USP22 is a Novel Target for Prostate Cancer Therapy

USP22 是前列腺癌治疗的新靶点

• 批准号: 8311321
• 负责人: Randy Schrecengost
• 金额: $ 4.15万
• 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 2013-05-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8311321
• 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.

描述(申请人提供)：前列腺癌(PCa)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。虽然局部疾病可以有效治疗，但非器官受限疾病没有有效的治疗方法。前列腺癌在所有阶段都依赖于雄激素受体(AR)信号，因此，AR活性的消融(称为雄激素剥夺疗法)是治疗播散性肿瘤的一线治疗措施。虽然最初是有效的，但由于AR活性的不适当恢复，复发的耐去势前列腺癌(CRPC)在2-3年内发展起来。多种途径可以诱导AR的反复活动，但最常见的改变是AR本身积聚增加。此外，一小部分协同的癌基因，特别是c-Myc，已被证明与AR协同作用，导致疾病进展。由于目前还没有找到有效的治疗方法来治疗这种不治之症，因此有必要确定导致AR活动和CRPC复发的机制，并设计有效的新疗法来治疗CRPC。这项应用鉴定了泛素特异肽酶22(USP22)去泛素化酶是在前列腺癌中上调的AR和c-Myc活性的组合效应因子，其活性为治疗干预提供了一种新的靶向分子。几个关键的初步发现表明：i.USP22在前列腺癌中显著上调；ii)。USP22调控c-Myc转录激活功能；USP22是AR积累和活性的有效调节因子；USP22是累积驱动CRPC形成的截短受体所必需的；USP22对于AR依赖的PCa和CRPC的有效增殖至关重要。基于这些数据，我们假设USP22在肿瘤的形成和向耐药疾病的转变中发挥了作用。这一假设将在两个目标上得到检验。首先，USP22控制c-Myc和AR的机制将在早期和耐药疾病的细胞模型中进行测试。该方法包括抑制USP22的表达，分析c-Myc和AR活性与靶基因转录、蛋白质稳定性/半衰期、蛋白酶体的贡献以及细胞周期的关系。其次，将确定USP22与前列腺癌生长和进展的相关性。我们将采用异种原位移植模型来研究USP22缺失或过度表达对激素敏感和治疗耐药的前列腺癌的影响。结果将根据肿瘤生长、肿瘤内增殖和血清PSA水平(代表AR活性)进行评估。这一实验设计是分析USP22调节两个控制PCa疾病形成和进展的癌基因信号活性的能力的合理而有效的方法。总之，这一建议支持这样的假设，即USP22是PCa中AR稳定性和c-Myc活性的主要调节因子，可以有效地靶向于人类疾病，用于预防和治疗CRPC。