USP22 Function in Advanced Prostate Cancer

USP22 在晚期前列腺癌中的功能

• 批准号: 9294005
• 负责人: KAREN E KNUDSEN
• 金额: $ 49.35万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9294005
• 关键词: Ablation; Advanced Malignant Neoplasm; Androgen Receptor; Androgens; Biochemical; Cancer Etiology; Castration; Cessation of life; Chromatin; Clinical; Complex; Data; Development; Diagnosis; Disease; Disease Progression; Equilibrium; Event; Gene Amplification; Gene Expression; Generations; Growth; Human; Intervention Studies; Lead; Ligands; Maintenance; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Mediator of activation protein; Modality; Modeling; Molecular; Morbidity - disease rate; Oncogenes; Oncogenic; Outcome; Output; Pathway interactions; Patients; Phase; Phenotype; Play; Post-Translational Protein Processing; Pre-Clinical Model; Process; Prostate Adenocarcinoma; Publishing; Recurrent tumor; Regulation; Resistance; Role; SAGA; SIRT1 gene; Suggestion; Therapeutic Intervention; Tumorigenicity; Up-Regulation; androgen deprivation therapy; base; c-myc Genes; castration resistant prostate cancer; chemotherapy; human disease; improved; in vivo; in vivo Model; inhibitor/antagonist; insight; member; men; novel; prevent; programs; public health relevance; receptor; receptor binding; receptor upregulation; targeted treatment; therapeutic target; therapy resistant; transcription factor; tumor; tumor growth; tumor progression; tumorigenic

 DESCRIPTION (provided by applicant): Prostatic adenocarcinoma (PCa) is resistant to chemotherapy, but is exquisitely dependent on the activity of the androgen receptor (AR), for growth, survival, and progression. As such, AR is the first line therapeutic target for all patient with disseminated disease. AR-directed therapies entail the use of androgen deprivation therapy (ADT), used in combination with direct AR antagonists. While initially effective, recurrent tumors arise within 2-3 years wherein the AR has been inappropriately reactivated. This stage of disease, termed "castration-resistant prostate cancer" (CRPC) is the incurable phase. Examination of human CRPC revealed that the major mechanism leading to therapy-resistance is inappropriately restored AR activity. Consonantly, preclinical modeling of AR upregulation showed that this event alone is sufficient to drive progression to CRPC. The mechanisms by which AR upregulation occurs during disease progression remained incompletely defined - while amplification of the AR locus accounts for a fraction of these observations, a significant proportion of CRPCs show upregulation of AR without gene amplification. Strikingly, collaborative efforts between the Knudsen and McMahon labs unexpectedly identified deregulation of the SAGA complex member USP22, a known deubiquitylase, as a master regulator of AR levels and output that is sufficient to induce CRPC formation. Moreover, USP22-dependent SAGA activity proved requisite for c- Myc function in prostate cancer, suggesting that USP22 activity is critical for the two major oncogenic pathways that drive prostate cancer progression. Our collective findings have potentially dramatic clinical implications, and strongly support the hypothesis that deregulation of USP22 plays a major role in the transition to CRPC via regulation of the AR/Myc axis, and that targeting the enzymatic function of USP22 can be developed as a novel means of therapeutic intervention. The novel aims herein will illuminate the means by which USP22 modulates the two major pathways that govern prostate cancer development and progression, delineate the mechanisms through which USP22 promotes lethal tumor phenotypes, and comprehensively assess the in vivo and ex vivo impact of USP22 on tumor development and progression. On balance, the studies described will challenge the transformative concept that underpins aggressive prostate cancer phenotypes that can be targeted for therapeutic benefit.

 描述（由申请人提供）：前列腺癌（PCa）对化疗耐药，但其生长、生存和进展完全依赖于雄激素受体（AR）的活性。因此，AR是所有播散性疾病患者的一线治疗靶点。AR定向治疗需要使用雄激素剥夺治疗（ADT），与直接AR拮抗剂联合使用。虽然最初有效，但复发性肿瘤在2-3年内出现，其中AR已被不适当地重新激活。这个阶段的疾病，称为“去势抵抗性前列腺癌”（CRPC）是不可治愈的阶段。对人CRPC的检查显示，导致治疗抵抗的主要机制是不适当地恢复AR活性。一致的是，AR上调的临床前建模表明，仅该事件就足以推动进展为CRPC。疾病进展期间AR上调发生的机制仍不完全确定-虽然AR基因座的扩增占这些观察结果的一小部分，但相当大比例的CRPC显示AR上调而无基因扩增。引人注目的是，Knudsen和McMahon实验室之间的合作努力意外地确定了佐贺复合物成员USP 22（一种已知的去泛素化酶）的失调，作为足以诱导CRPC形成的AR水平和输出的主要调节因子。此外，USP 22依赖性佐贺活性被证明是前列腺癌中c-Myc功能所必需的，表明USP 22活性对于驱动前列腺癌进展的两个主要致癌途径是关键的。我们的集体研究结果具有潜在的戏剧性临床意义，并强烈支持这一假设，即USP 22的失调在通过调节AR/Myc轴向CRPC的转变中起着重要作用，并且靶向USP 22的酶功能可以被开发为一种新的治疗干预手段。本文的新目标将阐明USP 22调节控制前列腺癌发展和进展的两个主要途径的方法，描述USP 22促进致死性肿瘤表型的机制，并全面评估USP 22对肿瘤发展和进展的体内和离体影响。总的来说，所描述的研究将挑战支持侵袭性前列腺癌表型的变革性概念，这些表型可以被靶向用于治疗益处。