Cancer Research with a Purpose CENTER FOR CANCER RESEARCH U.S. Department of Health & Human Services | National Institutes of Health HIGHLIGHTS 2021–2022 MILESTONES
The colors of the map highlight levels of social vulnerability in the Baltimore area by neighborhood and reflect on social injustice and existing disparities in health experienced by communities of color. Areas in green have a lower social vulnerability score than areas in red. This index indicates a community’s resilience when confronted with a natural disaster, health issue or other stressors. The cover map was inspired by the “Not Even Past: Social Vulnerability and the Legacy of Redlining” project, which was created in partnership with the University of Richmond’s Digital Scholarship Lab and the National Community Reinvestment Coalition. “Not Even Past” used the Center for Disease Control’s Social Vulnerability Index. Changes were made to the original image. Design credit: Allen Kane, Scientific Publications, Graphics and Media, Frederick National Laboratory, NCI, NIH CONTRIBUTORS Pamela Beltowski Brenda Boersma-Maland Chabelis Byamana Colleen Curran Li Gwatkin Veronica Falconieri Hays Michelle Hampson Kelly Haskins Allen Kane Jasmine Lee Joseph Meyer Jennifer Michalowski Mike Miller CENTER FOR CANCER RESEARCH The Nation’s Cancer Center The Center for Cancer Research (CCR) is the largest division of the National Cancer Institute’s intramural research program with nearly 250 basic and clinical research groups located on two campuses just outside of Washington, D.C. The CCR is home to an extraordinary group of scientists and clinicians exploring the cutting edge of cancer and HIV/AIDS research. Our scientists work on a wide spectrum of biological and biomedical problems that range from visualizing and understanding the structure of individual genes and proteins and developing novel methods for drug discovery to inventing biomedical devices and technology and creating innovative ways to treat patients. Our scientists enjoy complete intellectual freedom and are expected to creatively and innovatively explore the most important questions in the field of cancer research and treatment. We support projects over a long time horizon, allowing our investigators to pursue some of the most difficult, high-risk problems in the field, and we are always on the lookout for new challenges and the most pressing problems in modern cancer research. The success of CCR is grounded in an exceptionally strong discovery research program that provides the foundation for the seamless translation of insights into basic cellular and molecular processes to clinical applications and patient care. Examples of our success are the development of groundbreaking immunotherapy approaches, HIV/AIDS testing and the creation of a human papillomavirus vaccine. The CCR is a unique place of sciencewherewe combine diverse expertisewith the freedom to thoroughly pursue themost pressing questions in cancer biology and treatment. For more about our science, our training programs and our clinical trials, visit ccr.cancer.gov.
The MISSION of CCR is to improve the lives of all cancer patients by solving important, challenging and neglected problems in cancer research and patient care through: • A world-leading basic, translational and clinical research and patient care program • An institutional focus on high-risk and long-term projects, unmet needs and pursuit of unexplored ideas • Research to eliminate cancer health disparities • Leadership and coordination of national disease networks and development of technology resources for the cancer community • Partnerships with academic institutions, commercial entities and patient advocacy groups • Training of the next generation of a diverse and inclusive biomedical workforce
Contents 08 Microbiome: Boosted by Bacteria 06 FDA Approval: Decades in the Making 02 Health Disparities: A New Application for an Old Medicine 01 Director’s Note 10 Precision Oncology: One-Two Punch for Cancer 12 Immunotherapy: CAR T Cells for Solid Tumors 20 Cell Biology: Protection Strategy 18 Childhood Cancers: Deciphering DNA Clues 14 Kidney Cancer: Good for Bladder Cancer, Better for Kidney Cancer 22 FDA Approval: Reining in Rogue Immune Cells 16 Breast Cancer: Why Age Is an Advantage 24 Technology Development: Gelling Together Against Cancer 04 Tumor Metastasis: A Real GEMy of a Cancer Treatment 26 Precision Oncology: Divide and Conquer New Faculty 30 34 Awards & Honors CCR by the Numbers 38 CCR Resources 39 28 Microbiome: Better Microbes, Better Immunotherapy
Director’s Note Just as explorers have used maps for centuries, cancer researchers rely on them daily. We use gene maps to identify new cancer drivers, chart cancer pathways and visualize complex gene expression profiles. We also create three-dimensional maps of tumors to target them with radiation, and we increasingly map the complex spatial and functional heterogeneity of tumors at the single-cell level. The cover of this issue of Milestones stands symbolically for the many uses of various types of maps in cancer research. But it is more than a symbol. This map of Baltimore records differences in geographical distributions of social vulnerability, which includes cancer. It dramatically highlights the pressing issue of health disparities. Differences in cancer outcomes vary widely in local and global populations based on complicated socioeconomic factors, race/ethnicity and geographic location. While access to care is a primary cause for health disparities in cancer outcomes, scientists are discovering that other factors, including the environment and disease predispositions, contribute as well. Eliminating disparities in cancer treatment and care is a major goal in CCR. One example of our recent efforts in this area is a study into the molecular foundation of health disparities in prostate cancer featured in this issue of Milestones, which every year highlights some of the most creative, innovative and impactful work of CCR researchers. Despite the challenges of an ongoing global viral pandemic, activities at CCR have continued unabated. Our advances in the past year cover a broad range of cutting-edge topics in cancer research, including progress in basic studies on how genomes protect themselves from damage and new insights into how tumor growth is affected by the host tissue, by the bacterial microbiome of a patient and the age of a patient. We have also made major progress in precision medicine by inventing new ways to accurately diagnose cancers, optimize therapy options for patients and predict treatment responses. Our ultimate goal remains the development of new treatment options for patients and expanding the representation of patients in our clinical trials. These efforts culminated in the past year in the approval by the U.S. Food and Drug Administration of no fewer than four new drugs developed by CCR researchers. In addition, clever new clinical and surgical technology and new ways to harness the immune system for cancer therapy bring new options and hope to patients. Maps help guide and chart our discoveries in cancer research, but even the best maps cannot predict what is ahead. Discovery inherently contains an element of serendipity and adventure. At CCR, we fully embrace the challenges and the opportunities of the unknown as we continue to explore paths towards ending cancer as we know it. TomMisteli Director NCI Center for Cancer Research 1
2 A NEW FOR AN OLD MEDICINE APPLICATION
For thousands of years, a substance derived fromwillow tree bark has been used to treat pain. Today we know it as aspirin. Now, CCR researchers have uncovered how in African American men with prostate cancer, aspirin could also improve outcomes for the disease. This research, led by Senior Investigator Stefan Ambs, Ph.D., M.P.H., and published in the Journal of the National Cancer Institute, increases our understanding of how regular aspirin usemay benefit AfricanAmericanmenby potentially reducing their risk of developing aggressive prostate cancer and dying from the disease. The findings are especially important given that, compared to white men, African American men are more likely to develop prostate cancer and are twice as likely to die from it. Ambs and colleagues initially sought to explore whether the biology of the disease may contribute to these disparities. Through the long-standing NCI-Maryland prostate cancer case-control study, they had access to an ideal pool of patient information. Over many years, the study has recruited men diagnosed with prostate cancer for long-term monitoring to understand what contributes to the excessive burden of disease among African American men. Initial data from the study showed that many prostate tumors found in African American men harbor a distinct immune-inflammation signature that coincides with greater disease severity. Additional research revealed that this signature also occurs systemically. Moreover, a subgroup of African American men with prostate cancer has exhibited elevated levels of the metabolite thromboxane A2 (TXA2), which is primarily produced by the cyclooxygenase (COX) enzyme located in blood platelets. Ambs made a connection to aspirin because of its ability to inhibit the COX pathway. Early evidence suggested that regular aspirin use may protect against lethal prostate cancer in African American men. This prompted Ambs’ team to explore the role of TXA2, aspirin and disease severity and mortality in more detail. Their retrospective study showed that pro-metastatic TXA2 is often higher in African Americanmen with prostate cancer, but not in European American patients, and that high levels of the metabolite more than doubled the chances of developing metastases. Strikingly, African American men in the study who self-reported taking aspirin regularly had lower TXA2 levels and decreased risk of mortality. “It’s exciting and satisfying that we have discovered a mechanism that appears to have a significant effect and could potentially contribute to metastatic and lethal disease in this high-risk population for prostate cancer,” says postdoctoral fellow Maeve Bailey-Whyte, Ph.D., M.P.H., who worked on this study as part of her NCI Cancer Prevention Fellowship. Both Ambs and Bailey-Whyte agree that the NCI-Maryland prostate cancer study, for which recruitment has concluded but long-term data collection continues, is a unique and invaluable resource for studying prostate cancer in an underrepresented population. But they note some difficulties in moving forwardwith a prospective study, particularly because many minority groups are underrepresented in these studies and clinical trials, including African American men. This challenge is compounded by the fact that prostate cancer typically progresses slowly, requiring long-term data collection. “Without long-term studies, we will be unable to assess associations between cancer risk factors and survival outcomes, which may lead to prevention strategies in the future,” says Bailey-Whyte. “It reinforces the importance of including more diverse populations in future trials.” Kiely M, et al. J Natl Cancer Inst. 2021 Jul 15:djab129. Regular aspirin use may limit prostate cancer metastasis in African American men. Regular use of aspirin (shown here in pill andmolecule form) may benefit Black men by reducing their risk both of developing aggressive prostate cancer and of dying from the disease. This image represents a participant in this study, most of whom came from the greater Baltimore area, including patients fromboth the Baltimore Veterans Affairs Medical Center and the University of MarylandMedical Center. Amap of Baltimore is depicted on the front cover in a pattern that informs cancer researchers and the public about inequalities in health. Credit: Alan Hoofring, NIHMedical Arts; iStock Stefan Ambs, Ph.D., M.P.H. Senior Investigator Laboratory of Human Carcinogenesis 3
4 CANCER TREATMENT GEMYOF A A REAL
While treatment advances have greatly benefited patients with cancers diagnosed in early stages, cancers that have metastasized — spread to other parts of the body — still present a major treatment challenge and remain the leading cause of cancer deaths. Understanding how cancers spread, and how to prevent them from doing so, is a high priority in cancer research. In 2005, when still a research fellow at Weill Cornell Medical College and Memorial Sloan Kettering Cancer Center, now Senior Investigator Rosandra Kaplan, M.D., discovered that cancer cells, in addition to manipulating their local microenvironment to survive, can also prime distant areas in the body to promote future metastasis. The areas are known as “pre-metastatic niches,” and research in her lab focuses on better understanding the microenvironmental changes that promote metastasis and disrupt this priming process. This past year, a team led by Kaplan made a major step forward in this research. The results, described in Cell, could potentially yield a novel therapy for patients at high risk of cancer progression and related death. Kaplan and colleagues discovered that cancer cells can hide by causing the immune system to treat a tumor as a wound to be healed. Myeloid cells, which are a part of the immune system’s first line of defense, can either summon T cells, a type of white blood cell, to attack harmful agents like bacteria, viruses and cancer cells, or they can message T cells to stand down, to promote healing. Cancer cells are able to secrete signaling molecules that program myeloid cells into treating the cancer as a wound to be healed, thus encouraging tumor growth. Kaplan, postdoctoral fellows Sabina Kaczanowska, Ph.D., and Daniel Beury, Ph.D., made the important observation that cancer cells disperse signaling molecules to attract myeloid cells to distant pre-metastatic sites in the body that can help cancer spread, specifically to the lungs. Based on this information, the team created genetically engineered myeloid cells (GEMys) that promote an immune attack against cancer cells. The GEMys release a protein called interleukin-12, which recruits T cells to help fight cancer at early metastatic sites. The team tested the GEMys inmice with rhabdomyosarcoma, an aggressive human form of cancer that often spreads to the lungs. Mice treated with the novel therapy, along with a dose of chemotherapy, experienced a complete remission of their tumors. The tumors did not come back over the course of the 250-day study. “When we took these cured mice and tried to implant them with a new tumor, they were resistant to the tumor,” Kaplan says. Although this therapy was initially designed to treat cancer metastasis, Kaplan says that the original tumors in mice also responded to the treatment. Her team will continue to study GEMys as a possible therapy for advanced cancer before exploring its potential for treating early-stage disease. “I hope, even in a small way, we can make things better for patients with a high risk for metastasis or recurrent disease,” Kaplan says. Kaczanowska S, Beury DW, et al. Cell. 2021 Apr 15;184(8):2033-2052.e21. A novel therapy could prevent cancer from spreading. Tumor metastasis is an area of cancer research that is both a challenge and a high priority. Researchers previously discovered that cancer cells can prime distant locations in the body to enable metastasis. In this study, researchers created genetically engineered myeloid cells (GEMys) to promote immune responses in these primed locations. This unique “gem” of an approach, symbolized by the gemstones in this image, provides a novel method to stop cancer from spreading. Credit: iStock Rosandra N. Kaplan, M.D. Senior Investigator Pediatric Oncology Branch 5
6 INTHE DECADES MAKING
In von Hippel-Lindau (VHL) disease, patients develop many cancerous and non-cancerous tumors in the kidneys and other organs, such as the pancreas, brain and eyes. They often undergo repeated surgeries to remove their tumors as no other VHL therapy has been available. Following decades of CCR-led research on VHL that included the identification of the gene behind the disease in the 1990s, and work done in institutions around the world, a team led by Investigator Ramaprasad Srinivasan, M.D., Ph.D., tested the drug belzutifan (Welireg™) for VHL. It is now the first and only U.S. Food and Drug Administration (FDA) approved systemic therapy for certain patients with the disease. VHL disease develops when a mutation in the VHL gene occurs, making people unable to produce a protein that cells use for sensing and adapting to changes in oxygen levels. Cells respond by accumulating an excessive amount of several proteins called hypoxia-inducible factors (HIFs). Increased levels of HIFs can lead to tumor growth and the formation of new blood vessels that supply nutrients to the tumors. Scientists have been interested in targeting HIFs, particularly HIF2, to treat VHL-associated tumors. But directly targeting and inhibiting HIFs has proven difficult. A breakthrough came when researchers at the University of Texas Southwestern Medical Center designed several small-molecule drugs that could block the activation of HIF2 through what was considered “brilliant engineering,” according to Srinivasan. One of these drugs was belzutifan. When the time came to test belzutifan in patients, Merck & Co., Inc., the company behind the drug, turned to Srinivasan and other CCR researchers with established expertise in VHL disease and patient groups. Srinivasan, in collaboration with physician Eric Jonasch, M.D., University of Texas MDAnderson Cancer Center, recruited 61 patients with VHL and tested belzutifan in a phase II clinical trial at 11 centers in the United States, Denmark, France and the United Kingdom, including the U.S. National Cancer Institute and the NIH Clinical Center. A few months after the first patient was treated with belzutifan, Srinivasan reviewed an imaging scan to assess the patient’s response to treatment. He says he was “elated” with what he saw: dramatic tumor shrinkage. “This was a very emotional moment for all of us,” says Srinivasan, who has been studying VHL disease since the early 2000s. “We were overjoyed.” According to the results, published in the New England Journal of Medicine, most patients in the trial experienced tumor shrinkage in their kidneys, with about half of patients experiencing tumor shrinkage of 30 percent or more. Moreover, belzutifan was able to shrink or stop the progression of tumors in organs such as the pancreas, brain, spinal cord and eyes to an extent that has not been seen with other drugs tested for VHL disease. Srinivasan notes that the vast majority of patients remain enrolled in the trial and continue taking belzutifan because of its benefits and relatively few side effects. As a result of this research, the FDA approved belzutifan in 2021 for patients who require therapy but not immediate surgery and have VHL disease-associated renal cell carcinoma, pancreatic tumors or central nervous system hemangioblastomas. “In every respect you can imagine, we found this drug to be a big, big step in the right direction. It’s effective, it’s well-tolerated — everything that we could ask for in the first study of this agent in VHL,” says Srinivasan. “We now have a reasonable alternative to surgery for some patients.” Jonasch E, et al. N Engl J Med. 2021 Nov 25;385(22):2036-2046. New drug proves effective at shrinking von Hippel-Lindau-associated tumors. Kimbre Hall first came to the NIH Clinical Center in 2008 for laparoscopic surgery to remove a von Hippel-Lindau (VHL) disease-associated kidney tumor. After the surgery, she made regular trips from her home in Washington state to NIH to monitor the size of her other tumors. During this time, she developed a pancreatic neuroendocrine tumor. About four years ago, Kimbre learned about a trial using belzutifan for VHL-associated renal cell carcinoma. “I wanted to avoid surgery as much as possible, so I joined the trial at NIH,” she says. Since then, her kidney lesions have remained stable or decreased in size. “My favorite outcome is that my pancreatic tumor shrank so much they can’t see it,” she says. “I’m glad I joined this trial, and I feel so happy that it’s gone this well. It was an honor to be a part of it.” Kimbre hopes that this now FDA-approved drug will someday help others like her, including her family members who have VHL syndrome. Credit: Chris Hall Ramaprasad Srinivasan, M.D., Ph.D. Investigator Urologic Oncology Branch 7
8 BOOSTED BY BACTERIA
A tumor’s fate depends not just on the tumor alone. An entire community of cells influences how cancer grows, spreads and responds to treatment. Amazingly, that includes microbes that live in our guts. It has become clear that some gut bacteria can help the immune system keep tumor growth in check — and CCR scientists have now figured out one way bacteria do it. Stadtman Investigator Romina Goldszmid, Ph.D., and her team are studying how gut microbes affect tumors by looking at an important aspect of anti-tumor immunity: the white blood cells of the innate immune system. The innate immune system provides a first-line defense against cancer and invading pathogens. Its cells are usually well represented at tumor sites, where they both attack the threat directly and summon other immune cells to the fight. Goldszmid’s team has shown in animal studies that having a community of microbes in the gut is important for the innate immune system’s ability to defend the body against tumors. In mice raised in a sterile environment, whose guts remain microbe-free, innate immune cells are still present at tumor sites. But when Goldszmid’s team analyzed those immune cells, they found that the mix of cell types was different from the mix found at the tumor sites of mice with gut microbes. The tumors of microbe-free mice even contained innate immune cells that had been programmed to support tumor cells’ growth, rather than destroy them. In work reported in Cell, graduate student Khiem Lam and postdoctoral fellow Romina Araya, Ph.D., traced these differences to the absence of molecular signals produced by bacteria that activate an immune-stimulating pathway called STING. They found that when a normal mix of bacteria is present in the gut, some of those bacteria produce molecules that enter immune cells calledmonocytes; the molecules activate the STING protein to induce production of the immune mediator type I interferon (IFN). Type I IFN then triggers changes that help the innate immune system rally an antitumor defense. Goldszmid and her colleagues have reason to believe gut microbes may use the same signals to modulate anti-tumor immunity in patients. Other researchers have noted that the microbial communities in the guts of patients successfully treated with cancer immunotherapy are comprised differently from those of patients who do not respond to this treatment. And when Goldszmid’s team transferred the gut microbes of patients responsive to therapy to microbe-free mice, they saw a similar shift toward anti-tumor immunity, activated again by the STING pathway. Through analysis of published datasets, the researchers found an enhancement of the same innate immune signatures and type I IFN in the tumors of patients that responded to treatment. In their animal experiments, Goldszmid’s team identified several ways to boost gut microbes’ anti-tumorigenic immune signals, including a simple shift to a high-fiber diet. Goldszmid hopes that figuring out how microbes manipulate the innate immune system will lead to new ways to use the microbes in a patient’s gut to their benefit. Lam KC, Araya RE, et al. Cell. 2021 Oct 14;184(21):5338-5356.e21. Gut bacteria promote anti-cancer immunity by activating a key innate immune signaling pathway. Gut microbiota can influence the response to cancer therapy, and CCR researchers are beginning to understand how. This diagram illustrates how gut bacteria, depicted as different colored shapes in the bottom left-hand pink structure (the intestines) send signals (blue waves) to reprogram innate immune cells inside tumors (top right-hand side) and shape the anti-cancer immune microenvironment. Credit: Romina Goldszmid and Romina E. Araya, CCR, NCI, NIH Romina Goldszmid, Ph.D. Stadtman Investigator Laboratory of Integrative Cancer Immunology 9
10 ONE-TWO PUNCH FOR CANCER
Identifying a pathway mutation in a patient’s tumor and using it to guide cancer treatment has become a standard approach to designing personalized cancer treatments. Identifying two pathways that work synergistically may be even better. A team of computational researchers at CCR have developed a new algorithm, called SELECT, to predict the best treatment strategies for multiple tumor types.1 SELECT uses the powerful concept of synthetic lethality — where the combination of mutations in two pathways packs a one-two punch that results in cell death whereas a mutation in only one pathway alone does not. The team, led by Senior Investigators Eytan Ruppin, M.D., Ph.D., and Kenneth Aldape, M.D., is using SELECT to identify such pathway pairs and partner them with drugs that can disable a pathway in a cancer cell that already contains a mutation in another. Importantly, SELECT complements current precision oncology approaches that rely on genomic data by analyzing tumor transcriptome information, which represents the complete set of RNA molecules present in a cell and better reflects the cell’s functional status. The algorithm, described in Cell, also leverages another type of interaction called synthetic rescue, where a pathwaymutation reduces the cell’s viability, but a mutation in a different pathway rescues the cell from death. The team is using this information to predict whether checkpoint therapy — a type of immunotherapy — might benefit a patient. To test SELECT, the researchers used numerous publicly available datasets from targeted, chemotherapy and immunotherapy clinical trials and found that it can predict the efficacy of therapies in individual patients with 80 percent accuracy, outperforming existing prediction models. Ruppin has been developing prediction algorithms since 2013, and SELECT is his fourth such model. He says that the SELECT algorithm is among the most comprehensive current predictive approaches in oncology but underscores the need for more data to improve the algorithm. “Conceptually, what we are trying to do is actually quite simple. It is the details that are complicated, and sorting them out requires more work and patient data,” he emphasizes. To obtain enough data for the latest version of SELECT, Ruppin partnered with Aldape with whom he shares a vision of using additional molecular information, such as tumor methylation, proteomics and liquid biopsies, to develop better treatment strategies. Going forward, with the support of CCR leadership and in collaboration with many clinical colleagues at the NIH Clinical Center, Aldape and Ruppin hope that their tool will stimulate the development of precision oncology-based trials. These trials would prospectively test SELECT’s ability to improve patient treatment and collect more data that could in turn lead to improvements in the underlying SELECT prediction algorithms. Plans are underway to conduct studies in brain, breast, bladder and kidney cancers, among others. Lee JS, et al. Cell. 2021 Apr 29;184(9):2487-2502.e13. A new algorithm to SELECT the best therapy helps advance precision oncology. Normal cells can have two pathways for certain essential biological functions in case one fails. In this study, researchers developed a computer algorithm to identify cancer cells that have disabled such backup pathways. By finding cells that already have a mutation in one pathway, the researchers can knock out the second pathway to cause cell death via a “one-two punch.” Credit: Natalie Runnerstrom 11 1SELECT stands for SynthEtic LEthality and rescue-mediated precision onCology via the Transcriptome. Eytan Ruppin, M.D., Ph.D. Chief Cancer Data Science Laboratory Kenneth Aldape, M.D. Chief Laboratory of Pathology
12 CAR T CELLS FOR SOLID TUMORS
The emergence of chimeric antigen receptor (CAR) T-cell therapy has provided renewed hope for many patients with blood cancers who have not benefited from traditional therapies. However, ways to use this therapy for many other cancers have remained elusive — until now. Senior Investigator Mitchell Ho, Ph.D., and colleagues have discovered a way to target solid tumors through CAR T-cell therapy. In CAR T-cell therapy, physicians program a patient’s immune cells to recognize unique proteins on the surface of cancer cells to help them better target and kill the cancer. The key to success, however, is to target a protein that is found only on the cancer cells, not on healthy ones. While CAR T cells can safely target and destroy lymphoma and leukemia blood cells without harming other organs in the body, researchers have struggled to identify tumor-specific proteins that can be used in CAR T-cell therapy to target solid cancers without harming healthy organs in the process. Ho is in a unique position to solve this problem because he studies proteins that are only expressed in cancers. In 2014, Ho and postdoctoral fellow Nan Li, Ph.D., began to investigate one such protein, called GPC2. Early evidence showed that it is expressed in neuroblastoma, an extremely rare and notoriously difficult-to-treat form of cancer that mainly affects children. As Li studied GPC2 and investigated its prevalence in healthy human tissues, she found that almost all the tissues were GPC2-negative, which made GPC2 an ideal candidate for CAR T-cell therapy with the potential to treat neuroblastoma. The team reported their finding in Proceedings of the National Academy of Sciences. As a next step, the researchers sought to engineer a new type of CAR T cell capable of targeting GPC2. They identified an antibody called CT3, which is a protein that can bind to GPC2 but not to other targets. The researchers then modified T cells to express CT3, which helps the immune cells better target, bind to and kill GPC2-expressing cancer cells. When it came time to test their CAR T cells, their efforts proved fruitful. “With only a single CAR T-cell treatment, we could see a dramatic effect,” says Ho. “In all preclinical models we looked at, our CAR T cells showed activity against neuroblastoma, leading to complete remission of tumors in mice.” The results were described in Cell Reports Medicine. As a next step, the team is partnering with the Pediatric Oncology Branch to test this therapy in a first-in-human clinical trial led by Rosa Nguyen, M.D., Ph.D., a Physician-Scientist Early Investigator, with funding from the NCI Cancer MoonshotSM program. “If this therapy proves beneficial for patients, it would be a remarkable achievement in a short timeline,” Ho says, noting that the full spectrum of research on GPC2 CAR T cells — from basic science to a clinical trial — will be done by CCR. Ho, Li and Nguyen believe that this new therapy could improve outcomes for patients with neuroblastoma andmay even apply to other solid tumors. Li N, et al. Proc Natl Acad Sci U S A. 2017 Aug 8;114(32):E6623-E6631. Li N, et al. Cell Rep Med. 2021 Jun 1;2(6):100297. CAR T-cell therapy homes in on a new target: neuroblastoma. In this scanning electron microscopy image, CAR T cells attack a lung cancer cell, colored in blue at the center of the image. CAR T cells are immune cells that are artificially programmed to recognize unique proteins on the surface of cancer cells. Researchers discovered that CAR T cells can be programmed to fight neuroblastoma, an extremely rare and aggressive form of cancer that mainly affects children. Credit: Steve Gschmeissner/Science Photo Library Mitchell Ho, Ph.D. Deputy Chief Laboratory of Molecular Biology 13
14 GOOD FOR BLADDER CANCER, KIDNEY CANCER BETTER FOR
Some discoveries lead you in unexpected directions. When Senior Investigator Andrea Apolo, M.D., sought to explore a new combination of drugs for treating bladder cancer, the results yielded impressive benefits in another tumor type. Apolo had enrolled patients with bladder cancer as well as several patients with other genitourinary tumors including renal cell carcinoma (RCC), the most common form of kidney cancer, in a phase I clinical trial to evaluate drug safety. While the bladder cancer patients benefited from the drug combination, the patients with kidney cancer did even better and were twice as likely to experience an overall response. Their tumors shrank more than 30 percent from their original size. These initial results prompted Apolo and her colleagues, oncologists Toni Choueiri, M.D., Dana-Farber Cancer Institute, and Robert Motzer, M.D., Memorial Sloan Kettering Cancer Center, to study the novel drug combination in a larger clinical trial, specifically in patients with RCC. The positive results from this phase III trial, reported in the New England Journal of Medicine, led to U.S. Food and Drug Administration (FDA) approval of cabozantinib (Cabometyx®) combined with nivolumab (Opdivo®) for RCC in 2021. The combination is now considered a first-line therapy for patients with the disease. Cabozantinib works by inhibiting the activity of multiple protein receptors in cancer cells that are associated with tumor growth, thereby limiting the formation of new blood vessels that supply the tumor with nutrients and stopping the spread of cancer. Apolo initially studied cabozantinib with collaborators in the lab, and as she began to study the drug in patients, she realized that it was not only able to affect protein receptors in cancer cells, but it also interfered with the ability of cancer cells to manipulate the immune system for survival. This finding provided the rationale to pair cabozantinib with nivolumab for treating patients with RCC. Nivolumab is a checkpoint inhibitor that works by boosting the immune system’s ability to kill cancer cells. In the phase III trial, participants were given either the combination of cabozantinib and nivolumab or the drug sunitinib (Sutent®) alone, which is a standard therapy for kidney cancer that blocks a key enzyme needed for cancer growth. Although patients who received the novel drug combination experienced more adverse side effects, they had a longer progression-free survival period of 16.6 months, compared to 8.3 months for patients given sunitinib. “I knew this combination would be extremely effective in RCC based on the early phase I results,” Apolo says. “There were no patients treated with this combination that did not have some kind of response or, at minimum, stable disease — nobody’s disease progressed.” Apolo not only initiated the research of this drug combination for bladder cancer and RCC, but she guided the clinical trials that, in less than three years, led to FDA approval of the combination therapy. She notes that patients living with RCC have had few new treatment options for decades. “It feels amazing to have identified a newway to treat this cancer and to see it approved and helping patients,” she says. Apolo attributes her team’s ability to move quickly from a phase I to a phase III trial to support from the Cancer Therapy Evaluation Program, which oversees national extramural clinical trials funded by the National Cancer Institute, including cooperative research and development agreements for this study with industry partners Exelixis, Bristol Myers Squibb and Pfizer. “The NIH is a wonderful place,” Apolo says, “because of the basic laboratory resources and clinical trial infrastructure, which helps us conduct these kinds of trials that can eventually lead to effective cancer therapies.” Choueiri TK, et al. N Engl J Med. 2021 Mar 4;384(9):829-841. A novel drug combination becomes the standard of care for kidney cancer. CCR scientists discovered that a treatment being tested in bladder cancer patients was surprisingly effective in patients with kidney cancer. Upon this discovery, the treatment, represented in yellow, received FDA approval in less than three years following clinical testing. This image illustrates how abundant basic laboratory resources and robust clinical trial infrastructure at NIH can accelerate cooperative research and quickly lead to effective cancer therapies. Credit: Veronica Falconieri Hays, Falconieri Visuals, LLC Andrea B. Apolo, M.D. Senior Investigator Genitourinary Malignancies Branch 15
16 ADVANTAGE WHYAGE IS AN
The risk of being diagnosed with breast cancer increases with age. Yet, the risk of a poor outcome is higher for women who are diagnosed when they are young. Although only seven percent of women diagnosed with breast cancer are 40 years of age or younger, many of those cancers are lethal. Patients in this age group usually endure intense treatment, but many find their disease recurs and spreads. Compared to patients diagnosed later in life, they are more likely to develop metastatic tumors in the brain. The tumors can be treated with radiation or surgery, but they often return. Scientists have struggled to understand the more aggressive nature of breast cancer in young women. Now, Senior Investigator Patricia Steeg, Ph.D., and her team think they have an answer. The key difference between young and old, they say, may be less about the tumor cells themselves, and more about the tumor microenvironment in which those cells travel and grow. Steeg’s team has found evidence in animal studies, reported in Clinical Cancer Research, that a younger immune system supports breast cancer’s metastasis to the brain, whereas an older immune systemmakes the brain less hospitable to migrating breast cancer cells. To investigate whether identical cancer cells behave differently in young animals than they do in older ones, Steeg, Senior Investigator Lalage Wakefield, D.Phil., and postdoctoral fellow Alex Man Lai Wu, Ph.D., injected human breast cancer cells into mice of different ages and then monitored those mice for metastases. The mice in their experiments developed similar numbers of metastatic tumors in their livers and lungs, regardless of age. But the situation was different in the brain. Steeg’s team found up to four times more metastases in the brain of young animals than in older animals. The team traced this effect to age-related differences in the immune system. They found that in young animals, the brain contains more infiltrating macrophages and microglia — immune cells that are capable of both fighting tumors and protecting them, depending on circumstances. Macrophages and microglia were not only more abundant in the brains of young animals, they also behaved differently. According to the team’s experiments, in the brains of young animals, these immune cells promote the survival of metastatic cancer cells. Based on her team’s findings, Steeg is optimistic that modifying the immune environment might help stave off brain metastasis in young patients with breast cancer. The young mice in their experiments developed significantly fewer brain metastases when they were given a drug that reduced macrophages and microglia, making the immune environment in their brains more closely resemble that of older mice. They were able to achieve this by inhibiting an immune-system regulator called colony-stimulating factor-1 receptor. Steeg hopes a similar approach might benefit young patients with breast cancer, and she has begun investigating potential candidates for clinical studies. Wu AML, et al. Clin Cancer Res. 2021 Aug 1;27(15):4422-4434. Surprisingly, young immune systems may support breast cancer metastasis to the brain. CCR researchers studying mice found that a younger immune system supports the metastasis of breast cancer cells to the brain whereas an older immune systemmakes the brain less hospitable to breast cancer cells. On the left, an older woman’s silhouette is overlaid with a scene of small metastatic tumors and a few immune cells and neurons. On the right, in a younger woman’s silhouette, there are many more metastatic tumors, neurons and immune cells. In the team’s experiments, they found that immune cells in a younger setting promote the survival of metastatic breast cancer cells. Credit: Veronica Falconieri Hays, Falconieri Visuals, LLC Patricia S. Steeg, Ph.D. Deputy Chief Women’s Malignancies Branch 17
18 DECIPHERING CLUES DNA
Genetic analyses have become a critical part of many cancer diagnoses, and CCR scientists are seeking to expand the impact of this technology. They have teamed up with colleagues around the world to pore over DNA from patient samples, looking for patterns that reveal the presence of cancer or hint at the future behavior of a tumor. Their recent discoveries could lead to more personalized treatments for patients with the childhood cancer rhabdomyosarcoma and more reliable cancer screenings for people with another childhood condition, neurofibromatosis type 1 (NF1). Children diagnosed with rhabdomyosarcoma, a cancer that begins in the cells that give rise to muscle tissue, are usually treated with a combination of chemotherapy, radiation and surgery. Doctors use clinical features, such as the size and location of tumors, to determine how aggressive this treatment should be. These criteria are good at identifying patients whose risk of poor outcomes is particularly high or low, but most patients fall somewhere in between, where outcomes are difficult to predict. New findings from the largest-ever international study on rhabdomyosarcoma, led by Senior Investigator Javed Khan, M.D., and Lasker Clinical Research Scholar Jack Shern, M.D., will help clinicians refine their diagnoses and offer patients more personalized treatment plans. The CCR team and collaborators at the Institute for Cancer Research in London, U.K., analyzed DNA from the tumors of more than 600 children with rhabdomyosarcoma, focusing on 39 genes linked to the disease. They discovered that outcomes tended to be worse for patients whose tumors had mutations in a small handful of genes, including TP53, MYOD1 or CDKN2A, as reported in the Journal of Clinical Oncology. Additionally, patients with more than one mutation that drive cancer progression fared particularly poorly. This information is now guiding the design of clinical trials and will help in the development of new experimental therapies. Another application that is quickly becoming useful in diagnosing and monitoring pediatric patients is the genomic profiling of circulating tumor DNA. Shern collaborated with a team at Washington University School of Medicine in St. Louis, led by assistant professors Angela Hirbe, M.D., Ph.D., and Aadel Chaudhuri, M.D., Ph.D., to analyze DNA isolated from the blood of people with NF1 in search of a better way to detect malignant tumors. NF1 is a condition that can cause large growths to develop along nerves throughout the body. Most of these remain benign, but sometimes they turn into aggressive cancers, and evenwith regular MRI (magnetic resonance imaging) scans, it can be difficult to spot those that do. Shern’s team focused on DNA shed by cells into the blood, which included short fragments from tumor cells. When they sequenced the circulating DNA and compared the results of patients who had benign NF1 tumors to those from patients with malignant tumors, they found several features that set them apart. The discovery, reported in PLOS Medicine, suggests it may be possible to distinguish between benign and malignant tumors in patients with NF1 with a simple, non-invasive blood test. Because the amount of tumor DNA in the blood dropped when patients’ malignant tumors shrank following treatment, a liquid biopsy might also be used to monitor how patients respond to therapy. Khan and Shern are eager to see these genomic profiling tools move out of the lab to become routine for pediatric patients and help people with rhabdomyosarcoma and NF1. Shern JF, et al. J Clin Oncol. 2021 Sep 10;39(26):2859-2871. Szymanski JJ, Sundby RT, et al. PLoS Med. 2021 Aug 31;18(8):e1003734. Genetic analyses improve the detection and diagnosis of childhood cancers. Camp Fantastic (CF), a week-long adventure at which Dr. Jack Shern serves as lead physician, lets children with cancer and neurofibromatosis “just be kids.” Since 1983, the camp has offered outdoor activities, and since COVID, virtual offerings like crafting and online science. Pictured clockwise from top left: Travis Carpenter creates paper flowers at Virtual CF 2020; Ryan Kovacs launches a water balloon at CF 2019; (from left) Taylor Caquias, Dominic Ortega, Tsadet Brannon, Campbell Brandt and Carolyn Shaffer enjoy some teen time at CF 2019; Abby Furco flanked by CF 2018 staff K School (left) and Sarah Rostock (right); and Becca Chamberlain goes horseback riding at CF 2019. CF is a partnership between the National Cancer Institute (NCI) and Special Love, Inc., a Northern Virginia charity that also provides programming and financial assistance for siblings and young adults. “It’s wonderful that the NCI can provide a safe environment where patients and survivors can feel normal and connect to other kids who understand what they’re going through,” says Shern. Credit: Special Love, Inc.; iStock Javed Khan, M.D. Deputy Chief Genetics Branch 19 Jack F. Shern, M.D. Lasker Clinical Research Scholar Pediatric Oncology Branch
PROTECTION STRATEGY 20
Chromosome ends need special care. To a cell, the free strands of DNA at the end of chromosomes may look like pieces of broken DNA that need to be repaired. This would be detrimental because it would lead to the fusion of chromosomes. A DNA-protein complex, called a telomere, caps each chromosome end, protecting and hiding it from the DNA damage-response pathway. Telomeres gradually shorten as we age until eventually, cells lose their ability to divide because their telomeres become too short. To continue their growth, cancer cells must circumvent this limit, and understanding how telomeres work is important for finding better ways to keep cancer cells in check. Almost all of our cells use the same strategy to guard their telomeres against inappropriate DNA repair, but researchers led by Senior Investigator Eros Lazzerini Denchi, Ph.D., have discovered that embryonic stem cells — cells that arise early in development and have the potential to become virtually any of the body’s specialized cells — have a unique way of dealing with this problem. Findings that the team reported in Nature suggest that embryonic stem cells may be able to elongate vulnerable telomeres to avoid triggering a problematic DNA damage response. In their studies of mouse embryonic stem cells, Lazzerini Denchi and colleagues found that these cells can grow without a protein called TRF2. This was surprising because, for most other cell types, TRF2 is an essential telomere protection protein. Without it, chromosomes usually fuse together, and cells lose their ability to divide. Postdoctoral fellow Marta Markiewicz-Potoczny, Ph.D., found that when she eliminated TRF2, embryonic stem cells activated a set of genes that are usually only turned on in a newly fertilized egg. One of these, ZSCAN4, appears to be a key part of these cells’ unusual strategy for protecting their chromosome ends. Notably, this gene is sometimes active in cancer cells — so the discovery may tell us something about how cancer cells grow. Lazzerini Denchi notes that most cancer cells evade telomere-imposed growth limits by reactivating an enzyme called telomerase, which rebuilds chromosomes’ shortening ends. But about 10 percent of cancers manage to extend their telomeres without telomerase — and many of these cancers are particularly aggressive. If ZSCAN4 turns out to be important for enabling such cells to escape growth restrictions without telomerase, it might point researchers toward new targets for drug development. Markiewicz-Potoczny M, et al. Nature. 2021 Jan;589(7840):110-115. An unusual means of chromosome protection sheds light on cancer cell growth. For most cells, a protein called telomere-associated factor TRF2 is essential for protecting the ends of chromosomes. Without it, chromosomes usually fuse together, and cells lose their ability to divide. These images show the consequences of TRF2 deletion in differentiated cells, with DNA labeled in red and telomeres in green. CCR scientists have discovered that for embryonic stem cells, however, TRF2 may not be essential. This understanding may help to find better ways to keep cancer cells in check. Credit: Marta Markiewicz-Potoczny, CCR, NCI, NIH Eros Lazzerini Denchi, Ph.D. Senior Investigator Laboratory of Genome Integrity 21
22 ROGUE REINING IN IMMUNE CELLS
A life-saving hematopoietic stem cell transplant, which replaces cancerous cellswithahealthy immune system, allows many patients diagnosed with certain blood cancers to live for years with their cancer in remission. However, the treatment is not without side effects. One complication is chronic graft-versus-host disease (GVHD), an autoimmune-like condition with a wide range of potential symptoms. Because of work by CCR investigators, patients have a new option to treat the condition. In 2021, belumosudil (Rezurock™) became the first drug developed specifically to treat chronic GVHD to be approved by the U.S. Food and Drug Administration (FDA). Scientists at CCR have a long history of studying chronic GVHD. The disease has become more prevalent in the past few decades as increasing numbers of patients have received and recovered from stem cell transplants. Beginning in the early 2000s, Senior Clinician Steven Pavletic, M.D., M.S., led colleagues across NIH in an interdisciplinary effort to develop the clinical tools and diagnostic criteria that researchers needed to study the complex disease and evaluate potential treatments. Chronic GVHD develops when transplanted immune cells (the graft) attack a recipient’s tissues. The disease can cause a myriad of incapacitating problems, including thickening of the skin, the formation of scar tissue, dry eyes and mouth, painful joint stiffness as well as liver and lung disease. Chronic GVHD is usually treated with corticosteroids, but this only works for some patients. Even for those who respond well, steroid treatment is not suitable for long-term use due to significant side effects, though for most patients, chronic GVHD persists for years. Because the disease can affect nearly any organ in the body, Pavletic and the GVHD working group drew on expertise from across many fields of medicine to develop consensus guidelines on how to diagnose the disease and assess its severity. That work built the foundation for clinical studies, planned and coordinated in part by Pavletic and CCR colleagues, to test the safety and efficacy of belumosudil. They reported in Blood that the drug can reduce symptoms of treatment-refractory chronic GVHD and improve patients’ quality of life. Belumosudil treats chronic GVHD by blocking a signaling protein called ROCK2. This both reins in the activity of rogue immune cells and prevents the buildup of scar tissue. Pavletic, transplant physician Corey S. Cutler, M.D., M.P.H., F.R.C.P.C., Dana-Farber Cancer Institute, and colleagues tested the drug in a phase II clinical trial conducted at sites around the country. The trial included 132 participants who were in remission from cancer and had received prior treatments for chronic GVHD. Investigators on the trial relied on the guidelines established by Pavletic’s group to evaluate patients’ response to the treatment. Symptoms improved for three-quarters of trial participants, including many whose condition at the outset of the study was considered severe. Seven participants had a complete response, with complete resolution of symptoms in all eight of the organs that were evaluated for the study. Based on these findings, the FDA approved belumosudil as a treatment for chronic GVHD in patients for whom at least two other treatments have failed. It is now one of only three drugs approved since 2017 for treating the condition. Ongoing research aims to identify ways of predicting which treatment is best for an individual patient. Cutler C, et al. Blood. 2021 Dec 2;138(22):2278-2289. FDA approves new treatment for chronic graft-versus-host disease. Stephanie Britton received an allogenic stem cell transplant in June 2019 following a diagnosis of acute lymphoblastic leukemia. In October 2020, she was diagnosed with chronic GVHD after she noticed scaling as well as tight and itchy skin on her body, which limited her mobility and caused great discomfort. “I think it impacted about 80 percent of the skin all over my body,” she says. As a mother of three small children, it affected her daily life. After trying four different therapies with few results, she joined the ROCKstar study and immediately started to feel better. She noticed that her skin wasn’t as thick and itchy, tightness had been reduced, and her comfort level changed dramatically. Stephanie thanks the clinical team for her experience on the trial. “They’ve been so accommodating,” she says. “I have felt so blessed to have access to the amazing team at NIH.” Credit: Charlie Chang, NIH Events Management; Jacqueline W. Mays, NIDCR, NIH (background cells) Steven Z. Pavletic, M.D., M.S. Senior Clinician Immune Deficiency Cellular Therapy Program 23
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