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，去势是晚期前列腺癌患者的主要治疗方法。雄激素受体(AR)信号转导在去势耐受前列腺癌(CRPC)中持续活跃，雄激素信号转导抑制剂(ASI)正成为CRPC的一线治疗药物。然而，FDA批准的两种ASIS，阿比特龙和苯扎鲁胺，只能在几个月内改善患者的总体生存。因此，迫切需要寻找新的靶点和开发新的方法来治疗耐ASI的CRPC。二甲双胍是一种广泛使用了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和PCa的死亡率。然而，这一非常重要的观察背后的详细分子机制并不完全清楚。这项研究的长期目标是确定为ASI耐药CRPC患者提供更有效治疗选择的可用药信号通路。本研究的目的是明确Polo-like kinase1(Plk1)在调节mTOR(哺乳动物雷帕霉素靶标)通路和AR信号通路中的作用，并开发这一独特的通路作为ASI耐药CRPC患者的新治疗靶点。中心假设是Plk1抑制联合二甲双胍是治疗ASI耐药CRPC的新方法。这一假说将通过追求两个特定目标来验证-(1)剖析mTOR途径的负调控因子TSC1(结节性硬化症复合体1)的Plk1磷酸化如何在体内导致mTOR途径的激活；(2)确定Plk1抑制与二甲双胍联合使用是否是治疗ASI耐药CRPC的新方法。这两个互补的目标将通过对信号中间产物的生化分析和采用可诱导的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。这项研究的基本原理是，这将是第一次探索Plk1在mTOR/AR通路中的重要性，并检查Plk1抑制与二甲双胍联合使用是否是治疗ASI耐药CRPC的新方法。这一贡献意义重大，因为它将(I)确定Plk1调节mTOR/AR信号的分子机制；(Ii)从遗传学角度评估Plk1如何与PTEN信号丢失协同作用；以及(Iii)确认Plk1是提高二甲双胍疗效的关键治疗靶点。这项研究具有创新性，因为它从一种新的Plk1信号通路接近疾病，挑战了Plk1仅起调节有丝分裂事件功能的传统观点。这些研究准备好了 通过确定对产生和维持CRPC表型至关重要的mTOR/AR信号的关键调节因子，为改进患者的治疗提供新的范例。