# Targeting Early Drivers of Prostate Cancer Lineage Plasticity

> **NIH CA R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2026 · $500,241

## Abstract

Lineage plasticity (LP)—most commonly exemplified by loss of androgen receptor (AR) signaling and
switch from a luminal to an alternate differentiation program—is now recognized as a critical determinant of
lethality. Most efforts in the field are focused on factors that promote terminal differentiation of specific LP
subtypes such as neuroendocrine prostate cancer (NEPC). However, LP is a continuum, ranging from AR
activity-low tumors with persistent AR expression but low AR signaling to those with alternate differentiation
programs. Factors involved in the initiation and progression of LP have not been identified. The clarification of
such factors is essential because there are no effective therapies for prostate tumors that have undergone LP.
In this proposal we seek to target key factors involved in early LP events to prevent LP from occurring.
 Using an integrative genomic analysis of metastatic castration-resistant prostate cancer patient biopsies,
we determined that key transcriptional regulators are upregulated early on in the LP continuum in AR activity-
low tumors and that these factors progressively increase in terminally differentiated LP subtypes. Importantly,
gain of function studies of these transcriptional regulators in AR-driven tumors and loss of function studies in
tumors representing the continuum of LP demonstrate that these regulators block AR signaling and cooperate
with other factors to promote specific alternate differentiation programs. Targeting these transcriptional
regulators or their key epigenetic cofactors reduces survival of LP tumor cells in vitro and in vivo with good
animal tolerability, strongly suggesting we have a promising approach to block LP.
 We hypothesize that key transcriptional regulators we have identified are early drivers of LP that control
prostate cancer cell fate decisions by: 1) repressing AR signaling and luminal differentiation and 2) activating
alternate differentiation programs in concert with key cofactors.


## Key facts

- **NIH application ID:** 11318994
- **Project number:** 5R01CA291986-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Joshi James Alumkal
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** CA
- **Fiscal year:** 2026
- **Award amount:** $500,241
- **Award type:** 5
- **Project period:** 2025-04-09T00:00:00 → 2030-03-31T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11318994

## Citation

> US National Institutes of Health, RePORTER application 11318994, Targeting Early Drivers of Prostate Cancer Lineage Plasticity (5R01CA291986-02). Retrieved via AI Analytics 2026-07-22 from https://api.ai-analytics.org/grant/nih/11318994. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*