Molecular origins and evolution to treatment resistance in genitourinary cancers

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PROJECT SUMMARY Under Unit Director Dr. Eliezer Van Allen's leadership, the Van Allen laboratory's NCI funded research programs study genitourinary (GU) cancers (prostate, bladder, kidney, testes), with a focus on understanding treatment resistance in these diseases through integrative computational and molecular approaches grounded in the patient experience. With her multidisciplinary training and collaborative leadership, Research Specialist Dr. Jihye Park has been an integral part of these research programs contributing to various discovery and novel computational methods. Our research programs led to the discovery of the molecular basis of selective chemosensitivity in bladder and testes cancers, and biological understanding of androgen inhibitor resistance in prostate cancer, creating new drug discovery paradigms and means of patient stratification. We also developed integrative computational and experimental approaches to discover the interaction relevant to treatment resistance across the tumor, germline, and immune axes with our patient-centered paradigm in GU cancers. Furthermore, we discovered tumor-intrinsic factors determining cancer immunotherapy in solid tumors, directly invoking chromatin dysregulation as a cause of selective immunotherapy response and forming the basis for new files of drug development and therapeutic combinations. Despite these advances, the majority of patients with advanced GU cancers still experience resistance to therapies and the biological relevance and interplay of specific germline, somatic, or immune systems in these cancers are still largely unknown. Furthermore, we face computational challenges to handle vast amounts of new types of data to analyze efficiently. Dr. Park is now leading the effort to utilize integrated patient-centered approaches, specifically longitudinal single cell transcriptional and whole genome and epigenetic characterization of tumors, to understand the biological basis of molecular sensitization with tumor evolution perspectives and determine the paradigms that drive lethal immunotherapy resistant disease in GU cancers. Dr. Park will also contribute to the development of comprehensive and scalable analytic tools that can integrate multi-omics data and study systems level interactions between germline, somatic, and immune systems. These methods will be implemented within an open cloud-based platform (Terra) and amplify collaborations within the cancer community. Overall, Dr. Park's recent and ongoing contributions aim to reveal the integrated molecular factors that drive lethal disease in GU cancers and elucidate the biology of these processes, toward translation of effective therapeutic and patient stratification modalities, and broader accessibility of comprehensive computational methods utilizing cutting edge molecular profiling approaches. With Unit Director Dr. Eliezer Van Allen, Dr. Park's leadership and scientific and computational efforts will continue to establish an interdisciplinary and highly collaborative group with scientists from diverse scientific domains driving these comprehensive clinical computational research programs. 1