# Targeting convergent oncogenic signaling during AR inhibition to overcome metastasis and immune evasion in prostate cancer

> **NIH NIH R01** · DUKE UNIVERSITY · 2021 · $290,930

## Abstract

ABSTRACT
The major cause of death for nearly all men with prostate cancer is metastasis of therapy-resistant disease.
Current standard-of-care therapies to treat metastatic castration-resistant prostate cancer (mCRPC) include
novel hormonal agents that inhibit the androgen receptor (AR), including abiraterone acetate and
enzalutamide. These hormonal therapies have significantly prolonged survival of men with mCRPC; however,
acquired resistance to these drugs is inevitable within 1-2 years. Therefore, there is a major unmet clinical
need to identify mechanisms of resistance and innovative therapies to treat hormone therapy-resistant
disease. In our preliminary studies, we have determined that enzalutamide promotes evolutionary selection for
cells with a pro-survival, immuno-evasive, and metastatic phenotype mediated by a p38α/Snail/PD-L1 gene
regulatory network. Our central hypothesis is that the p38α/Snail/PD-L1 axis promotes both cell-intrinsic
hormone therapy resistance and cell-extrinsic immune evasion. The main objective of this R01 proposal is to
interrogate the importance of p38α and cellular plasticity signaling with hormone resistance and immune
evasion in preclinical studies and in patients with metastatic prostate cancer.
In aim 1, we will test the potential of p38α as a cell intrinsic mechanism of AR therapy resistance and
metastasis, and overcome this induced resistance with small molecule p38α inhibition in the mCRPC setting.
To accomplish this goal, we will conduct both preclinical mechanistic studies in vivo and clinical correlative
analyses in circulating tumor cells and metastatic biopsies from men with mCRPC.
In aim 2, we will test the hypothesis that the p38α/Snail/PD-L1 axis mediates cell extrinsic immune evasion in
AR therapy resistant tumors. Using immunocompetent transgenic mouse models and patient-derived
xenografts with humanized immune systems, we will mechanistically assess the relationship between p38α
and PD-L1 upregulation, dissect the downstream effects of p38α activation, and explore the therapeutic benefit
of targeting the p38α/PD-L1 axis in AR therapy resistant mCRPC. We will couple these experiments to clinical
correlative analysis using banked circulating tumor cells and metastatic tissues previously collected from men
with mCRPC before and after progression on abiraterone acetate or enzalutamide.
Our data provide strong evidence that AR therapy resistance converges on a p38α/Snail/PD-L1 stress-
plasticity axis that can be therapeutically targeted to improve clinical outcomes in prostate cancer. The overall
goal of this proposal is to provide the preclinical and clinical correlative studies to justify clinical trials to provide
near-term benefit for men with metastatic, hormone therapy-resistant prostate cancer.

## Key facts

- **NIH application ID:** 10224136
- **Project number:** 5R01CA233585-03
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Andrew J Armstrong
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $290,930
- **Award type:** 5
- **Project period:** 2019-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10224136

## Citation

> US National Institutes of Health, RePORTER application 10224136, Targeting convergent oncogenic signaling during AR inhibition to overcome metastasis and immune evasion in prostate cancer (5R01CA233585-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10224136. Licensed CC0.

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