Castration-resistant prostate cancer (CRPC) emerges following androgen deprivation therapy (ADT), where variable degrees of dependence on the androgen receptor (AR) are observed, and features of neuroendocrine (NE) carcinoma often arise. We have identified the developmental transcription factor, ONECUT2 (OC2/HNF6?), as a master regulator of AR networks in metastatic (m)CRPC. OC2 governs a lethal differentiation program, drives metastasis, and interacts with the AR at several levels, including as a multiprotein complex and a transcriptional regulator of AR target genes. Our studies indicate that OC2 appears to override AR-dependent mechanisms in a subset of mCRPC, and activates an NE differentiation program within the context of adenocarcinoma. To inhibit OC2, we developed a novel class of small molecules that bind OC2 directly and suppress growth and metastasis of AR/AR-V7-positive mCRPC xenografts. Additionally, we have developed profiling and immunohistochemistry (IHC) methods to identify OC2 activity in clinical specimens, laying a foundation for an OC2-targeted treatment approach in select patients. This project will test the hypothesis that OC2 is an actionable target in a subset of aggressive prostate cancer where OC2 is active.
The Specific Aims are:
Aim 1. Study the mechanism by which OC2 activity promotes aggressive behavior of CRPC. Determine whether OC2 can compensate for AR in CRPC. Determine whether OC2 upregulation can confer independence from AR. Determine whether OC2 interactors in AR-dependent and AR-independent transcription complexes are distinct. Determine whether OC2 is required for NE differentiation and growth of NE-CRPC.
Aim 2. Develop and optimize OC2 inhibitors for use in patients with early mCRPC. Synthesize and test derivatives of the OC2 targeting compound CSRM617. Perform in silico and high-throughput screening for structurally unrelated OC2 inhibitors. Test the safety and efficacy of OC2 inhibitors in pre-clinical models.
Aim 3. Identify the clinical scenarios where OC2-driven tumors emerge. Refine multiplex IHC detection of OC2/AR expression in OC2- active tumors. Determine the correlation between OC2 activity and IHC detection of OC2 and AR in independent sets of clinical samples. Evaluate OC2 activity along the clinical spectrum of prostate cancer progression, including sequential pre/post-ADT tumor specimens, metastases and xenograft models. Measure OC2/AR activity in diagnostic prostate needle biopsies (PNBX) of untreated men with high-grade prostate cancer, and determine the impact of OC2 activity on clinical outcome in univariate and multivariate analyses. These experiments will help clarify the role of alternative drivers of progression and ADT resistance that emerge to cause lethal disease. They will also advance, toward a phase I clinical trial, a therapeutic approach against a novel master regulator that we estimate operates in 1/3 or more of all patients with CRPC tumors.

Public Health Relevance

This project will test the hypothesis that the developmental transcription factor, ONECUT2, is a genome-wide modulator of androgen receptor function, a driver of a neural differentiation program, and a clinically relevant therapeutic target in castration-resistant prostate cancer (CRPC). The objectives are to understand the functional role of ONECUT2 in CRPC, identify clinical scenarios where ONECUT2 operates, and develop pathways to therapeutic targeting of this protein that will lead to a clinical trial.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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University of California Los Angeles
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Cheng, Larry C; Li, Zhen; Graeber, Thomas G et al. (2018) Phosphopeptide Enrichment Coupled with Label-free Quantitative Mass Spectrometry to Investigate the Phosphoproteome in Prostate Cancer. J Vis Exp :
Park, Jung Wook; Lee, John K; Sheu, Katherine M et al. (2018) Reprogramming normal human epithelial tissues to a common, lethal neuroendocrine cancer lineage. Science 362:91-95
Tan, Nelly; Shen, Luyao; Khoshnoodi, Pooria et al. (2018) Pathological and 3 Tesla Volumetric Magnetic Resonance Imaging Predictors of Biochemical Recurrence after Robotic Assisted Radical Prostatectomy: Correlation with Whole Mount Histopathology. J Urol 199:1218-1223
Donin, Nicholas M; Reiter, Robert E (2018) Why Targeting PSMA Is a Game Changer in the Management of Prostate Cancer. J Nucl Med 59:177-182
Nagarajan, Mahesh B; Raman, Steven S; Lo, Pechin et al. (2018) Building a high-resolution T2-weighted MR-based probabilistic model of tumor occurrence in the prostate. Abdom Radiol (NY) 43:2487-2496
Calais, Jeremie; Fendler, Wolfgang P; Eiber, Matthias et al. (2018) Impact of 68Ga-PSMA-11 PET/CT on the Management of Prostate Cancer Patients with Biochemical Recurrence. J Nucl Med 59:434-441
Vidal, Adriana C; Howard, Lauren E; de Hoedt, Amanda et al. (2018) Neutrophil, lymphocyte and platelet counts, and risk of prostate cancer outcomes in white and black men: results from the SEARCH database. Cancer Causes Control 29:581-588
Vidal, Adriana C; Howard, Lauren E; de Hoedt, Amanda et al. (2018) Obese patients with castration-resistant prostate cancer may be at a lower risk of all-cause mortality: results from the Shared Equal Access Regional Cancer Hospital (SEARCH) database. BJU Int 122:76-82
Jelinek, David; Flores, Aimee; Uebelhoer, Melanie et al. (2018) Mapping Metabolism: Monitoring Lactate Dehydrogenase Activity Directly in Tissue. J Vis Exp :
Lee, John K; Bangayan, Nathanael J; Chai, Timothy et al. (2018) Systemic surfaceome profiling identifies target antigens for immune-based therapy in subtypes of advanced prostate cancer. Proc Natl Acad Sci U S A 115:E4473-E4482

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