# Novel Mechanisms of ROS/RNS Signaling Underlying Castration-Resistant Prostate Cancer Emergence and Progression

> **NIH NIH R01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2021 · $76,970

## Abstract

Abstract
 Limited understanding of molecular mechanisms underlying castration-resistant prostate cancer (CRPC)is
a barrier to effective therapeutic development for this fatal disease. We identified the nitric oxide receptor
complex, soluble guanylyl cyclase (sGC), as a novel CRPC-inhibitory target via unbiased transcriptomics
screening of an emergent CRPC model developed in our lab. Analyses of human PC datasets and our
preliminary results support that sGC activity is inhibited during CRPC progression from androgen-dependent PC,
and that the sGC complex is oxidatively inactivated. However we find the redox-protective mechanisms induced
by androgen deprivation (AD) to protect CRPC cells from apoptosis provides a therapeutic window during which
sGC can be stimulated to maximal bioactivity. Thus, we hypothesize sGC activity inhibits CRPC growth and
that its stimulation by clinically-approved agonists will be therapeutically beneficial in combination with
standard-of-care AD. Our hypothesis is supported by our strong preclinical data showing that the FDA-approved
vasodilator and sGC agonist, riociguat, reduces in vivo growth of castration-resistant xenograft tumors,
decreases PSA and increases intratumoral cyclic cGMP, the product of sGC signaling and a measure of on-
target riociguat efficacy. Consistent with its biological function, sGC stimulation induces robust tumor
oxygenation as well as loss of the CD44 PC stem cell marker, suggesting that it destroys hypoxic stem cell
niches. Castration resistance is associated with tumor hypoxia and consequent radioresistance. We find that
riociguat increases the tumor-suppressive efficacy of radiation in CRPC xenograft tumors. Our objective is to
comprehensively establish molecular mechanisms underlying how and why stimulating the sGC pathway limits
CRPC growth and progression and to identify factors that predict anti-CRPC efficacy of sGC agonists in
preclinical models. We will assess 1) how mechanisms that control sGC levels and molecular reducing
partners that regenerate oxidized inactive sGC are altered in hormone-sensitive vs. castration-resistant cells,
2) how the physiologic effects of sGC bioactivity enact anti-CRPC outcomes, with consideration of hypoxia-
associated PC- relevant metabolic and redox stress mechanisms, and 3) test the efficacy of sGC agonists in
the spectrum of CRPC disease. Our in vitro studies will utilize robust preclinical models of emergence, growth,
progression and metastatic colonization of the bone milieu. We will utilize genetic and pharmacologic means to
modulate sGC expression and activity in gold standard culture models that recapitulate the relevant clinical
features of CRPC and we will utilize robust subcutaneous, orthotopic and metastatic preclinical mouse models
as well as patient-derived xenografts (PDXs). We will validate key molecular findings in de-identified PC
patient-derived specimens including fixed and frozen tissue, serum, and plasma. Our studies will uncover...

## Key facts

- **NIH application ID:** 10381045
- **Project number:** 3R01CA254100-02S1
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Priyamvada Rai
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $76,970
- **Award type:** 3
- **Project period:** 2020-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10381045

## Citation

> US National Institutes of Health, RePORTER application 10381045, Novel Mechanisms of ROS/RNS Signaling Underlying Castration-Resistant Prostate Cancer Emergence and Progression (3R01CA254100-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10381045. Licensed CC0.

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