# Glucocorticoid signaling, taxane resistance, and prostate cancer mortality disparity

> **NIH NIH R21** · LOMA LINDA UNIVERSITY · 2020 · $280,306

## Abstract

African American (AA) men develop highly aggressive prostate tumors and are twice as likely to die of this
malignancy than men from other racial backgrounds. Advanced prostate cancer (PCa) is usually treated with
androgen deprivation therapy and chemotherapy with taxane drugs. Unfortunately, death occurs once the
cancer becomes metastatic and resistant to therapy. Recent studies demonstrate that glucocorticoid receptor
(GR) signaling confers resistance to taxane chemotherapy; however, the underlying mechanisms have not
been clearly established or studied in the context of health disparities. Glucocorticoids are concurrently
administered to PCa patients to mitigate the side effects of therapy, but recent evidence suggests that they
may also accelerate disease progression. This poses a serious problem for AA men, who have chronically
elevated levels of endogenous glucocorticoids and amplified glucocorticoid signaling compared to European
American (EA) men. These observations implicate glucocorticoid signaling as a potential contributor to PCa
mortality disparities, and suggest that targeting GR may attenuate therapy resistance in PCa and reduce these
disparities. The proposed studies are aimed at mechanistically linking elevated GR signaling with resistance to
taxane chemotherapy in PCa, and targeting GR to reverse this resistance. Currently, there is a fundamental
lack in our understanding of the impact of GR-induced chemotherapy resistance in the context of racial
disparities in prostate cancer mortality. This is caused by critical barriers in the field that include lack of studies
linking GR signaling to PCa therapy resistance in the context of health disparities, and limited understanding of
molecular mechanisms underlying GR-induced chemotherapy resistance. This proposal addresses these
critical barriers by exploring the novel overall hypothesis that GR signaling is enhanced in AA prostate tumors
and promotes chemotherapy resistance by upregulating stress survival genes. The hypothesis is supported by
preliminary data suggesting that GR signaling robustly induces the expression of the chemoresistance-
associated proteins LEDGF/p75 and Clusterin in AA-derived cell lines. We will evaluate our overall hypothesis
through two specific aims: Aim 1. Test the hypothesis that GR directly induces chemoresistance in PCa cells
by upregulating stress survival proteins. This will be explored in mechanistic studies using AA and EA cellular
and xenograft models of PCa. Aim 2. Test the hypothesis that GR signaling is elevated in AA men with PCa,
leading to increased expression and circulation of stress survival proteins. This will be explored by examining
the expression of GR in prostate tumor tissues from AA and EA patients, as well as the circulating levels of
LEDGF/p75 and Clusterin in AA and EA men with and without PCa. These exploratory and innovative studies
use a mechanistic approach to establish the role of GR signaling in promoting chemotherapy resist...

## Key facts

- **NIH application ID:** 9904596
- **Project number:** 5R21CA226654-02
- **Recipient organization:** LOMA LINDA UNIVERSITY
- **Principal Investigator:** Carlos A. Casiano
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $280,306
- **Award type:** 5
- **Project period:** 2019-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9904596

## Citation

> US National Institutes of Health, RePORTER application 9904596, Glucocorticoid signaling, taxane resistance, and prostate cancer mortality disparity (5R21CA226654-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9904596. Licensed CC0.

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