# Inhibiting Emergence and Progression of Castration-resistant Prostate Cancer through Enforcement of Senescence and Alteration of the Tumor Microenvironment

> **NIH NIH F31** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2020 · $40,289

## Abstract

Project Summary
 Castration-resistant prostate cancer (CRPC) arises from a failure of standard-of-care
androgen deprivation (AD) therapy to suppress emergence of castration-resistant (CR) variants
from the original androgen deprivation-responsive PC (ADPC). Identifying molecular drivers of
emergence is critical for developing curative therapies, which are sorely needed. We have shown
AD induces cell senescence (ADIS), a permanent proliferative arrest, in ADPC (LNCaP) cells. Our
work was the first to show that ADIS selects for expansion of AD-resistant quiescent
subpopulations, hastening early CRPC outgrowths (termed LNCaP-SB5). These LNCaP-SB5
represent the earliest CR cells and are a unique model for evaluating acute molecular changes
underlying CRPC etiology. Unbiased microarray screening comparing LNCaP-SB5 with parent
LNCaP (SB0) cells shows a critical subunit of the soluble guanylate cyclase (sGC) complex,
GCSa3 (gene name: GUCY1A3), is increased under AD in the ADPC cells but downregulated in
their early CRPC LNCaP SB5 counterparts.
 Riociguat is an orally-bioavailable, FDA-approved sGC stimulator used to treat pulmonary
hypertension. Using BAY41-8543, a chemical analog of riociguat, we enhanced sGC signaling in
our in vitro model of prostate cancer progression and in an in vivo xenograft CRPC model. BAY41-
8543 enhanced expression of p53 and p16INK4a in ADPC LNCaP cells, suggesting enforcement of
AD-induced tumor suppression and reduced xenograft CRPC tumor formation by LNCaP-SB5 and
LNAI (an established CRPC variant of LNCaP) proportional to the extent by which sGC signaling
was enhanced, however, treatment did not affect viability in culture, suggesting a paracrine
component to tumor suppression in CRPC. Based on these findings, we hypothesize stimulation of
the sGC pathway will enhance AD-associated tumor suppression and limit CRPC emergence and
progression. Therefore, we propose: 1) to determine whether riociguat treatment can enhance AD
durability in ADPC to prevent CRPC emergence and 2) whether and how sGC stimulation creates a
hostile tumor microenvironment to limit established CRPC. Our study will potentially facilitate rapid
and safe clinical repurposing of riociguat in combination with standard-of-care AD for treatment of
incurable prostate cancer.

## Key facts

- **NIH application ID:** 9829485
- **Project number:** 5F31CA232653-02
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Clara Issabella Troccoli
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $40,289
- **Award type:** 5
- **Project period:** 2018-12-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9829485

## Citation

> US National Institutes of Health, RePORTER application 9829485, Inhibiting Emergence and Progression of Castration-resistant Prostate Cancer through Enforcement of Senescence and Alteration of the Tumor Microenvironment (5F31CA232653-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9829485. Licensed CC0.

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