Developing therapies to improve enzalutamide in CRPC

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PROJECT SUMMARY The goal of this proposal is to develop a new mechanism-based therapy to improve the antitumor efficacy and sustainability of enzalutamide. Metastatic prostate cancer (PCa) is the 2nd-leading cause of cancer death in men in the US. Castration resistant PCa (CRPC) is the most common and lethal form of the disease. Effective and life-saving treatment is an unmet need. Recently, the enzalutamide (Enz)-based treatment has shown promising clinical results. However, many patients do not respond or quickly develop resistance. New mechanistic understandings and treatment strategies are urgently needed to improve Enz. In CRISPR/Cas9- based screen, we identified glutamic pyruvate transaminases (GPT) as a novel vulnerability or target, sensitizing CRPC cells to Enz. Clinically, we found that GPT is amplified or upregulated in subsets of patient samples that were significantly associated with Enz-resistance and poor disease outcomes. Biologically, our preliminary studies suggest that GPT confers adaptive response and resistance to Enz by connecting 3 important oncogenic pathways in CRPC – i) unfolded protein response (UPR), ii) glutamine metabolism, and iii) synthesis of fatty acids and lipids (lipogenesis), which is known as the metabolic hallmark of CRPC and essential to PCa cell survival and proliferation. Therapeutically, we screened a panel of transaminase inhibitors and identified D-cycloserine (DCS), a clinically-approved antibiotic, as a specific and selective inhibitor to GPT, but not other transaminases. Based on these data, we will develop a new therapy approach to improve the antitumor efficacy and sustainability of Enz by targeting GPT with DCS. The central hypothesis is that GPT is a novel molecular vulnerability to PCa cells, especially CRPC, in Enz-based treatments; therefore, GPT can be therapeutically exploited by DCS to improve the efficacy and durability of Enz. We will test the hypothesis in 3 aims. Aim 1 is to understand the mechanisms defining GPT as a novel therapeutic vulnerability to sensitize Enz. We will reveal the biology, explaining why inhibiting GPT improves Enz. Aim 2 is to test the role of GPT-inhibitor DCS to improve Enz in vitro and in vivo. We will test a working hypothesis that DCS sensitizes PCa cells/tumors to Enz by arresting the growth of CRPC tumors and blocking the progression of ADPC tumors to CRPC. Aim 3 is to determine the relevance and significance of GPT in clinical progressions of PCa. We will use immunohistochemistry and single-cell RNA-sequencing to analyze PCa tissues and biopsy samples from patients undergoing Enz-treatments. We will test a working hypothesis that GPT mRNA/proteins are associated with CRPC progression and Enz-resistance.