Dissecting Early Tumor Evolution to Uncover Mechanisms of Tumor Initiation and Drug Resistance

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PROJECT SUMMARY/ABSTRACT Despite the prevalence of prostate cancer worldwide, we lack an understanding of the genetic events that drive tumor initiation or drug resistance. Only a few genetic models exist, leaving hundreds of recurrent mutations unaccounted for, and most studies interrogate gene function by overexpression or knockout rather than studying the mutational variants present in disease. Better understanding of the mutations driving tumor initiation and drug resistance could allow us to screen for precancerous lesions or prevent fatal disease progression, greatly relieving the global burden of disease. Therefore, there is an urgent need for a new functional genomic approach to enable the functional study of multiple genetic variants per cell to identify mechanisms of tumor initiation and drug resistance. We have developed such a system in mouse prostate organoids by knocking out the tumor suppressor Pten and the mismatch repair gene Msh2 to induce the accumulation of point mutations and indels. This system has allowed us to interrogate which mutations complement PTEN loss to drive tumor initiation and drug resistance in vivo. We have discovered that hotspot mutations in IRS4 and CDK4 are uniquely enriched during tumor initiation and drug resistance, respectively. Thus, I propose to determine the mechanisms by which IRS4 and CDK4 gain of function mutations complement PTEN loss to drive prostate cancer initiation and drug resistance, respectively. In my first aim, I will test the necessity and sufficiency of IRS4 gain of function to drive tumor initiation through MAPK activation and downstream transcriptional alterations. For my second aim, I will test the necessity and sufficiency of CDK4 gain of function to drive drug resistance through cell cycle dysregulation and investigate the reversibility of this phenotype in patient-derived organoids. My sponsor Rohit Bose, MD, PhD, has extensive experience in genetic and transcriptional network alterations underlying prostate tumor initiation. My co-sponsor Kevin Shannon, MD, has renowned experience studying MAPK circuitry and drug resistance in cancer. Additionally, I have secured scientific support and career mentorship from a respected and prolific cadre of investigators with complementary expertise, Dr. Felix Feng (prostate cancer genomics), Dr. Rahul Aggarwal (drug-resistant tumor samples), Dr. Catherine Smith (cell cycle dysregulation and tumor evolution), Dr. Franklin Huang (prostate cancer genomics and health disparities), and Dr. Hani Goodarzi (multi-omics and tumor evolution). Concurrently, I will continue bimonthly clinical preceptorships with Drs. Aggarwal, Bose, and Feng at the UCSF Helen Diller Family Comprehensive Cancer Center. Overall, the proposed work will further our understanding of tumor initiation and drug resistance in prostate cancer, laying the groundwork for improved detection and treatment. Moreover, this fellowship will foster my training in cancer biology and genetics, supporting me through combined MD/PhD training towards a career as an academic medical oncologist studying tumor evolution and drug resistance in prostate cancer.