Damon Runyon Cancer Research Foundation has announced the 2021 recipients of the Damon Runyon Clinical Investigator Award—six outstanding early career physician-scientists working to develop new cancer therapies under the mentorship of the nation's leading scientists and clinicians.

While there has never been a more pressing need or more promising time for clinical cancer research, fewer young physicians enter this area of investigation every year. Two of the factors contributing to this decline are the critically low number of institutions committed to training young physicians in the methodologies of clinical investigation and the burden of medical school debt discouraging many physicians from pursuing careers in research.

The Damon Runyon Cancer Research Foundation's Clinical Investigator Award offers solutions to these realities. Each awardee receives significant financial support for three years (totaling $600,000 each). The Foundation will also retire up to $100,000 of medical school debt owed by the awardee.

The Foundation also awarded Continuation Grants to three Damon Runyon Clinical Investigators for an additional two years of funding, totaling $400,000 each. The Continuation Grants are designed to support Clinical Investigators who are approaching the end of their original awards and need extra time to work on a promising avenue of research or a clinical trial. This program is possible through the generous support of the William K. Bowes, Jr. Foundation.

"The quality of research proposed by our Clinical Investigators is exceptionally strong. We are thrilled to be funding brave and bold physician-scientists who are taking risks to experimentally address the most important questions in cancer research and then translate them into improving patients' lives," says Yung S. Lie, PhD, Damon Runyon's President and Chief Executive Officer. "We are helping to launch the careers of tomorrow's brightest cancer researchers."

Through partnerships with industry sponsors and its Accelerating Cancer Cures initiative, the Damon Runyon Cancer Research Foundation has committed over $76 million to support the careers of 114 clinical investigators across the United States since 2000.

2021 Damon Runyon Clinical Investigators

Kelly L. Bolton, MD, PhD, with mentors Matthew J. Walter, MD, and Eytan M. Stein, MD, at Washington University School of Medicine, St. Louis

Myeloid neoplasms (MN), including acute myeloid leukemia and myelodysplastic syndrome, are lethal blood cancers. The genetic mutations in the blood that lead to MN can occur years before diagnosis and maintain almost normal function before transformation. Certain mutations, including those in the gene IDH2, have been identified as high-risk for developing MN. Individuals with a reduction in the number of mature blood cells (cytopenias) who harbor acquired mutations in their blood, yet do not meet criteria for a cancer diagnosis, have a condition called cytopenias of undetermined significance (CCUS). These individuals almost invariably develop MN. Dr. Bolton will conduct a clinical trial to evaluate whether the IDH2 inhibitor enasidenib can be used as a therapy for CCUS. She will assess mechanisms of resistance and determine whether enasidenib can prevent the development of MN. This represents the first use of genetically targeted therapy for cancer prevention.

Alexander C. Huang, MD [Damon Runyon-Doris Duke Clinical Investigator], with mentor Gerald P. Linette, MD, PhD, at University of Pennsylvania, Philadelphia

Immune checkpoint inhibitors (ICI), like anti-PD-1 therapy (αPD-1), have transformed clinical oncology by inducing long-term remissions, even in metastatic disease. However, fewer than 40% of cancer patients achieve such long-term remission with αPD-1, and immune-related toxicity limits more aggressive combined approaches, such as anti-PD1 and anti-CTLA-4 therapy. The question remains why a large portion of the immune response generated by combination immunotherapy is directed towards toxicity rather than anti-tumor immunity. A better understanding of the T-cell response to ICI is needed to develop safer and more effective treatment strategies. In humans, CD8+ T-cells are responsible for anti-tumor immunity. Dr. Huang is investigating the immune responses of different types of CD8+ T-cells to αPD-1 and whether they play a role in determining clinical efficacy and immune toxicity.

David Y. Oh, MD, PhD, with mentor Lawrence Fong, MD, at University of California, San Francisco

While immunotherapies such as anti-PD-1 therapy have provided an important treatment option for bladder cancer, the majority of patients do not respond to these regimens. This may reflect the distinct activation requirements of other immune T-cells besides CD8+ T-cells. In recent work, Dr. Oh and colleagues have identified cytotoxic (cancer cell-killing) CD4+ T-cells in human bladder cancer that are associated with immunotherapy responses. However, the regulation of cytotoxic CD4+ T-cells and how these mechanisms compare with CD8+ T-cells is not understood. Dr. Oh proposes to identify and validate surface receptors that enhance or inhibit the activity of cytotoxic CD4+ T cells in human bladder cancer, and the tumor antigens that are recognized specifically by these cells. He will also compare which of these regulatory mechanisms are unique to cytotoxic CD4+ T-cells relative to their CD8+ T-cell counterparts from the same patients. This work has the potential to increase both the proportion of bladder cancer patients who respond to immunotherapy as well as the quality of their response.

Philip L. Palmbos, MD, PhD, with mentor Joshi J. Alumkal, MD, at University of Michigan, Ann Arbor

Although immunotherapy results in improved survival for some patients with advanced bladder cancer, most tumors do not respond, and the molecular drivers of this resistance to immunotherapy are poorly understood. Dr. Palmbos' goal is to use advanced bladder cancer models and patient data to identify the molecular drivers of resistance to bladder cancer therapy and to develop therapeutic strategies to reverse therapy resistance. His group has identified a gene, TRIM29, which is expressed in 70% of bladder cancers and is associated with immunotherapy resistance. TRIM29 is a protein that promotes degradation of STING and other innate immune proteins that drive anti-tumor immune response. He is currently investigating the regulation of the TRIM29-STING pathway and developing strategies to sensitize bladder and other cancer types to immunotherapy.

Sangeetha M. Reddy, MD, with mentors Zhijian (James) Chen, PhD, and Hans Hammers, MD, PhD, at University of Texas Southwestern Medical Center, Dallas

Despite the success of immunotherapies such as immune checkpoint blockade in other solid tumors, breast cancer patients have shown limited responses, especially in cases of metastatic disease. Antigen-presenting cells, critical to initiate anti-tumor immunity and for efficacy of immune checkpoint blockade, are known to be defective in breast cancers. Dr. Reddy's research focuses on restoring effective antigen presentation to enhance anti-tumor immunity in breast cancers. Based on data generated in her lab, she is leading a clinical trial to test the combination of chemotherapy with two therapeutic molecules that promote different aspects of antigen presentation. This trial will assess the safety, clinical efficacy, and pharmacodynamics associated with this triplet therapy. Through this work, she hopes to improve long-term survival of patients with triple negative breast cancer and lay the foundation for systemically targeting antigen presentation as a therapeutic strategy in solid tumors.

Daniel R. Wahl, MD, PhD, with mentors Theodore S. Lawrence, MD, PhD, and Maria G. Castro, PhD, at University of Michigan, Ann Arbor

Glioblastomas are the most common and aggressive primary brain tumors in adults. Despite intensive treatment with therapies such as radiation, these tumors inevitably recur, and fewer than 10% of glioblastoma patients live longer than 5 years after diagnosis. Dr. Wahl and his research team have found that metabolites called purines, which are the building blocks that make up DNA, make glioblastomas resistant to treatments like radiation. Dr. Wahl will use patient samples and mouse models to determine what regulates glioblastoma purine metabolism and whether inhibition of these metabolic pathways can make radiation more effective. He will also perform a clinical study to directly measure these metabolic pathways in patients with glioblastoma.

2021 Continuation Grant Recipients

Collin M. Blakely, MD, PhD, with mentor Trever G. Bivona, MD, PhD, at University of California, San Francisco

Non-small cell lung cancers are frequently driven by specific genetic alterations that can be targeted by precision medicine therapies. However, these therapies often result in partial responses, allowing some cancer cells to survive and become fully resistant to therapy. This ultimately limits patients' long-term survival. Dr. Blakely focuses on a particular type of lung cancer that is driven by mutations in the EGFR gene. This type of lung cancer frequently develops in younger patients who are non-smokers. Treatment of this disease with the targeted therapy osimertinib results in partial (incomplete) responses in the vast majority of cases. His goal is to understand why responses to this treatment are almost always incomplete, and to identify new targets for therapies to be used in combination with osimertinib. Ultimately, the goal of this research is to identify novel combination therapy strategies that can improve the depth and duration of response to targeted therapies, allowing patients to live longer.

Matthew D. Hellmann, MD, with mentors Charles M. Rudin, MD, PhD, and Jedd D. Wolchok, MD, PhD, at Memorial Sloan Kettering Cancer Center, New York

The discovery that the immune system can be used to treat cancers has revolutionized treatment and given new hope for long-term response and survival to patients with lung cancer. Research has demonstrated that there are some predictors of response to immunotherapy, such as tumor mutation burden, which is increased in patients most likely to benefit from immunotherapy. Dr. Hellmann will focus on gaining a deeper understanding of how responses are initiated, how they remain durable, and what features characterize resistance when it occurs. He aims to use this information to build better immunotherapy strategies for patients with lung cancer--to broaden the number of patients who can benefit, improve the depth and durability of response, and have rational strategies for overcoming resistance if it occurs.

Catherine C. Smith, MD [Richard Lumsden Foundation Clinical Investigator], with mentors Neil P. Shah, MD, PhD, and Kevin M. Shannon, MD, at University of California, San Francisco

Acute myeloid leukemia (AML) is one of the deadliest blood cancers. Mutations in the FLT3 gene are the most common mutations in AML and are associated with poor outcomes in both adult and pediatric patients. Despite the importance of FLT3 mutations in AML, we still do not understand how FLT3 is regulated or the functional impact of novel FLT3 mutations identified in recent large AML sequencing studies. Drugs targeting FLT3 have been successful in achieving remission in AML patients but are limited by the rapid development of drug resistance, particularly due to reactivation of abnormal cancer signaling through the oncogene RAS. While signaling inhibitor combinations (i.e., FLT3i +/-MEK or AKT inhibitor) are an obvious strategy to combat RAS-mediated therapeutic resistance, such combinations have been poorly tolerated in AML patients. Using a genome-wide CRISPRi screen, Dr. Smith has identified a novel and exploitable dependency on a molecule called RNA Pol II in FLT3-mutant AML with RAS activation. She will test this hypothesis, which may lay the groundwork for future clinical trials of RNA Pol II inhibitor combinations in AML with RAS activation.