Defining Therapeutic Sensitivity of Patient-Derived Cancer Organoids in Cholangiocarcinoma

Candidate: I am a staff medical oncologist at the William S. Middleton Memorial Veterans Hospital and Assistant Professor of Medicine at the University of Wisconsin School of Medicine and Public Health. I obtained my MD from the University of Michigan and American Board of Internal Medicine research fast track in internal medicine

and medical oncology at the University of Wisconsin. I completed my post-doctoral training with Dr. Dustin Deming to study mechanisms of targeted therapeutic resistance in colorectal cancer organoid models. I currently serve as subject matter expert in gastrointestinal cancers with the VA National Precision Oncology Program. My

goal is to develop an independent research program specific to hepatobiliary cancers to improve the health outcomes of Veterans through precision applications informed from organotypic models. I was recruited to the William S. Middleton Memorial Veterans Hospital and the University of Wisconsin with support of clinical and

research efforts dedicated to building our research program through institutional mentorship, laboratory resources, and start-up funding. Research Project: Cholangiocarcinoma (CCA) represents a leading cause cancer-related mortality with 5-year survival estimated <10% in the United States. Patient-derived organoid models have improved pre-clinical modeling of gastrointestinal cancers. There remains a significant unmet need to standardize these models in CCA with a critical gap in knowledge to understand if these models can predict clinical outcomes. Chemotherapy is standard in clinical management for advanced CCA, however therapeutic resistance is universal for advanced disease. We propose a dedicated investigation of organoid modeling under therapeutic treatment for the prediction of clinical response. Cyclin-dependent kinase 7 (CDK7) functions as a key regulator of RNA polymerase II is overexpressed in nearly 40% of CCA. It has recently been shown to have activity using historic 2D models of CCA as monotherapy. Here, we present a dedicated assessment of CDK7 targeting in response to DNA damaging chemotherapy in CCA. Using models stratified by key mediators of cell cycle and homologous DNA damage, we propose to quantitate therapeutic response. We aim to understand the fundamental mechanisms specific to response by characterizing DNA damage, cell cycle arrest and the inhibition of RNA polymerase II. Our central hypothesis is that the sensitivity of CCA organoids will predict prospective clinical outcomes and that CDK7 inhibition (CDK7i) will improve sensitivity to chemotherapy-induced DNA damage as a lead therapeutic combination from patient-derived models. We will investigate this hypothesis with three specific aims. Specific Aim 1: Quantify the effect of CDK7i on cell cycle propagation, activation of RNA polymerase II, and DNA damage repair in CCA organoid models. Specific Aim 2: Validate the response of CCA organoids to chemotherapy as predictive of clinical outcomes. Specific Aim 3: Evaluate activity of CDK7i in combination with chemotherapy in patient-derived xenograft (PDX) models of CCA. Career Plan: My long-term career goal is to become an independently funded VA physician-scientist who is a leader in the field of treating gastrointestinal malignancy by targeting shared mechanisms of transcription- mediated resistance. My primary VA research mentor, Dr. Mark Albertini, will guide my progress and training. My additional mentors and collaborators will provide the training to accomplish my research aims and career goals and further my knowledge of cancer stem cell modeling and liver cancer biology. The results from this CDA-2 will provide me with the preliminary data and research experience to formulate a competitive MERIT Review proposal to further develop novel therapeutic targets for hepatobiliary cancers. Environment: I will complete the proposed research at the Madison VA and the University of Wisconsin. Both organizations provide an exceptionally collegial atmosphere and strong institutional support that include complementary laboratory resources, equipment, and core facilities.