Molecular Mechanisms of Castration Resistant Prostate Cancer Recurrence & Therapeutic Strategies

针对雄激素受体(AR)信号轴的治疗代表了 转移性前列腺癌患者的治疗，前列腺癌死亡人数最多 经常发生在对一线或二线AR产生抵抗力之后 包括恩扎鲁胺和阿比特龙在内的拮抗剂。我们发现在雄激素中- 缺乏环境或拮抗剂(如苯扎鲁胺)丰富的条件，AR招募非 受体酪氨酸激酶，AcK1(也称为TNK2)，它沉积了新的pY88-H4 AR基因座上的表观遗传标记，促进AR及其剪接变异体AR-V7转录。 值得注意的是，免疫组织化学染色显示，不仅AR的表达上调 随着疾病进展到CRPC期，还表现为AcK1上调。然而，如何 AcK1在CRPC中是否上调尚不完全清楚。 在我们寻求了解CRPC复发的机制细节时，我们观察到 对苯扎鲁胺耐药的CRPC在先前未知的位点Lys609显示AR乙酰化 (AC609-AR)。此外，ac609-AR与AcK1基因内含子1(在ARBA1处)结合，上调表达 它以雄激素不依赖的方式转录。这些数据揭示了一种以前未知的 促进CRPC复发的AcK1/acK609-AR/AcK1前馈信令环路。这些 数据为AcK1抑制剂(R)-9bMS的开发提供了动力，它不仅 抑制AR/AR-V7和随后的AcK1 mRNA表达，但也克服了 对苯扎鲁胺耐药。这些数据综合起来表明，(R)-9bMS具有最佳的 药物特性可能成为CRPC的“第三代”抑制剂 治疗。 本提案的总体目标是研究AcK1/acK609-AR/AcK1信号的作用 在CRPC复发中循环，并执行药物开发、生物标记物和临床前 Credential(R)-9bMS及其有效衍生物SG4-176作为治疗药物所需的治疗研究 治疗方法，长期目标是最终将这种疗法推向临床。 具体来说，我们会： 目的1：研究AcK1/acK609-AR/AcK1信号环作为CRPC进展的中介 也是治疗的靶点。 目的2：探讨AcK1和ac609-AR作为苯扎鲁胺耐药生物标志物的作用。 阿比特龙。 目的3：建立(R)-9bMS和SG4-176的体内药效并进行毒理学研究。

Therapies directed against the androgen receptor (AR) signaling axis represent the backbone of treatment for patients with metastatic prostate cancer, and death from prostate cancer most frequently occurs following the development of resistance to first- or second-line of AR antagonists that includes Enzalutamide and abiraterone. We have uncovered that in androgen- deficient environment or antagonist (e.g. enzalutamide)-rich condition, AR recruits a non- receptor tyrosine kinase, ACK1 (also known as TNK2), which deposits novel pY88-H4 epigenetic marks in the AR locus, facilitating AR and its splice variant, AR-V7 transcription. Significantly, immunohistochemical staining revealed that not only AR expression is upregulated as disease progress to CRPC stage, but also exhibited ACK1 upregulation. However, how ACK1 is up-regulated in CRPCs is not fully clear. In our quest to understand mechanistic details for CRPC recurrence, we observed that enzalutamide-resistant CRPCs exhibit AR acetylation at previously unknown site, Lys609 (ac609-AR). Further, ac609-AR bound to intron 1 of ACK1 gene (at ARBA1 site), upregulating its transcription in androgen-independent manner. These data reveal a previously unknown ACK1/acK609-AR/ACK1 feed-forward signaling loop that promotes CRPC recurrence. These data provided impetus to pursue development of ACK1 inhibitor, (R)-9bMS, which not only mitigated AR/AR-V7 and subsequently ACK1 mRNA expression, but also overcame enzalutamide resistance. Taken together these data suggests that (R)-9bMS with optimal pharmaceutical properties could emerge to be the `third generation' of inhibitors for CRPC treatment. The overall objective of this proposal is to examine the role of ACK1/acK609-AR/ACK1 signaling loop in CRPC recurrence and to perform drug development, biomarker, and preclinical therapeutic studies necessary to credential (R)-9bMS and its potent derivative SG4-176 as a treatment approach, with the long-term goal of ultimately advancing this therapy to the clinic. Specifically we will: Aim 1: Examine the ACK1/acK609-AR/ACK1 signaling loop as a mediator of CRPC progression and a therapeutic target. Aim 2: Investigate ACK1 & ac609-AR status as a biomarker of resistance to enzalutamide and abiraterone. Aim 3: Establish efficacy of (R)-9bMS & SG4-176 in vivo and perform toxicological studies.