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

基本信息

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
项目类别：
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&apos -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

项目摘要

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（由应用提供）：由于前列腺癌（PCA）需要雄激素进行发育，因此cast割是晚期PCA患者的主要治疗方法。由于雄激素受体（AR）信号在耐castration的前列腺癌（CRPC）中继续活跃，因此雄激素信号抑制剂（ASI）成为CRPC的第一行处理。但是，两个FDA批准的ASIS，阿比罗酮和恩扎拉胺，仅改善了几个月的总体患者存活。这是迫切需要确定新目标并开发新的方法来治疗ASI耐药性CRPC。二甲双胍是一种广泛使用40多年的抗糖尿病药物，现在被认为在不同类型的癌症中具有抗肿瘤活性。最近的临床数据表明，二甲双胍的使用可能会降低CRPC和PCA死亡率的发展。但是，尚未完全了解这种非常重要的观察的详细分子机制。这项研究的长期目标是确定可吸毒的信号通路，为ASI耐药性CRPC患者提供更有效的治疗选择。目的是定义polo样激酶1（PLK1）在调节MTOR（雷帕霉素的哺乳动物靶标）途径和AR信号传导中的作用，并利用这一独特的途径作为抗ASI-ASI-ASI-ASI-CRPC患者的新型治疗靶标。中心假设是，PLK1抑制与二甲双胍的结合是一种治疗ASI耐药性CRPC的新方法。该假设将通过追求两个特定的目的来检验 - （1）剖析MTOR途径的负调节剂TSC1的PLK1磷酸化如何导致体内MTOR途径的激活；（2）确定PLK1抑制与二甲双胍的组合是否是治疗ASI耐药性CRPC的新方法。这两个完整的目标将使用信号中间体的生化分析以及使用可诱导的PCA小鼠模型，培养系统和PCA异种移植方法采用遗传策略来实现。这项研究的理由是，它将是第一个探讨F plk1对MTOR/AR途径的重要性，并检查PLK1抑制与二甲双胍的组合是否是治疗ASI-耐药性CRPC的新方法。这种贡献很重要，因为它将（i）定义PLK1调节MTOR/AR信号传导的分子机制；（ii）遗传评估了PLK1如何与PTEN信号丢失坐标；（iii）验证PLK1作为提高二甲双胍效率的关键治疗靶标。这项研究具有创新性，因为它从新型的PLK1信号通路接近疾病时，挑战了PLK1仅作用以调节有丝分裂事件的传统观点。这些研究中毒通过识别MTOR/AR信号的关键调节剂，这对于生成和维持CRPC表型至关重要，为改善患者疗法提供了新的范式。