Project Summary/Abstract My long-term career objective is to be an independent scientist in an academic laboratory. I would like to improve our molecular understanding of cancer initiation and progression and translate these findings to new therapeutic approaches for cancer patients. The K99/R00 Pathway to Independence Award and the proposed research in this application will be instrumental in my professional career development as a scientist as I transition to a faculty position. MENTORING TEAM: During the mentored K99 phase of the award, I will perform the proposed research under the direct guidance of Dr. Owen Witte at the University of California at Los Angeles (UCLA). Dr. Witte is a world-renowned leader in the field of cancer research. His laboratory has developed a unique set of research approaches with human materials to address scientific questions and hypotheses in prostate cancer pathogenesis and cancer immunology. I have assembled an advisory board with a co-mentor and two consultants including Dr. Siavash Kurdistani, Professor in the Department of Biological Chemistry at UCLA and an expert in functional genomics; Dr. Thomas Graeber, Professor in the Department of Molecular & Medical Pharmacology at UCLA and an expert in systems biology; and Dr. Jiaoti Huang, Chairman and Professor in the Department of Pathology at Duke University who is a world expert in genitourinary pathology. I will obtain knowledge and new skills in the areas of functional genomics, computational biology, and translation of basic scientific findings therapeutic strategies for cancer patients. This training will allow me to reach my career goal as a scientist who can significantly contribute to the field of cancer biology and the many men and women who are affected by cancer. RESEARCH: We hypothesize that, under the pressure of current therapies, prostate adenocarcinoma (PrAd) undergoes cellular reprogramming and trans-differentiation to a lethal variant, neuroendocrine prostate cancer (NEPC), and this process is driven by dysregulated transcriptional networks. The goal of this proposal is to define the critical genetic elements required for the progression from PrAd to NEPC. The lack of human prostate cancer models has hampered functional studies investigating the molecular mechanisms by which advanced prostate cancer evolves. To address the hypothesis, we will conduct these aims: Aim 1. I will establish a diverse panel of advanced prostate cancer cell lines derived from the transformation of basal and luminal epithelial cells of origin by defined oncogenic drivers. Aim 2. I will perform integrative next-generation sequencing to define transcription factor networks in cancer differentiation states of advanced prostate cancer. Aim 3. I will functionally define a minimal essential set of transcription factors required to reprogram PrAd to NEPC. In future studies, we will build on the insight gained from these studies to pursue therapeutic approaches to prevent the evolution of lethal NEPC.