Modern molecular characterization of tumors of the urinary bladder has illuminated cellular pathways that may be important for bladder cancer development. Dr. Arora is investigating the role played by a family of proteins called nuclear receptors in driving bladder cancer development and progression. These studies will provide insights into the fundamental basis of bladder cancer, while validating potential drug targets. Nuclear receptors are particularly attractive drug targets because they are highly amenable to modulation with drugs. He hopes to pave the way for the development of drugs to effectively target nuclear receptors in bladder cancer.

Squamous cell carcinoma (SCC) can occur on a number of epithelial surface tissues ranging from the skin and lung to the esophagus and oropharynx, and collectively, are the most common form of cancer in the world. Recent sequencing studies have found that mutations in epigenetic regulators that control gene expression frequently occur in all forms of SCC. Dr. Capell aims to harness the great accessibility of human skin to understand how altered epigenetics promotes cutaneous SCC. Given that epigenetic changes are inherently reversible and numerous epigenetic drugs are currently in development, he hopes that by understanding these mechanisms he will identify better therapies for these incredibly common and potentially deadly cancers.

Dr. Didychuk is investigating the mechanism by which the Kaposi’s sarcoma herpesvirus (KSHV) co-opts the cellular host machinery to produce its own gene products in a manner distinct from other viruses and host cells. This research should reveal insights into this unique mode of transcriptional control. KHSV is an oncogenic virus that causes various cancers including, Kaposi’s sarcoma, primary effusion lymphoma, and multicentric Castleman’s disease, in immunocompromised individuals.

Dr. Durbin is developing new ways to target neuroblastoma, using chemical inhibitors and genetic techniques to disrupt small RNA species and enzymes that neuroblastoma cells require for survival. These new factors will also be inhibited in animal models of human neuroblastoma, alone and in combination with drugs similar to those entering clinical trials. These studies aim to identify new levels of gene regulation and methods to inhibit the genes involved in formation of neuroblastoma, with minimal side effects.

Dr. Flynn aims to understand the interplay between cancer metabolism and RNA biology at the level of protein modifications, such as glycosylation. The use of metabolites to fuel cellular processes including cell division and protein synthesis are critical in both healthy tissue and cancer growth. This work will define glycosylation events that respond to and regulate the cancer state within RNA-based networks, thereby establishing new layers of regulation for future therapeutic targeting.

Christopher’s research centers on the earliest steps whereby normal cells transform into abnormal cells with the potential to become cancer. He will focus on better understanding the first steps of the process by which normal blood cells become lymphomas, cancers that are generally thought to arise from blood cells that have already committed to becoming lymphocytes, an important component of the immune system. He hypothesizes, however, that some lymphomas actually arise from earlier hematopoietic stem cells (HSCs). He will interrogate this hypothesis by studying a cohort of lymphoma patients who also have detectable genetic mutations in HSCs that are known to be associated with blood cancers – a condition known as clonal hematopoiesis of indeterminate potential, or CHIP – to determine whether the mutations in the HSCs were the earliest events in the development of the patients’ lymphomas. Having a better understanding of lymphomas’ cellular basis will hopefully allow new insights into their clinical behavior and therapeutic vulnerabilities.

A form of cancer immunotherapy termed adoptive T cell transfer (ACT) can induce long-lasting remissions in patients with advanced blood cancers. In this approach, T white blood cells specific for proteins found on the surface of cancer cells (antigens) are activated and expanded outside the immunosuppressive environment of a cancer patient's body before re-infusion as a therapy. Thus far, this promising form of cancer immunotherapy has failed to work in most patients with cancers arising from solid organs, the leading cause of cancer-related deaths in adults. Two critical gaps in knowledge limit the ability of ACT to be successfully applied to solid cancers: 1) understanding which antigens on the surface of cancer cells can be targeted by T cells that do not have the potential to cross-react and injure normal tissues, and 2) insight into what factor(s) limit the ability of transferred T cells to expand and persist following re-infusion into a patient. Dr. Klebanoff seeks to use a genetic engineering approach to simultaneously address both these issues. Success of these efforts would be a decisive step forward toward extending the ability of ACT to deliver potentially curative responses in patients with common cancers, including those arising from the breast, uterus, cervix and colon.

Dr. Kory focuses on cancer cell metabolism. Cancer cells are characterized by rapid and uncontrolled cell growth. To sustain their accelerated growth, cancer cells rely on a constant supply of building blocks produced by specific metabolic pathways. One metabolic pathway, the mitochondrial one-carbon pathway, has recently been found to be especially important for the growth and survival of tumors and correlates with the survival of cancer patients. Inhibiting this pathway is a promising new strategy to treat cancer; however, its key components are still unknown. She aims to identify these components using a genetic screen applying the gene-editing CRISPR-Cas9 system to identify all genes required for its function in human cancer cells. She hopes to elucidate how cancer cells alter their metabolism to meet their high demands for building blocks and energy, which may also lead to the development of new drugs to treat cancers.

Immunotherapy is revolutionizing the clinical management of a variety of cancers. Unprecedented complete responses have been observed in hepatocellular carcinoma (HCC), a type of liver cancer that shows little response to conventional therapeutic approaches. Unfortunately, the clinical efficacy of nivolumab (Opdivo), a novel immune checkpoint inhibitor, is limited to less than 20% of HCC patients. Understanding the determinants of sensitivity and resistance to nivolumab and developing strategies that overcome resistance are therefore urgently needed to significantly improve the clinical management of HCC patients. Dr. Lujambio will combine the use of a novel mouse model of liver cancer and samples from HCC patients treated with nivolumab to identify genes that are involved in intrinsic and acquired resistance to this therapy. These findings will be critical to define biomarkers to select the HCC patients that are most likely to benefit from this immunotherapy. Moreover, a better understanding of the mechanisms of resistance to nivolumab will help design strategies to overcome resistance, providing novel therapeutic options for resistant patients.

Dr. Nandagopal is focusing on genes in the bHLH family and their role in signal integration to help decide whether cells grow and divide, differentiate, migrate, or even die. bHLH genes are involved in fate choices in stem cells of the brain, intestines, skin, and other tissues. They are also commonly misregulated in cancers, such as neuroblastomas and glioblastomas. By comparing signal integration by bHLH circuits in normal and cancer cells, Dr. Nandagopal aims to discover how errors in fate decisions occur, and how they can be corrected.