# Project 2: Understanding and Targeting the Lineage plasticity in the Genomic Umbrella Neoadjuvant Study (GUNS)

> **NIH NIH P50** · FRED HUTCHINSON CANCER CENTER · 2024 · $190,626

## Abstract

PROJECT SUMMARY/ABSTRACT
The androgen receptor (AR) is the main driver of prostate cancer (PC) development and progression, which has
led to a concerted effort to develop pharmacological agents to ablate AR activity and extend survival in men with
metastatic prostate cancer. However, paradoxically, increasingly potent AR pathway inhibitors (ARPI) therapies
have shaped the emergence of highly aggressive lineage plastic tumours with markedly distinct epigenetic
profiles, low canonical AR signaling, and activation of neuronal and developmental/stem cell-associated
transcriptional programs. Recent clinical observations support that ~20% of advanced PCa patients with distinct
genomic alteration including loss of TP53, RB1 and PTEN and upregulation of EZH2 are more primed to develop
lineage plasticity and neuroendocrine phenotype. Notably, prognosis remains poor due to a lack of our
understanding of the molecular and functional cell states underlying lineage reprogramming. Hence it is crucial
to improve our understanding of these emergent resistance mechanisms in genomically segmented populations
in order to better inform future development of novel therapeutic strategies. We developed a novel clinical and
translational neoadjuvant platform as a framework to understand the molecular basis for responses to intensive
ARPI therapy. This adaptive multi-stage, multi-arm trial, named the Genomic Umbrella Neoadjuvant Study
(GUNS, NCT04812366), will evaluate ARPI-based therapeutic combinations in biomarker pre-selected patients
with high-risk localized PC. We hypothesize that genomic alterations determine depth of response to ARPI, and
that co-targeting the AR with other contextually relevant targets defined by specific genomic subtype will increase
rates of pCR and minimal residual disease in high-risk localized PCa. Certain PC subtypes with loss (isolated or
combined) of TP53, RB, PTEN, BRCA or gain in MYC and upregulation of EZH2, are better primed to survive,
adapt, develop linage plasticity, and progress after ARPI.
We will test our hypothesis in the following aims:
Aim 1: Define the genomic predisposition of response to potent neoadjuvant ARPI in the GUNS trial.
Aim 2: Assess fidelity of response and pathways activation to ARPI with targeted therapies in PDX models with
 analogous genomic alterations matched with subprotocols in GUNS.
Aim 3: Conduct sub-protocol 5 in GUNS to evaluate combined ARPI with EZH2 inhibitor, tazemetostat, in PCs
 with defined genetic subtypes.

## Key facts

- **NIH application ID:** 10919786
- **Project number:** 5P50CA097186-23
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** Martin Edwin Gleave
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $190,626
- **Award type:** 5
- **Project period:** 2002-09-19 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10919786

## Citation

> US National Institutes of Health, RePORTER application 10919786, Project 2: Understanding and Targeting the Lineage plasticity in the Genomic Umbrella Neoadjuvant Study (GUNS) (5P50CA097186-23). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10919786. Licensed CC0.

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