which low HDI countries must not be excluded, nor vulnerable populations in nations with high HDI. The participation of a well-informed society will also be fundamental to achieve a global impact, as today we must fight not only against the disease, but also against movements and ideas (such as the anti-vaccine movement and the so-called miracle therapies) that can block the medical battle against cancer.

Final Comments

From the second half of the 20th century to the present day, progress in our knowledge about the origin and development of cancer has been extraordinary. We now understand cancer in detail in genomic, molecular, cellular, and physiological terms, and this knowledge has had a significant impact in the clinic. There is no doubt that a patient who is diagnosed today with a type of cancer has a better prospect than a patient diagnosed 20 or 50 years ago. However, we are still far from winning the war against cancer. The challenges are still numerous. For this reason, oncologic biomedical research must be a worldwide priority. Likewise, one of the fundamental challenges for the coming decades must be to reduce unequal access to health services in areas of low- to middle income, and in populations that are especially vulnerable, as well as continue improving prevention programs, including public health programs to reduce exposure to environmental chemicals and improve diet and physical activity in the general population. 74 , 84 Fostering research and incorporation of new technological resources, particularly in less privileged nations, will play a key role in our global fight against cancer.

Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.

Hector Mayani https://orcid.org/0000-0002-2483-3782

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Nancy u. lin, volkmar müller, giuseppe curigliano, barbara pistilli, description.

This ESMO Deep Dive Breast Cancer Webinar focused on HER2 positive metastatic breast cancer.

This webinar was developed with the aim to provide a second, deeper layer of educational experience in emerging data related to: molecular biology and classification, translational research and biomarkers for precision medicine, and unknowns, hypotheses, and ongoing research in areas of controversy or unmet need for optimal management of patients.

It began with a brief welcome and introduction, then four lectures were delivered on: brain metastases, optimal treatment sequences after guideline-based early breast cancer therapy and other potential targets, as well as the role of the molecular tumour board emerging concepts. The lectures were followed by a live discussion with the speakers’ panel.

This programme was designed to provide an overview of the latest understanding of molecular biology and the impact of targeting different pathways in the management of patients with breast cancers, offer expert opinion exchange, and provide some important considerations in this field.

Learning objectives

To acquire a deeper understanding of the clinical course of malignant disease of breast cancer.
To understand biological hypotheses on classification and risk stratification, ongoing/required research in therapeutics and knowledge of use of omics technologies for biomarker-enabled precision medicine for breast cancer.
To develop skills and abilities for critical analysis, interpretation of research data and therapeutic strategies.
To become better equipped for informed, innovative thinking and engagement in ongoing or new research projects.

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Scientists identify potential new immune system target to head off the spread of breast cancer cells

by Johns Hopkins University School of Medicine

In a study using human breast cancer cells, scientists say they have potentially identified immune system white blood cells that appear to be the closest neighbors of breast cancer cells that are likely to spread. The researchers say the finding, focused on a white blood cell called a macrophage, may provide a new biological target for immunotherapies designed to destroy spreading cancer cells that are often markers for worsening disease.

A report on the findings is published in the journal Oncogene .

For the study, researchers at the Johns Hopkins Kimmel Cancer Center used special imaging techniques to see the organization of individual cells within tumors, and built on work by colleagues at the Johns Hopkins Giovanis Institute, whose previous work focused on identifying biomarkers on breast cancer cells that are likely to spread.

"One of the most exciting developments in cancer treatment is immunotherapy—drugs that help the immune system attack a tumor," says Andrew Ewald, Ph.D., professor and director of the Department of Cell Biology and director of the Johns Hopkins Giovanis Institute. But he notes that such immunotherapies so far work only for a subset of patients, a clear indication that more—and more specific—cellular targets must be identified to broaden the effectiveness of such therapies.

The researchers' focus on immune system cells is logical, because such cells start their work by getting up close to cancer cells, says Ewald. Touches between cells start a kind of "handshake" process that lets immune cells such as macrophages identify a cell they encounter.

When those encounters occur, the immune system biologically "tags" some as "foreign" to the body and ripe for destruction, while leaving others alone. But one of the hallmarks of cancer cells is their ability to mask their identity and trick the immune system into leaving them alone to grow, change and spread.

In an effort to better determine which cells are closest to breast cancer cells, the Johns Hopkins scientists analyzed primary and metastatic breast cancer tissue samples from 24 people who died from breast cancer and who donated their tissues to Johns Hopkins researchers through a rapid autopsy program.

Kimmel Cancer Center oncologist and imaging expert Won Jin Ho, M.D., used an imaging tool called mass cytometry to analyze and map cells in the tissue samples.

Other scientists have mapped cells in such tissues, but the Johns Hopkins researchers say their study focused not on what surrounds an average cancer cell, but what is closest to those cancer cells that are most likely to spread.

Hundreds of cells span the width of a single tissue sample. "When we analyze dissociated cells, it's like looking at a smoothie of cells, all blended together, but with imaging, we get to see where all of the pieces are," says Ho, an assistant professor of oncology and director of the Mass Cytometry Facility at Johns Hopkins.

Ewald and former postdoctoral fellow Eloïse Grasset, Ph.D., now at the National Centre for Scientific Research in France, had previously identified the biomarker signature common to breast cancer cells that are likely to spread, or metastasize.

The researchers used 36 such biomarkers to pinpoint metastasis-initiating cells and other "signatures" to identify cells next to them—those that were up close (within about 10–20 microns), others about three to four cells out, and cells further away.

"What popped out at us, among immune system cells, was a subset of macrophages very close to or touching metastasis-initiating cells in the primary and metastatic tissue samples," says Ho. The macrophage subsets are a minority—about 1%–5%—of the cells present in the tumor.

The research team confirmed the presence of key macrophage subsets in another set of more than 100 breast cancer samples from a tumor bank published in a previous study , showing that such distinct macrophage subtypes are indeed components of the breast cancer microenvironment.

A type of white blood cell, macrophages can swallow and destroy "foreign" cells on their own, but can also recruit other immune system cells to fight off cells they identify as foreign to the body. Ho says that other studies have shown that tumors with many macrophages may indicate a poorer prognosis and lower response to immunotherapy.

"As discovery-based scientists, we're looking for ways to change the immune system's spatial organization in the microenvironment surrounding cancer cells," says Ewald. "Eventually, we could develop biologic therapies to change how neighborhoods of cancer cells are organized."

Other researchers involved in the study are Atul Deshpande, Jae Lee, Yeonju Cho, Sarah Shin, Erin Coyne, Alexei Hernandez, Xuan Yuan, Zhehao Zhang and Ashley Cimino-Mathews from Johns Hopkins.

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Frontiers in Cell and Developmental Biology
Cancer Cell Biology
Research Topics

Clinical Advances and Practice of Digestive System Cancer Progression and Metastasis Induced by Immune Factors

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The global incidence of immune-related digestive system cancers is rising, significantly impacting patients' quality of life and health. Additionally, the progression and metastasis of digestive system tumors pose severe challenges due to the complex tumor microenvironment and the immune response mechanisms involved. These diseases often involve intricate pathophysiological mechanisms, including abnormal activation of the immune system and persistent inflammation. In recent years, advances in molecular biology and immunology have enhanced our understanding of these mechanisms, providing a scientific basis for developing new therapeutic strategies. While traditional treatment methods such as chemotherapy and radiotherapy can control tumor progression, their side effects and long-term efficacy remain controversial. Emerging immunotherapies and targeted therapies offer new hope, particularly for patients with metastatic digestive system cancers. However, developing precise treatment plans tailored to individual differences remains a significant challenge. The integration of multidisciplinary collaboration and personalized treatment strategies shows considerable promise in improving treatment outcomes and prognosis, becoming a crucial focus in current research and practice. The primary goals of this research topic are to summarize the latest treatment methods and techniques for immune-related digestive system cancers, analyze the clinical outcomes and prognoses of various treatment approaches, explore the molecular mechanisms and biomarkers of immune factors related to the progression of these cancers, and share successful case studies and lessons learned to enhance clinical treatment standards. This research topic will encompass a broad range of themes, with a particular emphasis on the following types of articles: Review Articles: • Epidemiology and Pathophysiology of Immune-Related Digestive System Cancer progression and metastasis: Investigate the roles and influencing factors of immune factors in digestive system cancer. • Latest Treatment Techniques and Methods: Include immunotherapy, targeted therapy, and discuss their indications and limitations. • Molecular Mechanisms and Biomarkers: Study the molecular mechanisms associated with immune-related digestive system cancer progression and metastasis, explore potential biomarkers, and provide insights for precision medicine. Clinical Experience: • Multidisciplinary Collaborative Treatment Models: Share collaborative experiences and successful cases from multidisciplinary teams in treating immune-related digestive system cancer progression and metastasis. • Personalized Treatment Strategies: Develop and evaluate individualized comprehensive treatment plans based on specific patient conditions, assessing their efficacy and safety. Case Reports: • Typical Case Analysis: Present representative cases of immune-related digestive system cancer progression and metastasis for detailed analysis, highlighting key points and lessons learned during the treatment process. • Rare Case Reports: Document rare cases of immune-related digestive system cancer progression and metastasis, discussing their uniqueness and the challenges encountered in treatment.

Keywords : digestive cancer, progression, metastasis, immunology, treatment strategies, clinical outcomes

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Apalutamide for non-metastatic castration-resistant prostate cancer (nmCRPC): real world data of a multicenter study

Open access
Published: 09 September 2024
Volume 150 , article number 414 , ( 2024 )

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Axel Hegele 1 , 2 ,
Rainer Häußermann 1 , 2 ,
Stefan Schultheis 3 ,
Lennart Skrobek 4 ,
Meike Vink 5 ,
Sebastian Hollwegs 6 ,
Martin Ludwig 7 ,
Petra Huwe 8 ,
Manfred Maywurm 9 ,
Anke Bartsch-Polle 6 ,
Jost Weber 4 ,
Markus Thiemer 10 &
Denny Varughese 3

Apalutamide plus androgen-deprivation therapy (ADT) improved outcomes in patients with non-metastatic castration-resistant prostate cancer (nmCRPC). Nevertheless real-world data are limited. The aim of this multicenter study was to generate real-world data from nmCRPC patients treated with ADT plus apalutamide.

In this observational cohort based investigator initiated trial data of nmCRPC patients receiving apalutamide plus ADT were collected focusing on patient demographic data, prostate-specific antigen (PSA) declines, safety profile including dose modification/discontinuation as well as subsequent therapy and metastasis-free survival (MFS).

Data from a total of 31 nmCRPC patients were documented. Compared to the Phase III study Spartan real-world patients are older, showed a higher ECOG-PS and more aggressive tumors. In the cohort PSA decreased about 98.1%, 74% of patients showed a PSA decrease over 90% and 54.8% reached a PSA-level < 0.2ng/ml. Apalutamide was well tolerated in real world patients: adverse events occurred in 67.7% but were in the majority mild (≥ grade 3: 6.5%). Dose reduction was necessary in 38.7% and 32.2% discontinued apalutamide treatment. MFS was 43 months and majority of patients were subsequently treated with abiraterone.

In real world more comorbid nmCRPC patients with a higher ECOG-PS and more aggressive tumors are treated with apalutamide plus ADT. Nevertheless efficacy results as well as side effects are similar in real-world compared to Spartan trial showing also a rapid, durable and deep PSA response with a median MFS of 43 months.

Avoid common mistakes on your manuscript.

Introduction

Patients with non-metastatic castration-resistant prostate cancer (nmCRPC) without further treatment are developing metastases associated with significant morbidity and mortality despite ongoing androgen-deprivation therapy (ADT) (Scher 2015 , Crona 2017 ; Smith 2011 ). A short PSA doubling time (PSADT) ≤ 10 months and a PSA-level ≥ 8ng/ml may help to identify nmCRPC patients who were at high risk for disease progression (Smith 2011 and 2013 ). In 2018 the Phase III trial Spartan showed that the oral non-steroidal anti-androgen apalutamide increased metastasis-free survival (MFS) as well as overall survival (OS) in high-risk nmCRPC patients compared to placebo leading to approval of apalutamide for patients with high-risk nmCRPC (Smith 2018 and 2021 ). Apalutamide binds directly to the ligand-binding domain of the androgen-receptor (AR) thus preventing AR translocation, DNA binding and transcription mediated by AR (Clegg 2012 ). Results of randomized clinical trials (RCT) represents the highest level of evidence (Dahm 2020 ). Nevertheless RCTs have limitations – most notably used inclusion criteria often do not reflect real-world patient population. Elderly and more comorbid patients were common especially in cases of prostate cancer. To date patients of this type are often underrepresented or even not represented at all in clinical trials. So real-world data adding valuable data to the information obtained from RCTs are of high interest (Schad 2022 ; Baumfeld 2020 ). The aim of our study was to generate real-world data in nmCRPC patients treated with apalutamide in daily practice concerning patient population, used imaging tools, efficacy, safety as well as dosage-changes and subsequent therapy.

Materials and methods

This study (Use of A paluta m ide in p rostate cancer in C e ntra l Hessen: AmPel) is an observational retrospective cohort based investigator initiated trial (IIT) with focus on real world evidence. The study was performed from November 2021 (ongoing) in nine urological practices in the middle of Hessen/Germany. Patients who started apalutamide therapy due to nmCRPC were added and followed as commonly done in each practice without a universal protocol and specifications concerning imaging controls and time intervals.

The study followed the principles of the Declaration of Helsinki and was approved by the local ethics committee of the Philipps University Marburg, Medicine school (authorization number: 163/21).

Patients data included age, time of follow-up, ECOG performance Score (ECOG PS), date of initial prostate-cancer diagnosis, Gleason-Score, initial PSA-level, prior cancer-specific treatment, time to castration resistance, PSADT as well as used imaging method.

Efficacy variables included PSA levels prior start of apalutamide treatment (baseline) and during treatment – normally all 3 months like it was performed routinely in the participating urological practices. Decrease of PSA levels after time and best achieved individual percentage PSA-decrease (≥ 50% PSA reduction , ≥ 90% PSA reduction) as well as patient reaching a PSA ≤ 0.2ng/ml were estimated.

Discontinuation of treatment due to various reasons (progression, toxicity, patients request) and subsequent therapies were documented. MFS was calculated.

Safety variables were the type of adverse event (AE) and the respective grade according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 5.0).

Data were collected and analyzed using Excel for Windows (Version 2013). Kaplan Meier survival analysis on MFS was performed with Graphpad Prism 9.5.1.

In this ongoing IIT data was analyzed in a total of 31 nmCRPC patients and documented from November 2021 until November 2023. These patients were included in 9 urological practices in Hessen/Germany. 39.1% of the patients underwent previous prostate cancer treatment (prostatectomy , radiation). The median PSA-level before starting apalutamide therapy was 7.21 ng/ml , median PSA doubling time (PSADT) was 4 months and 81.5% showed a PSADT ≤ 6 month. All patients started with the full apalutamide dosage of 240 mg daily. Median follow-up was 18 months (range 3–50). Median time to castration resistance was 72 months (range 12–264). Patients and disease characteristics before starting apalutamide treatment are summarized in Table 1 in comparison to the pivotal trial Spartan (Smith 2018 ).

PSA response of the cohort was observed at all time points. PSA of the cohort decreased about 91.3%, 95% and 98.1% after 3 months, 6 months and 9 months, resp. (see Fig. 1 ). Additional individual PSA reduction of ≥ 90% and ≥ 50% was achieved after 3 months in 74.2% and 90.3% of the patients resp. Initial PSA progression was seen in only 3.2%. PSA level decreased ≤ 0.2 ng/ml in 54.8% of patients after 3 month (see Fig. 2 ). During treatment 19.4% of patients showed progression to metastatic disease resulting in a median MFS of 43 months (see Fig. 3 ).

Median PSA levels of the cohort at different time points after starting apalutamide treatment showing a rapid and durable PSA response

Number of patients [%] who achieved decreased PSA-levels ≥ 50%, ≥ 90% and PSA increase (blue bars) after 3 months. Yellow bar show the number of patients [%] with PSA decrease ≤ 0.2 ng/ml

Median metastasis-free survival (MFS) was 43 months

Safety and subsequent therapy

In 32.3% of the patients no adverse events were documented. In 67.7% of the patients any adverse event, but only in 6.5% of them an adverse event grade ≥ 3 occurred. No death occurred. Table 2 presents a summary as well as most frequent types of adverse events. In 38.7% of the patients apalutamide dose reduction was necessary due to toxicity. 32.3% of the patients discontinued apalutamide treatment due to any reason: progression to metastatic disease was observed in 19.4%, toxicity in 6.5% and patients request in 9.7%. After discontinuation of apalutamide treatment due to progression 12.9% received abiraterone and 3.2% radiation therapy only. In 6.5% therapy was switched to enzalutamide due to toxicity.

Non-metastatic castration-resistant prostate cancer (nmCRPC) frequently advances to metastatic disease associated with poor clinical outcome as well as reduction of quality of life (Smith 2005 and 2011 , Rönningas 2022 ). Recently the phase III trial Spartan demonstrated that apalutamide a novel receptor axis-targeted agent significantly improved metastasis-free survival (MFS) as well as overall survival (OS) in nmCRPC patients compared to placebo (Smith 2018 and 2021 ). However, due to lack of evidence it remains unclear if apalutamide in real-world clinical practice also results in improved outcome.

In our multicenter real-world study there are some important demographic differences: compared to Spartan trial our nmCRPC patients showed a higher ECOG PS (> 70% ≥ ECOG PS 1) and nearly 30% of the cohort a ECOG PS ≥ 2. Especially this patient group is even not included in the Spartan trial (Smith 2018 ). In addition real-world patients showed a higher proportion of high-grade Gleason score (57.9% vs. 43.5%) as well as PSADT ≤ 6 months (81.5% vs. 71.5%). Similar differences were described by Sánchez JC et al. ( 2023 ) in a smaller real-world nmCRPC cohort ( n = 18). In Spartan trial number of pre-treated patients were nearly doubled compared to our cohort , maybe explained by the larger number of patients. In both real-world and Spartan trial conventional imaging was performed in about 55% of the patients (Smith 2018 ). Nowadays there is a broader availability of PSMA-PET/CT as preferred and guideline-recommended staging imaging tool in nmCRPC reaching almost 100% detection rate of metastases. So using PSMA-PET/CT routinely therapy modalities of nmCRPC will change in the near future (Fendler 2019 , Baboudjian 2022 ).

Our real-world cohort showed a rapid and durable PSA response. Median PSA levels of the cohort are decreasing with the lowest level after 9 months (0.1ng/ml). After 3 months a PSA reduction ≥ 90% and ≥ 50% was achieved in 74.2% and 90.3% resp. Deep PSA response reflected in a PSA-level ≤ 0.2ng/ml was obtained in 54.8% in real-world setting. Our data are in line with Spartan trial showing a PSA decrease ≥ 90% in 62% but a lower level of patients reaching PSA ≤ 0.2ng/ml (34%) despite higher percentage of PSADT ≤ 6months and high-grade Gleason score in our cohort. Nevertheless MFS was 43 months in our real-world cohort and comparable to the pivotal trial (40.5 months) (Smith 2018 , Saad 2022 ).

Apalutamide treatment was also safe in real-world use. The documented overall AE rate (67.7%) as well as AE ≥ 3 (6.5%) was distinct lower compared to Spartan trial (96.5%, 45.1% resp.). In clinical trials reporting of AE´s are more strict and detailed compared to real-world practice (Eichler 2021 ). Additional patients maybe consult directly the specialist of the affected organ e.g. dermatologist in case of rash (Katsuta 2024 ). So the AE differences are not surprising and are in line with other real-world data (Sánchez JC 2023, Hussain 2022 ). Nevertheless beside the known and described side effects of apalutamide like rash and fatigue about 10% of the real-world patients mentioned hot flashes. In Spartan trial incidence of hot flashes are not reported as frequent side effect (> 15%) or adverse events of interest. Only a small number of patient (0.5%) in Spartan trial discontinued apalutamide therapy due to hot flashes (Smith 2018 ). Our data clearly identify the higher incidence and severity of hot flashes in a real-world population and should be considered when treating nmCRPC patients with apalutamide. Discontinuation of apalutamide treatment in real-world was also similar to Spartan trial (32.2% vs. 39.1%) as well as nmCRPC patients with disease progression (19.4% vs. 19.3%). Apalutamide dosage was reduced in 38.7% due to toxicity – reflecting the higher ECOG PS with more comorbidities however reaching satisfactory treatment efficacy.

Subsequent therapy in case of progression was abiraterone acetate (plus prednison) similar to the Spartan population. Another real-world study focusing ADT/apalutamide in nmCRPC patients ( n = 18) used predominantly taxan-based chemotherapy (Sánchez JC 2023). This might depend on local reimbursement modalities and therapy restrictions. If AE´s were the reason for discontinuation a second hormonal agent was preferred because changing mode of action was not meaningful and other potential agents could be reserved for future use.

However our results are in line with the pivotal trial but there are several limitations of our real-world study. The small number of patients reflecting the increasing use of PSMA-PET/CT in the event of rising PSA-levels as well as the short follow-up. In Spartan trial the number of pre-treated patients were nearly doubled compared to our real-world cohort hamper the comparability of the findings. Another limitation is the missing standard of imaging to assess metastatic disease under treatment illustrating the typical limitations of real-world studies beside for instance medical records with unavoidable lack of data especially in a multicenter setting.

In conclusion in this largest nmCRPC real-world cohort more comorbid patients with a higher ECOG PS – not included in clinical trials- and more aggressive tumors were treated with apalutamide. Nevertheless efficacy results as well as adverse events are consistent with data of the phase III trial Spartan showing a rapid, durable and deep PSA response with similar MFS. As a matter of fact in real-world hot flashes are a clinical relevant and notable side effect.

Data availability

The data cannot be shared openly. Data of the findings have been deposited on the server of Urological Center Mittelhessen and can be aprehended after contacting the corresponding author.

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Smith MR, Saad F, Chowdhury S, Oudard S, Hadaschik BA, Graff JN, Olmos D, Mainwaring PN, Lee JY, Uemura H, De Porre P, Smith AA, Brookman-May SD, Li S, Zhang K, Rooney B, Lopez-Gitlitz A, Small EJ (2021) Apalutamide and overall survival in prostate Cancer. Eur Urol 79:150–158. https://doi.org/10.1016/j.eururo.2020.08.011

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Hegele, A., Häußermann, R., Schultheis, S. et al. Apalutamide for non-metastatic castration-resistant prostate cancer (nmCRPC): real world data of a multicenter study. J Cancer Res Clin Oncol 150 , 414 (2024). https://doi.org/10.1007/s00432-024-05928-7

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Meet CRI’s New CEO Alicia Zhou, PhD

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Cancer Research Institute (CRI) Appoints Alicia Zhou, PhD, as Chief Executive Officer to Advance Next Generation of Cancer Immunotherapy Science and Innovation

NEW YORK, NY — The Cancer Research Institute (CRI), the preeminent nonprofit organization focused on advancing breakthroughs in cancer immunology and immunotherapy, announced the appointment of Alicia Zhou, Ph.D. , as its Chief Executive Officer, effective August 26, 2024. Dr. Zhou succeeds Jill O’Donnell-Tormey, Ph.D., who has served as CEO and Director of Scientific Affairs since 1993.

Dr. Zhou’s unique background blends deep academic and industry expertise with a relentless passion for translating scientific innovation into improved outcomes for cancer patients. She holds a B.S. in Biology from the Massachusetts Institute of Technology, a Ph.D. in Biological and Biomedical Sciences from Harvard University, and completed her postdoctoral research in cancer biology at the University of California, San Francisco.

Over the past decade, Dr. Zhou served as the Chief Science Officer at Color Health Inc. In this role, she spearheaded groundbreaking research and scientific initiatives with the goal of ensuring equitable access to cancer prevention and treatment for all patients. While at Color, she established large-scale research collaborations and partnerships, including the American Cancer Society and the National Institutes of Health.

Dr. Zhou’s appointment heralds a bold new era for CRI, seamlessly integrating its pivotal role in the immunotherapy revolution with a visionary approach to the future. Under her leadership, CRI will not only uphold its legacy of pioneering lifesaving innovations but also spearhead breakthroughs in personalized medicine, advanced vaccines, cell therapies, and gene therapies — all grounded in data-driven science and innovation. Dr. Zhou will leverage the institute’s esteemed global network of leading researchers, clinicians, and data scientists to push the boundaries of innovation. Her leadership will propel CRI’s mission with transformative impact, enhancing its influence and establishing a dynamic presence on both coasts, in New York City and the San Francisco Bay Area.

Nobel laureate and CRI’s Scientific Advisory Council Director, Dr. James P. Allison remarked, “I’ve seen firsthand the pivotal role strong leadership plays in driving progress. I’m confident that under her direction, CRI will make great strides as we collectively work to expand the benefits of immunotherapy to more patients.”

Recruiting firm NU Advisory Partners, along with CRI’s Board of Trustees, led a sustained and comprehensive search to identify the organization’s new CEO. The CRI Board of Trustees extends its warmest congratulations to Dr. Zhou on her appointment and expresses its deepest appreciation to Dr. O’Donnell-Tormey for her exceptional leadership and contributions to the organization and the field of immunotherapy.

For press inquiries, please contact [email protected] . To read more about this story, go to: www.cancerresearch.org/blog/september-2024/ceozhou

About Cancer Research Institute

CRI, established in 1953, is the preeminent U.S. nonprofit organization dedicated exclusively to saving more lives by fueling the discovery and development of powerful immunotherapies for all cancers. Guided by a world-renowned Scientific Advisory Council that includes four Nobel laureates and 35 members of the National Academy of Sciences, CRI has invested over $517 million in support of research conducted by immunologists and tumor immunologists at the world’s leading medical centers and universities and has contributed to many of the key scientific advances that demonstrate the potential for immunotherapy to change the face of cancer treatment. To learn more, go to cancerresearch.org .

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“We Are Part of This Excitement:” Husband-and-Wife Cancer Researchers Come to Sylvester

Drs. Erden Atilla and Pinar Ataca Atilla join Dr. Damian Green at Sylvester Comprehensive Cancer Center to research CAR T-cell therapy.

Erden Atilla, M.D., and Pinar Ataca Atilla, M.D., in a wooded area

After living, learning, teaching and conducting research in multiple locations worldwide, Erden Atilla, M.D., and Pinar Ataca Atilla, M.D., are settling in Miami.

As research assistant professors, the medical-scientist couple has joined the immunotherapy research program at Sylvester Comprehensive Cancer Center , part of the University of Miami Miller School of Medicine. They’ve come here to make breakthroughs in CAR T-cell therapy and lay down roots, create a home and raise their young son.

It’s been quite a ride for the Atillas. Erden was born in Samsun, a city on Turkey’s Black Sea coast. Pinar comes from Izmir, in western Turkey. They met as hematology fellows at Ankara University, began working together, became friends, fell in love and married.

The CAR T-Cell Breakthrough

When the Atillas worked on their fellowships, chimeric antigen receptor T-cell therapy emerged. CAR T was a breakthrough.

“The first centers were all in the U.S.,” said Erden. “It was like a dream to use these patients’ own immune cells against their leukemia. We couldn’t remain indifferent to this situation.”

They immediately began to seek training opportunities. Their search brought them first to Baylor College of Medicine in Houston and then to Fred Hutchinson Cancer Center in Seattle.

“T cells are the physiological fighters of cancer,” said Erden. “We’re just trying to enforce their power” by engineering them into CAR T cells.

Today, genetically modified CAR T cells are one of the most powerful tools for fighting cancer.

CAR T-Cell Therapy for Acute Myeloid Leukemia

After moving to Houston, the Atillas used their bone marrow transplant experience at Baylor, working with patients with treatment refractory or relapsed disease in the Center for Cell and Gene Therapy under Malcolm Brenner, M.D., Ph.D. Their research project started with acute myeloid leukemia (AML).

“AML is still one of the toughest challenges in our area,” said Erden.

The Atillas are highly skilled, dedicated and terrific partners who are willing to take some risks, such as moving across the world in the pursuit of advancing science for patients.” —Dr. Damian Green

During the COVID pandemic, the Atillas started a collaboration with University of Granada in Spain. The project involved manufacturing donor (allogeneic) CAR T-cell products for AML, “which will open the way for off-the-shelf availability of CAR T cells,” said Erden.

Thus far, CAR T-cell therapy has been more successful in treating multiple myeloma and lymphoma than AML. The Atillas are set to understand why—and to develop CAR T-cell therapy for AML. The first FDA-approved tumor target was CD19 for B cell lymphoma/leukemia. The second was B cell maturation antigen (BCMA) for multiple myeloma.

With AML, there are more challenges and unforeseen mechanisms that need to be defined.

“That’s why I call it a black hole,” Erden said. “We’re waiting for a big bang on the AML side.”

Shooting for Breakthrough Cancer Discoveries

In Miami, the Atillas work in the lab of Damian Green, M.D., chief of Sylvester’s Division of Transplantation and Cellular Therapy and assistant director of translational research.

“I started working with Dr. Green almost three years ago,” said Pinar. “I was interested in refractory disease and I was enthusiastic about learning about the relapse of these cells.”

“My goal is to build a program that allows us to work in partnership with the community to make breakthrough discoveries,” said Dr. Green. “The Atillas are highly skilled, dedicated and terrific partners who are willing to take some risks, such as moving across the world in the pursuit of advancing science for patients.”

Dr. Green came from the Fred Hutchinson Cancer Center in Seattle, where he worked with the Atillas.

“I hired the Atillas as part of my plan to develop new therapies,” he said.

According to Dr. Green, the new immunotherapy research program can accelerate the time it takes to move processes from the lab to the clinic.

“Our dream is to create the environment in the lab that facilitates rapid translation of our own discoveries to the clinic,” he said. “We’re also unique in that we bring a set of skills that will allow Sylvester to flourish by leveraging our outstanding clinicians’ skills in new ways that put us at the forefront of developing cutting-edge therapies.”

The Right Time for Miami

Erden recalls the couple’s first visit to Miami with their 5-year-old son, Eren. On the campus tour, they were excited to see new buildings being constructed.

“We are a part of this excitement,” he said.

Fittingly, outside the building housing the Atilla’s new laboratory home is a giant Banyan tree.

“These members of the Ficus family are unique because new roots constantly spring from their branches and they are always growing outward,” said Erden.

The Antillas see that kind of growth in Sylvester.

“We definitely want to be part of the growth in T-cell therapy,” Pinar said. “Our aim is to work with the physicians and the researchers at Sylvester to develop CAR T cells and new treatments.”

“And we need some roots,” added Erden.

Tags: Acute Myeloid Leukemia , cancer research , CAR T cells , Dr. Damian Green , Sylvester Comprehensive Cancer Center

Cell Therapy is Now on The Table for Metastatic Melanoma

The first cell immunotherapy for metastatic melanoma patients will soon be available to patients at Sylvester Comprehensive Cancer Center.

Easing the Side Effects of Immunotherapy

A new study shows that treating cytokine release syndrome prior to teclistamab appears to slash the rate of CRS in multiple myeloma patients.

Immunotherapy Program Ready to Tackle Cancer Side Effects

A Sylvester Comprehensive Cancer Center team is working to understand and reduce immunotherapy side effects in cancer patients.

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