USP22 is a Novel Target for Prostate Cancer Therapy

USP22 是前列腺癌治疗的新靶点

• 批准号: 8059290
• 负责人: Randy Schrecengost
• 金额: $ 4.84万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8059290
• 关键词: Ablation; Address; Androgen Receptor; Androgens; Automobile Driving; Cancer cell line; Castration; Cell Cycle; Cell model; Cessation of life; Clinical; Data; Diagnosis; Disease; Disease Progression; Disease Resistance; Enzymes; Excision; Experimental Designs; Fibroblasts; Genetic Transcription; Growth; Half-Life; Histones; Hormones; In Vitro; Ligand Binding Domain; Ligands; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Mediating; Mediator of activation protein; Methods; Modeling; Modification; Mutation; Oncogenes; Oncogenic; Operative Surgical Procedures; Organ; Outcome; PC3 cell line; PSA level; Pathway interactions; Patients; Peptide Hydrolases; Play; Process; Production; Prostate Cancer therapy; Proteins; Publishing; RNA Splicing; Radiation therapy; Receptor Signaling; Recurrence; Recurrent Malignant Neoplasm; Regimen; Regulation; Relapse; Reporting; Resistance; Role; Second Primary Neoplasms; Signal Transduction; Staging; Stimulus; Testing; Therapeutic Intervention; Transcriptional Activation; Ubiquitin; Up-Regulation; Variant; Xenograft Model; base; c-myc Genes; clinically relevant; combinatorial; deprivation; design; disorder prevention; effective therapy; gain of function; hormone refractory prostate cancer; human disease; in vivo; male; multicatalytic endopeptidase complex; novel; novel strategies; novel therapeutics; overexpression; protein expression; receptor; receptor expression; serum PSA; therapy resistant; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): Prostate cancer (PCa) is the most commonly diagnosed malignancy and second leading cause of male cancer death in the U.S. While local disease can be effectively treated, there is no effective cure for non-organ confined disease. PCa is exquisitely dependent on androgen receptor (AR) signaling at all stages; therefore, ablation of AR activity (known as androgen deprivation therapy) is the first line of therapeutic intervention for disseminated tumors. While initially effective, recurrent, 'castrate-resistant' prostate cancers (CRPC) develop within 2-3 years as a result of inappropriately restored AR activity. Multiple pathways can induce recurrent AR activity but the most frequently observed alteration is enhanced accumulation of AR itself. Additionally, a small subset of cooperating oncogenes, especially c-Myc, has been shown to act in concert with AR to induce disease progression. Since no effective treatment has been identified for this incurable stage of disease, there is a significant need to determine the mechanisms that contribute to resurgent AR activity and CRPC, and to design effective new therapeutics for CRPC management. This application identifies the Ubiquitin-Specific Peptidase 22 (USP22) deubiquitylating enzyme as a combinatorial effector of both AR and c-Myc activity that is upregulated in PCa, and whose activity affords a novel, targetable molecule for therapeutic intervention. Several key preliminary findings demonstrate that: i. USP22 is significantly upregulated in prostate cancer; ii). USP22 regulates c-Myc transcriptional activation function; iii. USP22 is a potent regulator of AR accumulation and activity; iv. USP22 is required for accumulation of truncated receptors that drive CRPC formation; and v.) USP22 is critical for efficient AR-dependent PCa and CRPC proliferation. Based on these data, we hypothesize that USP22 is playing a role in tumor formation and transition to resistant disease. This hypothesis will be tested in two aims. First, the mechanism by which USP22 controls c-Myc and AR will be tested in cell models of both early stage and resistance disease. This approach involves depletion of USP22 expression and analysis of c-Myc and AR activity with respect to target gene transcription, protein stability/half- life, contribution of the proteasome, and cell cycle profile. Second, the relevance of USP22 towards PCa growth and progression will be determined. Orthotopic xenograft models will be employed to investigate the impact of USP22 depletion or overexpression in hormone sensitive and therapy resistant PCa. The outcome will be appraised based on tumor growth, intratumor proliferation, and serum PSA levels (representative of AR activity). This experimental design is a logical and efficient method to analyze the ability of USP22 to regulate the activity of two oncogenic signals that control PCa disease formation and progression. Together this proposal supports the hypothesis that USP22 is a master regulator of AR stability and c-Myc activity in PCa that could be effectively targeted in human disease for prevention and treatment of CRPC. PUBLIC HEALTH RELEVANCE: Prostate cancer is the most commonly diagnosed malignancy and second leading cause of male cancer death in the U.S. Despite initially effective androgen-depravation treatments, a large percentage of patients will relapse and ultimately die from recurrent cancer. This proposal aims to investigate a novel approach to inhibit two dominant stimuli that are directly involved in cancer formation and transition to resistant disease.

描述（由申请人提供）：前列腺癌（PCa）是美国最常诊断的恶性肿瘤，也是男性癌症死亡的第二大原因。虽然局部疾病可以有效治疗，但对于非器官局限性疾病尚无有效治愈方法。PCa在所有阶段都非常依赖于雄激素受体（AR）信号传导;因此，AR活性的消融（称为雄激素剥夺疗法）是播散性肿瘤的一线治疗干预。虽然最初有效，但复发性“去势抵抗性”前列腺癌（CRPC）在2-3年内发展为不适当恢复AR活性的结果。多种途径可诱导复发性AR活性，但最常见的改变是AR本身的积累增强。此外，一小部分协同致癌基因，特别是c-Myc，已被证明与AR协同作用，诱导疾病进展。由于尚未确定该不可治愈疾病阶段的有效治疗方法，因此非常需要确定有助于AR活性和CRPC复发的机制，并设计有效的CRPC管理新疗法。本申请鉴定了泛素特异性肽酶22（USP 22）去泛素化酶作为在PCa中上调的AR和c-Myc活性的组合效应物，并且其活性提供了用于治疗干预的新型可靶向分子。 几个关键的初步研究结果表明：i。USP 22在前列腺癌中显著上调; ii）. USP 22调节c-Myc转录激活功能; iii. USP 22是AR积累和活性的有效调节剂; iv. USP 22是驱动CRPC形成的截短受体积累所必需的;和v.）USP 22对于有效的AR依赖性PCa和CRPC增殖至关重要。基于这些数据，我们假设USP 22在肿瘤形成和向耐药疾病的转变中发挥作用。这一假设将在两个目标中得到检验。首先，USP 22控制c-Myc和AR的机制将在早期和抗性疾病的细胞模型中进行测试。该方法涉及USP 22表达的消除以及c-Myc和AR活性在靶基因转录、蛋白质稳定性/半衰期、蛋白酶体贡献和细胞周期谱方面的分析。其次，将确定USP 22与PCa生长和进展的相关性。将采用原位异种移植模型研究USP 22耗竭或过表达对激素敏感性和治疗抗性PCa的影响。将根据肿瘤生长、瘤内增殖和血清PSA水平（代表AR活性）评价结局。该实验设计是分析USP 22调节控制PCa疾病形成和进展的两种致癌信号的活性的能力的逻辑和有效的方法。总之，这一提议支持了以下假设：USP 22是PCa中AR稳定性和c-Myc活性的主要调节剂，可以在人类疾病中有效靶向以预防和治疗CRPC。 公共卫生相关性：前列腺癌是美国最常见的恶性肿瘤，也是男性癌症死亡的第二大原因。尽管最初进行了有效的雄激素恶化治疗，但仍有很大比例的患者会复发并最终死于复发性癌症。该提案旨在研究一种新的方法来抑制直接参与癌症形成和向耐药疾病转变的两种主要刺激。