Pharmacological Jak2 inhibition to overcome androgen receptor aberrations in prostate cancer

药理学 Jak2 抑制可克服前列腺癌中的雄激素受体畸变

• 批准号: 10576409
• 负责人: Scott M. Dehm
• 金额: $ 55.95万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10576409
• 关键词: 3-Dimensional; AR gene; Acceleration; Acetates; Androgen Receptor; Androgen Suppression; Androgens; Automobile Driving; Cancer Patient; Castration; Cell Nucleus; Cell Survival; Cells; Cessation of life; Clinical; Clinical Research; Combined Modality Therapy; Data; Development; Dimerization; Disease; Disease Progression; Distant; FDA approved; Failure; Gene Expression; Generations; Genes; Genetic Transcription; Genome engineering; Growth; Growth and Development function; In Vitro; Investigation; Length; Ligand Binding Domain; Malignant neoplasm of prostate; Medical; Messenger RNA; Modeling; Molecular Target; Mus; Myelofibrosis; Nuclear Translocation; Pathway interactions; Patients; Phase; Phenotype; Phosphorylation; Protein Tyrosine Kinase; Proteins; RNA Splicing; Receptor Inhibition; Regulation; Residual state; Resistance; Serum; Signal Induction; Signal Pathway; Signal Transduction; Therapeutic; Toxic effect; Translating; Variant; Work; Xenograft procedure; abiraterone; advanced prostate cancer; androgen deprivation therapy; antagonist; cancer genome; castration resistant prostate cancer; chromatin immunoprecipitation; chromosome conformation capture; clinical development; companion diagnostics; efficacious treatment; efficacy evaluation; enzalutamide; field study; in vivo; in vivo Model; inhibitor; mRNA Expression; next generation; next generation sequencing; novel; novel therapeutic intervention; pharmacologic; phase II trial; phase III trial; preclinical efficacy; preclinical study; predict responsiveness; prevent; prostate cancer cell; prostate cancer cell line; prostate cancer metastasis; prostate cancer model; prostate cancer progression; protein expression; receptor expression; refractory cancer; single-cell RNA sequencing; standard of care; targeted treatment; therapeutic evaluation; therapy development; transcription factor; transcriptome; transcriptome sequencing; transcriptomics; tumor; tumor growth; tumor xenograft; virtual

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.

开发更有效的去势抵抗性（CR）疗法的医疗需求尚未得到满足 前列腺癌（PC）。前列腺癌的去势抵抗状态是无法治愈的，是雄激素缺乏的结果。 剥夺疗法（ADT），其靶向PC细胞中的雄激素受体（AR）活性。这导致了发展 第二代AR靶向治疗，更有效地拮抗AR配体结合域 （恩杂鲁胺）或减少雄激素合成（醋酸阿比特龙）。然而，在AR靶向治疗后，AR 其剪接变体仍然以高水平表达，并在CRPC中保持转录活性， 去势抵抗性生长最终导致患者死亡 该领域的一个主要空白是缺乏对诱导持续性AR的靶向机制的理解 CRPC中的表达和转录活性。在这个mPI提案中，我们将询问新的概念， Jak 2-Stat 5信号转导代表PC中AR基因表达的关键驱动因素，因此， 通过新一代Jak 2抑制剂靶向Jak 2信号传导代表了一种新的治疗策略， CRPC中的AR。这得到了我们严格的初步数据的支持，这些数据表明Jak 2-Stat 5信号转导的激活是一个重要的机制。 AR基因转录的强诱导剂，导致PC中高AR mRNA和蛋白水平。同样，抑制 Jak 2-Stat 5信号传导阻断了PC细胞系、PC异种移植瘤体内和体内AR和AR-Vs的表达。 作为外植体培养物离体生长的患者来源的临床PC。总的来说，这些发现支持了这一假设 Jak 2-Stat 5的激活通过维持AR的表达而关键性地促进CRPC进展， 组成型活性AR变体。我们将追求两个目标：1）确定AR的潜在控制机制 PC中Jak 2信号传导的AR变体mRNA表达，以及Jak 2-Stat 5和AR转录组的重叠; 2)确定新一代Jak 2抑制剂Fedratinib（FED）和Pacritinib（PAC）在 在体外消除CRPC中AR-FL/V7/V9 mRNA和蛋白的表达并抑制CRPC的生长， in vivo. 这项工作是重要的，因为它将确定Jak 2信号驱动的机制 CRPC中持续的AR表达。此外，所提出的工作将确定PAC是否抑制Jak 2， FED可以阻断AR表达和对AR靶向治疗耐药的PC的生长。建议的新奇 Jak 2对AR的调节开辟了一条全新的途径，可以直接控制AR水平和PC增长。 通过目前FDA批准或临床上使用的新一代Jak 2抑制剂的药理学抑制， 发展为其他目的。这些首次实地研究将对治疗产生近期影响 因为他们预计将PAC和FED确立为靶向的新型药物， PC中的AR，并转化为CRPC中的I/II期临床研究。