# The Role of PDEF in Prostate Cancer

> **NIH VA I01** · SOUTHEAST LOUISIANA VETERANS HEALTH CARE · 2022 · —

## Abstract

Project Summary:
Prostate Cancer (PCa) accounts for ~30000 deaths annually in the USA. There is urgent, yet unmet, need for
identification and characterization of new targets for therapeutic intervention in PCa. Our goal is to address this
vital knowledge gap by characterizing the role of Prostate Derived Ets Transcription Factor (PDEF) in PCa, thereby
reducing the prostate cancer-related deaths. Our central hypotheses are that, “PDEF suppresses CRPC phenotype
and PCa metastasis in part by modulating AR cistrome and in part by restricting lineage plasticity and as such may
help sensitize CRPC men to current therapies”. This novel paradigm, implies that loss of PDEF tumor progression
and therapy resistance in part by allowing re-targeting of AR to non-canonical AR cistrome, and in part by
promoting lineage plasticity and emergence of CRPC, is a groundbreaking conceptual advancement, which holds
translational promise in identifying new therapeutic targets in CRPC, for which there is no cure to date. Our
hypotheses are driven by our novel observations that there is graded decrease in PDEF levels in prostate cancer
cells with increasing aggressive phenotype, and that PDEF inhibits cell migration, invasion in vitro, and tumor
metastasis in vivo. We discovered that PDEF negatively enriches gene sets associated with cell migration and tumor
metastasis. We observed that PDEF inhibits expression of sets of genes associated with EMT, NEPC and Stemness,
and that there is decreased PDEF during PCa progression in experimental (TRAMP) mouse model. Moreover, we
observed that PDEF promotes distinct transcription profiles related with canonical AR cistrome and luminal
differentiation. We now propose to test our hypothesis in three specific aims: AIM 1) To evaluate the role of PDEF
in modulating AR cistrome, AIM 2) To determine the role of PDEF in cellular plasticity and resistance to AR
pathway inhibitors, and; AIM3) To evaluate if prostate cancers with PDEF loss respond more favorably to
combination of AR targeted therapies (Enzalutamide (Enz) and EZH2 inhibitor (EPZ-6438) as compared to Enz
alone. The accomplishment of the goals proposed herein should substantially advance our understanding of the
mechanisms by which PDEF inhibits prostate cancer progression and metastasis. Our proposed investigation is
highly relevant to the mission of VA and is likely to have a significant impact on saving lives of Veterans by
characterizing novel targets for intervention against prostate cancer in the immediate future.

## Key facts

- **NIH application ID:** 10385704
- **Project number:** 5I01BX005351-02
- **Recipient organization:** SOUTHEAST LOUISIANA VETERANS HEALTH CARE
- **Principal Investigator:** HARI K KOUL
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10385704

## Citation

> US National Institutes of Health, RePORTER application 10385704, The Role of PDEF in Prostate Cancer (5I01BX005351-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10385704. Licensed CC0.

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