# Developing New Treatment Strategies for Neuroendocrine Prostate Cancer

> **NIH CA R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2026 · $544,206

## Abstract

Project Summary/Abstract
 Neuroendocrine prostate cancer (NEPC) is the most virulent form of the disease. Loss of the tumor
suppressors TP53/RB1 is ubiquitous in NEPC, but molecular mechanisms that explain how loss of TP53/RB1
promotes NEPC development are largely unknown. Further, there are no effective therapies for NEPC. Thus,
there is a clear need to clarify targetable mechanisms in NEPC so we may develop new treatments.
 Loss of epithelial differentiation is one critical hallmark of NEPC. We identified specific transcriptional
repressors turned on by TP53/RB1 loss that block androgen receptor signaling and epithelial differentiation.
Activation of a neuroendocrine differentiation/epithelial-mesenchymal transition (EMT) program is another
hallmark of NEPC. We identified important activators of this program that are also turned on by TP53/RB1 loss.
Importantly, blocking the repressor proteins with drugs approved for use in other cancers or blocking the
activator proteins with a drug that is currently in clinical trials in prostate cancer reduces growth of NEPC
tumors in vitro and in vivo. However, we find that combination therapy is particularly effective. This application
is designed to clarify mechanisms by which this treatment combination blocks NEPC cell survival.
 We hypothesize that TP53/RB1 loss activates key factors that suppress epithelial differentiation while also
activating those that promote NEPC differentiation; co-targeting this combined axis is more effective because it
restores epithelial differentiation and blocks neuronal/EMT pathways, and—in doing so—blocks adaptive,
single agent resistance mechanisms.
Aim 1: Determine mechanisms by which loss of TP53/RB1 loss represses epithelial differentiation gene
expression. Completion of this aim will provide a detailed understanding of how TP53/RB1 loss turns on key
downstream repressors to block epithelial differentiation so we can prevent that from occurring.
Aim 2: Determine mechanisms by which block

## Key facts

- **NIH application ID:** 11322632
- **Project number:** 5R01CA282005-03
- **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:** $544,206
- **Award type:** 5
- **Project period:** 2024-04-01T00:00:00 → 2029-03-31T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11322632

## Citation

> US National Institutes of Health, RePORTER application 11322632, Developing New Treatment Strategies for Neuroendocrine Prostate Cancer (5R01CA282005-03). Retrieved via AI Analytics 2026-07-07 from https://api.ai-analytics.org/grant/nih/11322632. Licensed CC0.

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