# Defining and Targeting Lineage Transition Programs Operative in AR Pathway Independent Prostate Cancer

> **NIH NIH R01** · FRED HUTCHINSON CANCER CENTER · 2024 · $395,515

## Abstract

PROJECT SUMMARY/ABSTRACT
The Androgen Receptor (AR) may be the earliest known example of a lineage oncogene: a master regulator of
cell survival and growth to which neoplastic cells derived from prostate epithelium are addicted. Recognizing this
unique feature, concerted efforts have focused on developing therapeutics capable of suppressing AR signaling.
Emerging strategies, mirroring successes in treatment for infectious diseases, will eventually deploy
combinations of drugs that will likely extinguish AR signaling, an event that may cure a subset of prostate
cancers. However, the plasticity of carcinomas, in part generated by highly unstable genomes, suggests that
prostate cancers are likely to emerge from this therapeutic pressure with a phenotype/genotype that is entirely
independent of AR signaling. This proposal is designed to anticipate that combinatorial AR pathway inhibition
will contribute to cell plasticity and select for subpopulations of resistant tumor cells that are completely
independent of AR signaling and do not exhibit neuroendocrine characteristics. We will test the hypothesis that
AR Pathway-Independent Prostate Cancers (APIPC) activate, and are dependent upon, a limited set of specific
survival and growth regulatory pathways that are regulated via de-repressed feedback loops and/or
genetic/epigenetic alterations in specific oncogenic networks.
Our Aims and strategies are as follows:
Specific Aim 1: Determine the mechanisms by which fibroblast growth factor (FGF) signaling promotes the
 progression of AR-dependent PC to AR-null APIPC and assess outcomes of FGF-targeted
 therapeutics. Cell lines and PDX models of disease representing a spectrum of AR-dependent
 and AR-independent lines will be evaluated.
Specific Aim 2: Determine the mechanisms contributing to FGF pathway activation in APIPC. We will utilize
 relevant in vivo model systems and biospecimens to determine genomic and epigenomic
 mechanism(s) that activate FGF signaling and determine how the FGF pathway promotes
 adverse prostate cancer phenotypes.
Specific Aim 3: Identify and target mechanisms of resistance to FGF pathway inhibition and to other drivers
 of prostate cancer lineage plasticity. We will evaluate relevant model systems and human
 biospecimens for the heterogeneity and diversity of mechanisms contributing to tumor cell
 plasticity, and assess the effectiveness of therapeutics that intercept, reverse or inhibit
 emerging drivers.
In order for effective therapeutics to be developed that can adequately address this new class of malignancy,
the pathways utilized by APIPC must first be clearly defined; this project aims to elucidate those underlying
mechanisms.

## Key facts

- **NIH application ID:** 10832575
- **Project number:** 5R01CA234715-06
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** PETER S NELSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $395,515
- **Award type:** 5
- **Project period:** 2020-08-15 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10832575

## Citation

> US National Institutes of Health, RePORTER application 10832575, Defining and Targeting Lineage Transition Programs Operative in AR Pathway Independent Prostate Cancer (5R01CA234715-06). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10832575. Licensed CC0.

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