# Androgen Activation of Innate Immune Signaling to Enhance Prostate Cancer Immune Response

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2022 · $527,817

## Abstract

Bipolar androgen therapy (BAT) is a paradoxical approach for the treatment of castration-resistant prostate cancer
(CRPC) whereby testosterone levels are rapidly cycled between supraphysiologic and castrate concentrations.
Understanding how BAT works at the molecular and cellular levels might help in rationally combining BAT with
other agents to achieve increased efficacy and tumor responses. Previous observations suggest that
supraphysiological testosterone (SupraT) induce DNA double strand breaks (DSB). It has been speculated that if
left unrepaired, DSBs may lead to cellular crisis and apoptosis. In this proposal, we provide novel evidence that
unrepaired DSBs induced by SupraTs are routed to the autophagosomes where they activate cytoplasmic nucleic
acid sensors that trigger the downstream interferon stimulated genes (ISGs) and innate immune pathways. Based
on our preliminary data, we propose a novel idea that: i) Unrepaired DSBs induced by SupraTs are routed for
specialized autophagic degradation termed nucleophagy; ii) SupraTs induced autophagosomal DNA can activate
cytoplasmic DNA sensing pathways~ specifically the nucleic acid sensing pathway (cGAS-STING and RIG-I
pathway); iii) Activation of nucleic acid sensing pathway by SupraTs would be more pronounced in prostate tumors
that have DNA repair defect; and iv) BAT might activate innate and adaptive immune cells specially, in a subset of
patients having DNA repair defect. In this proposal, we will determine the role of nucleic acid sensors in mediating
immune signaling by SupraTs in PCa. Utilizing tumor biopsies from PCa patients receiving BAT, we will evaluate
whether nucleic acid sensor mediated innate immune signaling serves as a molecular determinant of treatment
response. To test our hypothesis, we will utilize several innovative tools and resources including CRISPR-Cas9
generated knockout cellular models, GeoMx Digital Spatial profiling of immune landscape in the tumor
microenvironment, unique patient derived prostate cancer xenografts models, a humanized mouse models that has
functional innate and adaptive immune cells, and serum and tumor biopsies from patients receiving BAT. We think
these unique resources position us well to undertake the proposed work with immediate clinical impact. We have
assembled a team of experts in basic and clinical prostate cancer biology and immunotherapy who will provide their
unique expertise to successfully accomplish our goals. Successful completion of the proposed work will generate:
a) mechanistic insights into modulation of immune response by SupraTs, b) valuable clinical insights into activation
of immune cells by BAT, c) novel tumor- and serum-based markers that can be utilized for the development of
biomarkers predictive of therapy response, and d) provide a rationale for strategically utilizing BAT to activate
immune response and combine it with immunotherapeutics that empower the adaptive immune system such as
immune checkpoint blockade and...

## Key facts

- **NIH application ID:** 10366325
- **Project number:** 1R01CA243184-01A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Samuel R Denmeade
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $527,817
- **Award type:** 1
- **Project period:** 2021-12-01 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10366325

## Citation

> US National Institutes of Health, RePORTER application 10366325, Androgen Activation of Innate Immune Signaling to Enhance Prostate Cancer Immune Response (1R01CA243184-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10366325. Licensed CC0.

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