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

基本信息

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
项目类别：
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

项目摘要

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（CR）疗法的医疗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，是由于雄激素失败造成的剥夺疗法 (ADT)，针对 PC 细胞中的雄激素受体 (AR) 活性。这导致了发展第二代 AR 靶向疗法更有效地拮抗 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 靶向治疗之后，AR 其剪接变体在 CRPC 和驱动中仍以高水平表达并保持转录活性去势抵抗性生长，最终导致患者死亡。该领域的一个主要差距是缺乏对诱导持续 AR 的靶向机制的了解 CRPC 中的表达和转录活性。在这个 mPI 提案中，我们将探讨以下新概念： Jak2-Stat5 信号传导是 PC 中 AR 基因表达的关键驱动因素，因此，药理学新一代 Jak2 抑制剂靶向 Jak2 信号传导代表了一种新的治疗策略，以消除 CRPC 中的 AR。我们严格的初步数据支持了这一点，表明 Jak2-Stat5 信号的激活是 AR 基因转录的强诱导剂，导致 PC 中 AR mRNA 和蛋白质水平较高。同样，抑制 Jak2-Stat5 信号通路在体内和体外阻断 PC 细胞系、PC 异种移植肿瘤中 AR 和 AR-V 的表达源自患者的临床 PC 作为离体培养物进行培养。总的来说，这些发现支持了这一假设 Jak2-Stat5 的激活通过维持 AR 和本构型活性 AR 变体。我们将追求两个目标：1）确定 AR 控制的机制 PC 中 Jak2 信号传导导致的 AR 变体 mRNA 表达，以及 Jak2-Stat5 和 AR 转录组的重叠； 2) 确定新一代 Jak2 抑制剂 Fedratinib (FED) 和 Pacritinib (PAC) 在治疗中的疗效消除 CRPC 中的 AR-FL/V7/V9 mRNA 和蛋白表达并抑制 CRPC 的体外生长和体内。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 AR 持续表达。此外，拟议的工作将确定 PAC 和 Jak2 抑制是否 FED 可以阻断 AR 表达和对 AR 靶向治疗耐药的 PC 生长。提议的新颖性概念是 Jak2 对 AR 的调节开辟了一条直接控制 AR 水平和 PC 增长的全新途径通过目前 FDA 批准或临床中的新一代 Jak2 抑制剂进行药理抑制为其他目的而开发。这些首次领域研究将对治疗产生近期影响 CRPC 患者的开发，因为他们预计将 PAC 和 FED 作为新的靶向药物 AR 应用于 PC，并转化为 CRPC 的 I/II 期临床研究。