Enhancing anti-neoplastic activity of metformin in prostate cancer

 描述（由申请方提供）：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，雄激素信号抑制剂（ASI）正成为CRPC的一线治疗药物。然而，两种FDA批准的ASI，阿比特龙和恩杂鲁胺，仅改善了几个月的总患者生存期。因此，迫切需要确定新的靶点并开发新的方法来治疗ASI-CRPC。二甲双胍是一种广泛使用超过40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减少CRPC和PCa死亡率的发展。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理解。本研究的长期目标是确定可药物化的信号通路，为AS I耐药CRPC患者提供更有效的治疗选择。目的是确定polo样激酶1（Plk 1）在调节mTOR（雷帕霉素的哺乳动物靶标）通路和AR信号传导中的作用，并利用这种独特的通路作为ASI耐药CRPC患者的新治疗靶点。中心假设是Plk 1抑制与二甲双胍的组合是治疗AS I耐药CRPC的新方法。该假设将通过追求两个特定目的进行测试-（1）剖析TSC 1（结节性硬化症复合物1）（mTOR通路的负调节剂）的Plk 1磷酸化如何导致体内mTOR通路的激活;（2）确定Plk 1抑制与二甲双胍的组合是否是治疗AS I耐药CRPC的新方法。这两个互补的目标将通过使用信号中间体的生化分析和采用具有诱导型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，它将是第一个探索Plk 1对mTOR/AR通路的重要性，并检查Plk 1抑制与二甲双胍的组合是否是治疗AS I耐药CRPC的新方法。这一贡献是重要的，因为它将（i）定义Plk 1调节mTOR/AR信号传导的分子机制;（ii）从遗传学上评估Plk 1如何与PTEN信号传导的丧失合作;和（iii）验证Plk 1作为关键治疗靶点以增强二甲双胍的疗效。这项研究是创新的，因为它从一种新的Plk 1信号通路来研究这种疾病，挑战了Plk 1仅用于调节有丝分裂事件的传统观点。这些研究准备 通过鉴定对产生和维持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。

 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.