# Targeting Metabolic Vulnerabilities with Synergistic Therapeutic Agents for Treatment of Metastatic Castration-Resistant Prostate Cancer.

> **NIH NIH F31** · UNIVERSITY OF TEXAS AT AUSTIN · 2024 · $39,539

## Abstract

PROJECT SUMMARY
Broad Impact: Prostate cancer (PCa) is the most commonly diagnosed cancer in American men and in 2022
alone will result in the death of over 34,000 men. PCa mortality is typically caused by disease that has
advanced to the metastatic castration-resistant stage (mCRPC) and has spread to distant sites such as the
bone, brain, liver, and lymph nodes. Currently, there are no effective or curative therapeutic strategies for
mCRPC, which is in part due to high rates of acquired drug resistance to androgen deprivation therapy (ADT)
and the standard-of-care chemotherapy drug for mCRPC, docetaxel (DTX). Consequently, there is a critical
need for novel and effective therapeutic options for mCRPC. Recent findings have indicated glutamine and
related glutamate metabolism as significant drivers of the metabolic reprogramming of mCRPC that contributes
to drug resistance mechanisms. Indeed, a metabolic switch has been identified in PCa following ADT that
allows the cells to rely on the androgen-independent isoform of glutaminase (GLS1, the enzyme that converts
glutamine to glutamate) rather than the isoform that is inhibited by ADT, affording drug resistance. Efforts to
chemically inhibit GLS1 to overcome this issue have failed since there is a steady influx of glutamate via the
xCT transporter when there are physiologically-relevant levels of cystine. However, our preliminary data shows
that concurrently inhibiting GLS1 as well as glutamate dehydrogenase (GDH, the enzyme that converts
glutamate to the TCA cycle intermediate alpha-ketoglutarate) may be sufficient to overcome this resistance
mechanism across PCa subtypes including mCRPC. The overall goal of this project is to identify novel
combinatorial treatments for mCRPC that synergize with DTX to target metabolic vulnerabilities and overcome
drug resistance for improved treatment outcomes. Central hypothesis: Concurrent inhibition of GLS1 and GDH
in combination with DTX can circumvent drug resistance mechanisms and increase therapeutic efficacy
compared to SOC in mCRPC. Aim 1: Determine the metabolic role of GLS1 inhibition with CB-839 plus DTX
for the synergistic inhibition of PCa tumor growth in vivo. Aim 2: Elucidate the impact of concurrent GLS1 and
GDH inhibition plus DTX on PCa growth, proliferation, metabolism, aggressiveness, and invasiveness
compared to SOC in vitro. Aim 3: Evaluate whether combination treatment with a GLS1 inhibitor and a GDH
inhibitor plus DTX can synergistically inhibit PCa growth more effectively than SOC in vivo. Experimental
techniques including metabolomics, metabolic flux analysis using stable isotope tracers, in vitro and in vivo
modeling of mCRPC, and validation of drug treatment efficacy will be undertaken to achieve the research
goals. These findings will be used to inform novel treatment strategies to accompany docetaxel to prevent
cancer growth, proliferation, and aggressiveness in mCRPC for more effective treatments and improved
outcomes for patients ...

## Key facts

- **NIH application ID:** 10929951
- **Project number:** 5F31CA275318-02
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** Gabrelle Lavender Hackman
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $39,539
- **Award type:** 5
- **Project period:** 2023-08-21 → 2026-08-20

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10929951

## Citation

> US National Institutes of Health, RePORTER application 10929951, Targeting Metabolic Vulnerabilities with Synergistic Therapeutic Agents for Treatment of Metastatic Castration-Resistant Prostate Cancer. (5F31CA275318-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10929951. Licensed CC0.

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