Damon Runyon News

Intra-tumoral heterogeneity (ITH), or the evolution of distinct cell types within a tumor, underlies most fatal features of cancer and presents a great therapeutic challenge. Using small cell lung cancer (SCLC), a highly heterogeneous and lethal form of lung cancer, as a model, Dr. Bhattacharya [Robert Black Fellow] will study how ITH arises during cancer progression. She will employ emerging genomics techniques to characterize the cellular subtypes that comprise SCLC tumors and identify “druggable” transcription factors which, if targeted, could reduce tumor heterogeneity in this cancer.

Dr. Ardy [Robert Black Fellow] is investigating the genetic determinants that govern the behavior of fibroblasts, a type of connective tissue cell that has been implicated in arthritis, heart disease, and cancer. Activated fibroblasts can exacerbate disease through various mechanisms, including remodeling tissue architecture and modulating the immune system. Dr.

Skin cancer is the most common type of cancer worldwide, and sun exposure is known to be one of the main risk factors for developing skin cancers. Melanin pigment gives our hair, eyes, and skin their color, and it also shields skin cells from the carcinogenic effects of sun exposure. Combining just one enzyme (tyrosinase) and two substrates (oxygen and tyrosine) in the lab results in the generation of melanin—yet we know that dozens of other proteins affect pigmentation in humans.

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.

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.

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.

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.

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.

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.

Dr. Thawani [Merck Fellow] studies selfish DNA sequences—so called because they copy and paste themselves within the human genome despite offering no specific fitness advantage. Dr. Thawani will utilize advanced methods such as cryo-electron microscopy to reveal the cellular machinery that assists these selfish elements and thus delineate their mechanism of mobility.