Candidate Background: I received my Ph.D. from the University of Michigan for my dissertation studies with Dr. Mark L. Day, focusing on soluble E-cadherin signaling through EGFR in benign prostatic hyperplasia and prostate cancer (PCa). I am continuing my PCa research studies with Dr. Robert J. Matusik at Vanderbilt University as a postdoctoral research fellow by focusing on how androgen receptor (AR) cofactors can support progression to castrate resistant PCa (CRPCa) and therapy acquired neuroendocrine PCa (NEPCa). Career Goals and Objectives: My career goal is to become an independent, tenure-track faculty member at a high-caliber research institution, working with an interdisciplinary team, and focusing on identifying new therapies for CRPCa. Achievement of my career goals requires additional mentored time through the K99/R00. Career Development and Training Activities: My training plan revolves around mentorship, didactic training, and protected research time to support my transition to independence. Dr. Matusik will serve as my primary mentor; he will train me in animal husbandry, mouse model characterization, and personnel management. Dr. Peter Clark, a urologic oncologist, will serve as my clinical mentor, and Dr. Simon Hayward will provide mentorship in tumor microenvironment. I will also complete a biostatistics course and ASPIRE modules, attend immunology seminars, and continue responsible conduct in research (RCR) training. Research Strategy: Significance and Innovation: This project is significant because it examines how NFIB drives lethal CRPCa and supports progression from neuroendocrine differentiation (NED) to therapy acquired NEPCa. This project is innovative because it explores how NFIB can drive resistance to androgen deprivation therapy (castrate resistance) through interactions with AR and AR splice variants (AR-V), as well as induce IL-1?, which supports NED. It also explores how NFIB mediates communication between distinct CRPCa tumor cells. Approach: Patients with advanced PCa inevitably progress to CRPCa following androgen deprivation therapy. Progression to CRPCa can be achieved through multiple mechanisms, including expression of AR-V and NED. AR-V lack the ligand binding domain of full length AR and are therefore constitutively active and unresponsive to therapies which block AR activity. AR is lost altogether in areas of NED or therapy-acquired NEPCa. NED is a focal change whereby PCa begins to lose AR expression, and gains neuroendocrine marker expression. Focal NED occurs in 40-100% of CRPCa samples, and it is common to observe areas of NED within adenocarcinomas. Importantly, secretions from these areas can support castrate resistance of the adenocarcinoma. NED can also be progressive, and 25% of CRPCa patients treated with next generation androgen deprivation therapy will develop therapy-induced NEPCa through NED. Successful treatment of CRPCa, therefore, requires therapies targeting AR action independently of the ligand binding domain. I have discovered that nuclear factor I/B (NFIB) is a potent modulator of AR action. CRPCa samples strongly express NFIB, and NFIB is upregulated in PCa cells which have become castrate resistant through NED. Significantly, knockdown of NFIB prevents NED in vitro. NFIB also appears to be critical for expression of IL-1? which has been implicated in NED in vitro. Based on these observations, I hypothesize that NFIB is a major driver of CRPCa by supporting AR-target gene expression and driving expression of pro-tumorigenic cytokines.
Specific Aim 1 : Examine how NFIB interacts with the AR/FOXA1 complex to drive CRPCa. 1a) Determine whether NFIB, FOXA1, AR and AR-V interact in PCa cell lines. 1b) Examine the consequences of NFIB knockout on AR and AR-V action in CRPCa cell lines. 1c) Explore the consequences of NFIB overexpression on AR and AR-V action in PCa cell lines capable of undergoing NED.
Specific Aim 2 : Determine whether NFIB expression is required for progression to CRPCa and/or NEPCa. 2a) Characterize the consequences of NFIB loss in a mouse model of CRPCa. 2b) Determine the consequence of NFIB loss in a mouse model of CRPCa progression to NEPCa.
Specific Aim 3 : Characterize how NFIB expression supports NED through IL-1? secretion. 3a) Explore changes in IL-1? in response to NFIB modulation. 3b) Determine how changes in IL-1? drive castrate resistant growth. 3c) Evaluate whether secreted IL-1? drives CRPCa. Successful completion of these studies will determine the consequences of NFIB expression in CRPCa. These studies will serve as the basis for an NCI R01 application to be submitted during the end of my third year. Transition to Independence: I will transition to independence by applying to faculty positions during the K99 phase and accepting a tenure track position at a new institution to complete the R00 phase. I have designed these aims independent of Dr. Matusik, and he will not pursue projects relating to NFIB in PCa.

Public Health Relevance

The enclosed application, entitled ' Nuclear Factor I/B Action in Castrate Resistant Prostate Cancer' for the K99/R00 Pathway to Independence award mechanism includes a comprehensive training plan and research strategy for supporting my development into a tenure-track and independent translational prostate cancer researcher. This application is relevant to public health because it explores how nuclear factor I/B (NFIB) interacts with androgen receptor and androgen receptor splice variants to drive lethal castrate resistant prostate cancer, as well as how NFIB supports cytokine secretions that promote development of highly aggressive therapy acquired neuroendocrine prostate cancer. Moreover, the training plan proposed will prepare me for a career in translational prostate cancer research by providing additional coursework in biostatistics, training in laboratory management, grant administration, and mentored experiences with my committee of prostate cancer experts (Drs. Robert J. Matusik, Ph.D.; Peter E. Clark, M.D.; and Simon W. Hayward, Ph.D.).

National Institute of Health (NIH)
National Cancer Institute (NCI)
Career Transition Award (K99)
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Subcommittee I - Transistion to Independence (NCI)
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Schmidt, Michael K
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Vanderbilt University Medical Center
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