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

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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 with mCRPC.