# Project 4: A Targetable Master Regulator of Lethal Prostate Cancer

> **NIH NIH P50** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $262,192

## Abstract

PROJECT SUMMARY/ABSTRACT
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/HNF6β),
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.

## Key facts

- **NIH application ID:** 10000847
- **Project number:** 5P50CA092131-17
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Michael R. Freeman
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $262,192
- **Award type:** 5
- **Project period:** 2002-09-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10000847

## Citation

> US National Institutes of Health, RePORTER application 10000847, Project 4: A Targetable Master Regulator of Lethal Prostate Cancer (5P50CA092131-17). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10000847. Licensed CC0.

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