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: 10443971
• 负责人: Scott M. Dehm
• 金额: $ 57.67万
• 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 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10443971
• 关键词: 3-Dimensional; AR gene; Acetates; Androgen Receptor; Androgen Suppression; Androgens; Automobile Driving; Cancer Patient; Cell Nucleus; Cell Survival; Cells; Cessation of life; ChIP-seq; 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; Pharmacology; Phase; Phenotype; Protein Tyrosine Kinase; Proteins; RNA Splicing; Receptor Inhibition; Regulation; Residual state; Resistance; Serum; Signal Pathway; Signal Transduction; Therapeutic; Toxic effect; Translating; Variant; Work; Xenograft procedure; abiraterone; advanced prostate cancer; androgen deprivation therapy; antagonist; base; 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; 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.

开发更有效的治疗去势抵抗（CR）的医学需求尚未得到满足。