# Mechanisms and vulnerabilities of ERG-driven luminal fate in prostate cancer

> **NIH NIH K99** · SLOAN-KETTERING INST CAN RESEARCH · 2024 · $173,016

## Abstract

Project Summary and Abstract: Prostate cancer (PCa) is the most frequent cancer in American men.
Luminal histology is a hallmark of PCa. Hormone therapy effectively targets luminal cells, but resistance
inevitably occurs. The ERG oncoprotein is overexpressed in half of PCa cases. Prostatic ERG expression in
mice recapitulates invasion with a luminal program seen in human PCa, thus presenting a clinically relevant
model to study PCa. However, the molecular mechanisms by which ERG drives a luminal fate and invasive
PCa remain unclear, insights from which may reveal new treatment paradigms. Project objective: To
elucidate the mechanisms and vulnerabilities of ERG-driven luminal fate and PCa invasion. Preliminary data:
1) pseudo-basal cells (those with a mixture basal/luminal marker profile) rather than luminal cells are the most
proliferative, and invasion-associated population in PCa; 2) a genome-wide CRISPR screen reveals that ERG
stimulates luminal fate by alleviating aryl-hydrocarbon receptor (AHR) signaling, which provides a druggable
vulnerability. Central hypothesis: ERG stimulates a progenitor state, characterized as pseudo-basal cells,
that sustains invasion and luminal output of PCa. The proposed project leverages innovative mouse and
organoid models, genome-wide screen data, and patient samples to test this hypothesis. Specific Aims: 1)
determine the luminal progenitor and oncogenic potential of pseudo-basal cells in ERG-driven PCa; 2) define
how AHR and other screen candidates modulate lineage output as a mechanism and vulnerability of ERG
function; 3) characterize the pseudo-basal state in human PCa. Impact: Success of this work will 1) advance
mechanistic understanding, 2) identify novel vulnerabilities of ERG-driven PCa, the most frequent PCa
subtype, and 3) provide tools and approaches with wide applicability to studying lineage fate choices in cancer.
This work will be performed under the collaborative and resourceful research environment at MSKCC. I have
recently developed CRISPR editing tools for rapid PCa modeling (Proc Natl Acad Sci), which will be critical to
advance the proposed work. My long-term career goal is to establish an independent research team that
focuses on mechanistic understanding of PCa to develop novel therapeutic strategies. I have developed a
detailed career plan to obtain skills in leadership, management, mentoring, grant writing, and scientific
communications. I will work under the mentorship of Dr. Charles Sawyers, a leader in PCa research with a
stellar track record of trainees that went on to faculty positions. In addition, I have assembled an Advisory
Committee that will collaborate with me and offer training on science and career development, including Drs.
Michael Shen (prostate lineage specification), Yu Chen (ERG biology), Gary Perdew (AHR biology), Anuradha
Gopalan (patient sample assessment), and Christina Leslie (computational biology). My research and career
development plan, together with my me...

## Key facts

- **NIH application ID:** 10811757
- **Project number:** 5K99CA276888-02
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Weiran Feng
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $173,016
- **Award type:** 5
- **Project period:** 2023-04-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10811757

## Citation

> US National Institutes of Health, RePORTER application 10811757, Mechanisms and vulnerabilities of ERG-driven luminal fate in prostate cancer (5K99CA276888-02). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10811757. Licensed CC0.

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