Background: All prostate cancers first manifest as androgen dependent tumors and most patients are initially treated with surgery or radiation. About 30% of these patients return to clinic with recurrent prostate cancer that initially responds to androgen ablation therapy (ADT). Unfortunately, almost all of them fail ADT and develop castrate resistant disease (CRPC) that responds poorly to most cancer therapies and progress to often lethal metastatic CRPC (mCRPC). There are accumulating evidence that at a certain state of progression of hormone sensitive prostate cancer (HSPC) to CRPC, prostate cancer cells adopt to androgen signaling axis targeted therapy (ASI) by switching their metabolism from glycolysis to mitochondrial oxidative phosphorylation (OXPHOS). High OXPHOS activity induces mitochondrial dysfunction, autophagy, cancer invasion, and metastasis. A mitochondrial enzyme glutaminase (GLS) produces L-glutamate from L-glutamine. L-glutamate is utilized in mitochondrial metabolism for energy production through TCA cycle. GLS inhibitors CB-839 and IACS-6274 are being clinically developed for treatment of various human malignancies. We have shown that growth of prostate cancer patient derived xenografts (PDX) is markedly inhibited by a combination treatment of a clinically used ASI enzalutamide (ENZA) followed by a GLS inhibitor.

Methods: We followed the growth of one HSPC and two CRPC PDX tumors in mice and collected tumor tissues and circulating human tumor cells (CTC) from mouse blood samples at sacrifice. We used super resolution STED confocal microscopy to image mitochondria in the tissue samples and in the CTCs, desorption ionization mass spectrometry (DESI-MS) imaging of multiple metabolites in the tissue samples as well as hyperpolarized MRI (HP-MRI) of the xenografted tumors to follow the changes in cellular central carbon metabolism in vivo.

Results: We observed that growth of PDXs developing ENZA resistance is markedly inhibited when ENZA is followed by adding GLS inhibitors with a concomitant reduction in OXPHOS activity. In addition, the ex vivo and in vivo methods introduced to monitor tumor metabolic activities can be easily translated into clinic to monitor the metabolic status of the tumors for early detection of resistance development and as a pharmacodynamic marker for metabolic inhibitor therapy.

Conclusion: GLS inhibitors added to ASI could be effective against CRPC and mCRPC developing resistance to ASI treatment.

Citation Format: Hirak Subhra Basu, Meredith Spradlin, Tian Weihua, Jose Enriquez, Pratip Bhattacharya, Livia Eberlin. Glutaminase inhibitors block metabolic switch in prostate cancer and prevents anti-androgen treatment resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6035.