Role and targeting of PRMT5 in prostate cancer

前列腺癌是美国男性癌症死亡的第二大原因。这样做的目的是 该项目旨在通过克服前列腺癌的机制，开发一种治疗前列腺癌的新方法。 抵抗。雄激素受体(AR)信号驱动前列腺癌的发生和发展，以及 雄激素剥夺疗法(Adt)是治疗局部晚期和转移性激素缺乏的标准疗法。 前列腺癌(HNPC)。不幸的是，大多数患者患上耐去势前列腺癌(CRPC)。 在2-3年内通过AR重新激活(例如，AR过度表达、AR突变、AR剪接变体)，这也是 两种新一代抗AR信号转导抑制剂阿比特龙和阿比特龙的耐药机制 苯扎鲁胺。此外，所有这些药物都会诱导AR阴性的神经内分泌前列腺的发展。 癌症(NEPC)，约占CRPC病例的25%，是一种致命的晚期前列腺癌 没有任何治疗选择的癌症。因此，迫切需要开发新的目标定位方法 前列腺癌的治疗。蛋白精氨酸甲基转移酶5(PRMT5)是一种新出现的癌基因，通常 表观遗传学抑制靶基因的转录，如肿瘤抑制因子和细胞周期抑制因子 癌细胞。初步研究结果表明，PRMT5在体外和体内都能促进前列腺癌细胞的生长 在HNPC和CRPC细胞中通过表观遗传激活AR转录。与ADT和ASI不同，PRMT5 使用我们的体外实验，我们的新型抑制物不会诱导前列腺癌细胞发生NEPC 模型系统。鉴于AR转录先于AR剪接以及野生型和突变体的翻译 AR蛋白，我们假设靶向PRMT5将提供一种有效和独特的治疗方法 通过克服AR重新激活的机制而不会导致NEPC的发生。至 检验这一假设，我们将追求以下目标。目标1将确定PRMT5在调节AR中的作用 在CRPC细胞系中的表达和细胞生长。目标2将阐明PRMT5的表观遗传学机制 调节AR转录和细胞生长以及神经内分泌分化。AIM 3将评估是否 在动物模型上，PRMT5靶向治疗HNPC和CRPC均有较好的疗效。目标4 将改善PRMT5抑制剂的效力和药代动力学特性，同时保持其对 前列腺癌临床前研究。 影响：成功完成拟议的研究将获得对PRMT5如何 表观遗传学调节前列腺癌细胞的AR转录，并将提供临床前证据 靶向PRMT5是治疗HNPC和CRPC而不诱发NEPC的有效方法 发展。进一步改进和鉴定有效和特异的PRMT5抑制剂可能会导致 未来临床试验中PRMT5抑制剂的开发。

Prostate cancer is the second leading cause of cancer death among American men. The objective of this project is to develop a novel therapeutic approach to treat prostate cancer by overcoming the mechanisms of resistance. Androgen receptor (AR) signaling drives prostate cancer development and progression, and androgen deprivation therapy (ADT) is the standard of care for locally advanced and metastatic hormone naïve prostate cancer (HNPC). Unfortunately, most patients develop castration resistant prostate cancer (CRPC) within 2-3 years via AR reactivation (e.g., AR overexpression, AR mutations, AR splice variants), which is also the mechanism of resistance to the two next generation anti-AR signaling inhibitors (ASI) abiraterone and enzalutamide. Further, all of these agents induce the development of AR negative neuroendocrine prostate cancer (NEPC), which constitutes approximately 25% of CRPC cases, a lethal and late stage of prostate cancer without any treatment option. Thus, there is an urgent need to develop novel targeting approaches for prostate cancer treatment. Protein arginine methyltransferase 5 (PRMT5) is an emerging oncogene that often epigenetically represses transcription of target genes such as tumor suppressors and cell cycle inhibitors in cancer cells. Preliminary findings show that PRMT5 promotes prostate cancer cell growth in vitro and in vivo via epigenetic activation of AR transcription in both HNPC and CRPC cells. Unlike ADT and ASI, PRMT5 inhibition by our novel inhibitor does not induce NEPC development in prostate cancer cells using our in vitro model system. Given that AR transcription precedes AR splicing and the translation of wild-type and mutant AR proteins, we hypothesize that targeting PRMT5 will offer an effective and unique treatment approach for prostate cancer by overcoming the mechanisms of AR reactivation without inducing NEPC development. To test this hypothesis, we will pursue the following aims. Aim 1 will determine the role of PRMT5 in regulating AR expression and cell growth in CRPC cell lines. Aim 2 will elucidate the epigenetic mechanism by which PRMT5 regulates AR transcription and cell growth as well neuroendocrine differentiation. Aim 3 will evaluate whether PRMT5 targeting demonstrates a better treatment effect for both HNPC and CRPC in animal models. Aim 4 will improve the potency and pharmacokinetic properties of PRMT5 inhibitors while preserving its specificity for prostate cancer preclinical studies. Impact: Successful completion of proposed research will gain mechanistic insight into how PRMT5 epigenetically regulates AR transcription in prostate cancer cells and will provide preclinical evidence that targeting PRMT5 is an effective approach for treatment of both HNPC and CRPC without inducing NEPC development. Further improvement and identification of potent and specific PRMT5 inhibitors will likely lead to the development of PRMT5 inhibitors for future clinical trials.