Regulation of androgen receptor signaling in prostate cancer by protein arginine methylation

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PROJECT SUMMARY Prostate cancer is the second most common cause of cancer death among men in the United States. While early-stage prostate cancers often respond to hormonal therapy, a subset progresses to an incurable “castration- resistant” state (CRPC), which is resistant to standard hormonal therapies. A defining molecular feature of CRPC is the reactivation of androgen receptor (AR) signaling, indicating that the AR remains central to prostate cancer pathogenesis across disease states. Therefore, novel means of ablating AR signaling can inspire new treatment strategies for CRPC. Through a genome-scale CRISPR/Cas9 screen, we identified the protein arginine methyltransferases 1 and 5 (PRMT1/PRMT5) as novel regulators of the AR pathway. Both PRMT1 and PRMT5 modulate diverse biological processes, including AR signaling, through post-translational modification of substrate proteins on arginine residues. As small molecule inhibitors of PRMT1 and PRMT5 have recently entered clinical development, this pathway can also be therapeutically modulated in patients. This proposal tests the hypothesis that PRMTs may have a specific role in regulating AR-driven transcriptional programs through direct effects on AR and/or its co-factors, and that combination therapy with PRMT inhibitors and direct AR antagonists may be an effective therapeutic strategy in advanced prostate cancer. In Aim 1, we will dissect the molecular mechanisms by which PRMT1 and PRMT5 regulate AR signaling. Specifically, we will compare the effects that PRMT1 and PRMT5 have on AR signaling in various cellular contexts. We will then investigate roles for these PRMTs in modulating AR signaling at various nodes, including histone modification, chromatin architecture, modification of AR co-regulators, and modification of the AR itself. In Aim 2, we will establish the therapeutic potential of combining PRMT1 and/or PRMT5 inhibitors with an AR antagonist in in vitro and in vivo prostate cancer models. Since our preliminary data indicate that both PRMT1 and PRMT5 modulate AR signaling, we hypothesize that inhibiting both enzymes in combination with direct inhibition of AR may be an effective strategy to treat castration-resistant prostate cancer and to delay the emergence of castration resistance. Moreover, prior studies have shown that the combination of PRMT1 and PRMT5 is synergistic and well-tolerated in preclinical in vivo models. We will therefore test the activity of direct AR antagonists in combination with PRMT1 and/or PRMT5 inhibitors in in vivo patient-derived xenograft models of hormone- sensitive and castration-resistant prostate cancer. Finally, we will interrogate the relationship between PRMT1, PRMT5, and AR expression in clinically-annotated prostate cancer tissue specimens and in large-scale prostate cancer sequencing datasets. These experiments will validate PRMT1 and PRMT5 as therapeutic targets in prostate cancer and will lend insight into the mechanisms by which AR signaling is regulated. Overall, this work advances a mechanism-driven therapeutic hypothesis with the potential to improve outcomes for patients with advanced prostate cancer.