Enhancing anti-neoplastic activity of metformin in prostate cancer

增强二甲双胍在前列腺癌中的抗肿瘤活性

• 批准号: 9220731
• 负责人: XIAOQI LIU
• 金额: $ 35.76万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-08 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9220731
• 关键词: 5' -AMP-activated protein kinase; Acceleration; Androgen Receptor; Androgens; Antidiabetic Drugs; Antineoplastic Agents; Biochemical; Cancer Patient; Castration; Cell Proliferation; Clinical; Clinical Data; Clinical Research; Consumption; Data; Development; Disease; Disease Progression; Event; FDA approved; FRAP1 gene; Fostering; Genetic; Gluconeogenesis; Glucose; Goals; Growth and Development function; Health; Hyperinsulinism; Investigation; Liver; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metastatic Prostate Cancer; Metformin; Methodology; Mission; Mitotic; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Outcome; PLK1 gene; PTEN gene; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Phosphorylation; Phosphotransferases; Prostate; Protein Biosynthesis; Public Health; Receptor Signaling; Research; Resistance; Resistance development; Role; Side; Signal Pathway; Signal Transduction; System; TSC1 gene; Testing; Therapeutic; Tuberous sclerosis protein complex; Work; Xenograft procedure; abiraterone; anticancer research; base; cancer therapy; cancer type; castration resistant prostate cancer; cell growth; chemotherapy; design; diagnostic biomarker; docetaxel; effective therapy; improved; in vivo; inhibitor/antagonist; innovation; mTOR Inhibitor; mTOR inhibition; mortality; mouse model; new therapeutic target; novel; novel strategies; overexpression; predictive marker; prostate cancer cell; protein degradation; public health relevance; therapeutic target; therapy development; treatment effect; tumor growth; tumor progression; tumor xenograft

 DESCRIPTION (provided by applicant): Because prostate cancer (PCa) requires androgen for development, castration is the primary treatment for patients with late stage PCa. Because androgen receptor (AR) signaling continues to be active in castration-resistant prostate cancer (CRPC), androgen signaling inhibitors (ASI) are becoming the first line treatment for CRPC. However, two FDA-approved ASIs, abiraterone and enzalutamide, only improve overall patient survival for several months. Thus, it is urgent to identify new targets and develop new approaches to treat ASI-resistant CRPC. Metformin, an antidiabetic drug widely used for over 40 years, is now believed to have anti-neoplastic activity in different types of cancers. Recent clinical data suggests that metformin use may reduce development of CRPC and PCa mortality. However, the detailed molecular mechanisms underlying this very important observation is not completely understood. The long-term goals of this study are to identify druggable signaling pathways that offer more effective treatment options for patients with ASI-resistant CRPC. The objective is to define the role of polo-like kinase 1 (Plk1) in regulating the mTOR (mammalian target of rapamycin) pathway and AR signaling, and to exploit this unique pathway as a novel therapeutic target for ASI- resistant CRPC patients. The central hypothesis is that a combination of Plk1 inhibition with metformin is a new approach to treat ASI-resistant CRPC. This hypothesis will be tested by pursuing two Specific Aims - (1) to dissect how Plk1 phosphorylation of TSC1 (tuberous sclerosis complex 1), a negative regulator of the mTOR pathway, leads to activation of the mTOR pathway in vivo; (2) to determine whether a combination of Plk1 inhibition with metformin is a novel approach to treat ASI-resistant CRPC. These two complementary aims will be accomplished using biochemical analyses of signaling intermediates and employing genetic strategies with inducible PCa mouse models, culture systems and PCa xenograft methodologies. The rationale for the research is that it will be the first to probe the importance f Plk1 to the mTOR/AR pathways and to examine whether a combination of Plk1 inhibition with metformin is a novel approach to treat ASI-resistant CRPC. This contribution is significant because it will (i) define the molecular mechanism by which Plk1 regulates the mTOR/AR signaling; (ii) genetically evaluate how Plk1 cooperates with loss of PTEN signaling; and (iii) validate Plk1 as a critical therapeutic target to enhance the efficacy of metformin. The research is innovative as it approaches the disease from a novel Plk1 signaling pathway, challenging the traditional view that Plk1 functions solely to regulate mitotic events. These studies are poised to provide a new paradigm for improved patient therapies by identifying the key regulator of the mTOR/AR signaling that is critical for generating and maintaining the CRPC phenotype.

 描述（申请人提供）：由于前列腺癌（PCa）的发展需要雄激素，因此去势是晚期 PCa 患者的主要治疗方法。由于雄激素受体 (AR) 信号在去势抵抗性前列腺癌 (CRPC) 中持续活跃，因此雄激素信号抑制剂 (ASI) 正在成为 CRPC 的一线治疗方法。然而，FDA 批准的两种 ASI，阿比特龙和恩杂鲁胺，只能提高患者几个月的总体生存率。因此，迫切需要确定新的靶点并开发新的方法来治疗 ASI 耐药的 CRPC。二甲双胍是一种广泛使用 40 多年的抗糖尿病药物，现在被认为对不同类型的癌症具有抗肿瘤活性。最近的临床数据表明，二甲双胍的使用可能会降低 CRPC 的发展和 PCa 死亡率。然而，这一非常重要的观察结果背后的详细分子机制尚未完全了解。这项研究的长期目标是确定可药物化的信号通路，为 ASI 耐药的 CRPC 患者提供更有效的治疗选择。目的是明确 Polo 样激酶 1 (Plk1) 在调节 mTOR（哺乳动物雷帕霉素靶点）通路和 AR 信号传导中的作用，并利用这一独特通路作为 ASI 耐药 CRPC 患者的新治疗靶点。核心假设是 Plk1 抑制与二甲双胍联合治疗是治疗 ASI 耐药性 CRPC 的新方法。这一假设将通过两个具体目标进行检验 - (1) 剖析 TSC1（结节性硬化症复合物 1）（mTOR 通路的负调节因子）的 Plk1 磷酸化如何导致体内 mTOR 通路的激活； (2) 确定 Plk1 抑制与二甲双胍联合治疗是否是治疗 ASI 耐药 CRPC 的新方法。这两个互补的目标将通过信号中间体的生化分析以及采用可诱导 PCa 小鼠模型、培养系统和 PCa 异种移植方法的遗传策略来实现。该研究的基本原理是，它将首次探讨 f Plk1 对 mTOR/AR 通路的重要性，并检查 Plk1 抑制与二甲双胍的组合是否是治疗 ASI 抵抗性 CRPC 的新方法。这一贡献意义重大，因为它将 (i) 定义 Plk1 调节 mTOR/AR 信号传导的分子机制； (ii) 从基因角度评估 Plk1 如何与 PTEN 信号丢失协同作用； (iii) 验证 Plk1 作为增强二甲双胍疗效的关键治疗靶点。这项研究具有创新性，因为它从一种新颖的 Plk1 信号通路研究疾病，挑战了 Plk1 仅发挥调节有丝分裂事件作用的传统观点。这些研究旨在 通过鉴定对于产生和维持 CRPC 表型至关重要的 mTOR/AR 信号传导的关键调节因子，为改善患者治疗提供了新的范例。