# Leveraging PMN immune response to overcome ADT resistance in bone metastatic prostate cancer

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2022 · $351,131

## Abstract

Metastatic castration-resistant prostate cancer (mCRPC) is deadly and currently incurable. Approximately 90%
of patients CRPC become resistant to 2nd line androgen deprivation therapy (ADT; which primarily target
androgen receptor (AR) signaling and present with bone metastatic disease. Although ADT remains a beneficial
therapy for mCRPC patients, mechanisms of cancer resistance in mCRPC and specifically, in the bone
environment, the most frequent site of CRPC metastasis, is poorly understood. Understanding contributing
factors to PCa disease progression is needed for further development of efficacious therapies. ADT was
previously shown to be critical for differentiation and function of polymorphonuclear leukocytes/neutrophils
(PMNs) which are “first responder” innate immune cells that comprise ~40-50% of the bone marrow cavity. We
recently showed that PMNs are protective against bone metastatic prostate cancer (BM-PCa) however, the PMN
anti-tumoral immune response diminishes as the tumor progresses. To examine PMN phenotypical changes
throughout PCa progression in patients, my group functionally and molecularly characterized peripheral blood
PMNs from PCa patients at different stages: 1) Localized PCa, 2) bone metastatic hormone-sensitive (mCSPC),
and 3) mCRPC patient. We found that PMN function was highly suppressed by 2nd line ADT through increased
receptor 1 expression of transforming growth factor beta (TGFβ), an anti-inflammatory cytokine important for
promoting BM-PCa and cancer-induced bone disease. Using preclinical bone metastasis mouse models, we
were able to significantly suppress mCRPC growth in bone using 2nd line ADT in combination with either bipolar
androgen therapy (BAT; exogenous testosterone) to boost PMN anti-tumor response OR PMN-specific genetic
deletion of TβR1. Based on our preliminary findings, we hypothesize that: anti-tumor PMNs are suppressed/
“switched off” by androgen regulation via TβR1 signaling and this can be leveraged to improve mCRPC
outcomes. This will be tested in the following aims: Aim 1. Define the impact of androgen regulation on PMN
anti-tumor immune response. Aim 2. Determine the mechanism of TβR1-mediated PMN immune response in
BM-PCa. Aim 3. Delineate the therapeutic potential of dual TβR1/AR regulation for improving mCRPC
therapeutic outcomes. Primary Objective: To develop a novel immunotherapeutic strategy for treating BM-PCa
by enhancing PMN anti-tumor response and overcoming PCa resistance to ADT. Study Design: For Aim 1,
we will identify the impact of androgen signaling on PMN polarization ex vivo (using patient-derived PMNs and
mouse bone marrow PMNs) and in vivo using normal PCa, non-metastatic and bone metastatic PCa cells) and
in vivo (using mouse intratibial bone metastasis models). For Aim 2, we will delineate the role of TβR1 in PMN
response to mCRPC using TβR1 knockout models. For Aim 3, we will define the therapeutic potential for using
combination BAT with a novel bone-targeted TβR1 i...

## Key facts

- **NIH application ID:** 10522915
- **Project number:** 1R01CA274605-01
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Leah Marie Cook
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $351,131
- **Award type:** 1
- **Project period:** 2022-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10522915

## Citation

> US National Institutes of Health, RePORTER application 10522915, Leveraging PMN immune response to overcome ADT resistance in bone metastatic prostate cancer (1R01CA274605-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10522915. Licensed CC0.

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