Pharmacological Jak2 inhibition to overcome androgen receptor aberrations in prostate cancer

开发更有效的去势抵抗疗法(CR)的医学需求尚未得到满足。 前列腺癌(PC)。PC的去势抵抗状态是无法治愈的，是雄激素失效的结果 剥夺疗法(ADT)，针对PC细胞中雄激素受体(AR)的活动。这导致了发展 更有效地拮抗AR配体结合域的第二代AR靶向治疗 (苯扎鲁胺)或减少雄激素合成(醋酸阿比特龙)。然而，在AR靶向治疗之后，AR 它的剪接变异体仍然在CRPC和DRIVE中高水平表达，并保持转录活性 抗阉割生长，最终导致病人死亡。 该领域的一个主要空白是缺乏对诱发持续性AR的目标机制的了解 在CRPC中的表达和转录活性。在这份MPI提案中，我们将询问 JAK2-Stat5信号代表了PC中AR基因表达的关键驱动因素，因此，在药理学上 通过新一代JAK2抑制剂靶向JAK2信号转导是一种新的治疗策略 CRPC中的AR。这一点得到了我们严格的初步数据的支持，该数据表明JAK2-Stat5信号的激活是一种 强烈的AR基因转录诱导剂导致PC中AR基因的高水平表达。同样，抑制也是如此 JAK2-Stat5信号转导通路阻断PC细胞株、PC体内移植瘤AR和AR-VS的表达 患者来源的临床PC作为体外培养的外植体培养。总体而言，这些发现支持这一假设 JAK2-Stat5的激活通过维持AR和 构成活性AR变异体。我们将追求两个目标：1)确定AR的潜在控制机制 通过JAK2信号在PC中表达AR变异体，以及JAK2-Stat5和AR转录本的重叠； 2)测定新一代JAK2抑制剂Fedratinib(FED)和Pacritinib(PAC)对 消除CRPC中AR-FL/V7/V9基因和蛋白的表达，抑制CRPC的生长 在活体内。 拟议的工作意义重大，因为它将确定JAK2信号驱动的机制 CRPC中持续的AR表达。此外，拟议的工作将确定PAC和JAK2对JAK2的抑制 FED可阻断AR靶向治疗耐药PC的AR表达和生长。建议的新颖性 JAK2对AR的调控为直接控制AR水平和PC生长开辟了一条全新的途径 通过目前FDA批准或临床使用的新一代JAK2抑制剂进行药理抑制 用于其他目的的开发。这些第一领域的研究将对治疗产生近期影响。 CRPC患者的开发，因为他们有望建立PAC和FED作为靶向的新药物 PC中的AR，并转化为CRPC的I/II期临床研究。

There is an unmet medical need for development of more efficacious therapies for castrate-resistant (CR) prostate cancer (PC). The castrate resistant state of PC is incurable and results from a failure of androgen deprivation therapy (ADT), which targets androgen receptor (AR) activity in PC cells. This has led to development of second-generation AR-targeted therapies that more effectively antagonize the AR ligand binding domain (enzalutamide) or reduce androgen synthesis (abiraterone acetate). However, after AR-targeting therapies, AR and its splice variants are still expressed at high levels and remain transcriptionally active in CRPC and drive castrate-resistant growth, ultimately causing patient death. A major gap in the field is the lack of understanding of targetable mechanisms that induce persistent AR expression and transcriptional activity in CRPC. In this mPI proposal, we will interrogate the novel concept that Jak2-Stat5 signaling represents a critical driver of AR gene expression in PC and, therefore, pharmacological targeting of Jak2 signaling by the new-generation Jak2 inhibitors represents a novel therapeutic strategy to eliminate AR in CRPC. This is supported by our rigorous preliminary data showing that activation of Jak2-Stat5 signaling is a strong inducer of the AR gene transcription leading to high AR mRNA and protein levels in PC. Likewise, inhibition of Jak2-Stat5 signaling blocks expression of AR and AR-Vs in PC cell lines, PC xenograft tumors in vivo and in patient-derived clinical PCs grown as explant cultures ex vivo. Collectively, these findings support the hypothesis that activation of Jak2-Stat5 critically promotes CRPC progression by sustaining expression of AR and constitutively active AR variants. We will pursue two aims:1) Determine the mechanisms underlying control of AR and AR variant mRNA expression by Jak2 signaling in PC, and the overlap of the Jak2-Stat5 and AR transcriptomes; 2) Determine the efficacy of the new-generation Jak2-inhibitors Fedratinib (FED) and Pacritinib (PAC) in eliminating AR-FL/V7/V9 mRNA and protein expression in CRPC and suppressing growth of CRPC in vitro and in vivo. The proposed work is significant because it will determine the mechanisms by which Jak2-signaling drives persistent AR expression in CRPC. Moreover, the proposed work will establish whether Jak2 inhibition by PAC and FED can block AR expression and growth of PC resistant to AR-targeted therapy. The novelty of the proposed concept is that Jak2 regulation of AR opens an entirely new avenue to directly control AR levels and PC growth through pharmacological suppression with new-generation Jak2 inhibitors currently FDA-approved or in clinical development for other purposes. These first-in-the-field studies will have near-term impact for therapy development for CRPC patients because they are expected to establish PAC and FED as novel agents to target AR in PC, and translate to a phase I/II clinical study in CRPC.