Repurposing Metformin and Aspirin for Prostate Cancer Prevention and Control

 描述（由申请人提供）：前列腺癌（PCa）仍然是最常见的诊断癌症，也是美国男性癌症相关死亡的第二大原因。尽管肥胖（体重指数，BMI ≥30）与PCa发病率之间的相关性存在争议，但肥胖一直与更侵袭性形式的PCa和死亡率的风险增加相关。然而，目前还没有使用药物预防肥胖相关PCa进展的建议。大约25-33%接受手术或放射治疗的PCa患者会出现生物学复发，表现为血液中PSA水平升高。作为一名科学家， 寻找新的、有效的方法来降低前列腺癌的发病率和死亡率，特别是在PSA水平升高的肥胖前列腺癌患者中。这个K 07职业发展奖是我开始实现这些目标并成为一名富有成效的转化型癌症预防研究人员的最有效手段。为了实现这一目标，我将在临床/转化研究，临床结果，临床试验管理和方法以及生物统计学方面接受广泛的教学培训。作为我职业发展计划的一部分，我组建了一个跨学科团队，由PCa成果研究、转化研究、小鼠研究和随机临床试验方面的杰出导师组成。我将定期与我的导师互动，并将参加AACR会议，PCa计划项目资助会议和癌症预防和控制研讨会。新泽西罗格斯癌症研究所和罗格斯大学欧内斯特·马里奥药学院癌症预防研究中心的技术装备精良、智力丰富的环境为我提供了独特而宝贵的工具，以促进我的培训和实现我的目标。这个K 07奖将帮助我评估二甲双胍和阿司匹林对抑制炎症和胰岛素的潜在协同作用。mTOR信号通路，从而提供了预防肥胖相关PCa进展的机制。由于其对抑制mTOR、降低高胰岛素血症、调节炎症反应和选择性杀死癌症干细胞的作用，最近Metastasis作为抗癌药物和/或化学预防剂受到关注。然而，二甲双胍抑制前列腺肿瘤发生的潜在机制尚未确定。阿司匹林也被评估为用于治疗和/或预防癌症（包括PCa）的有前景的化学预防剂。然而，阿司匹林是否有助于改善二甲双胍对肥胖相关前列腺进展的抑制作用尚未探讨。二甲双胍的降胰岛素作用和阿司匹林的抗炎特性分别被认为是介导其抗肿瘤疗效的重要机制。我们假设二甲双胍单用或与阿司匹林联用可通过抑制胰岛素/mTOR信号通路和炎症通路延缓肥胖相关PCa进展。为了验证我们的假设，提出了两个综合的具体目标。目的1）在高脂饮食诱导肥胖的前列腺特异性Pten基因敲除（Ptenpc-/-）小鼠中，确定单独使用二甲双胍或与阿司匹林联合使用对前列腺肿瘤发展的体内疗效。我们将首先 确定二甲双胍是否抑制小鼠前列腺肿瘤的发展（即肿瘤的发生率、大小和重量）和/或延迟向浸润性癌的进展，以及阿司匹林是否增强其作用。然后，我们将阐明二甲双胍和阿司匹林影响的主要靶点或途径，以及它们对肥胖相关前列腺进展的潜在协同作用。目的2）在前列腺切除术或放疗后前列腺特异性抗原（PSA）值升高的男性中进行随机安慰剂对照临床试验，评估二甲双胍和阿司匹林（按肥胖分层）的临床获益。本项目将系统评价二甲双胍和阿司匹林对PCa进展的影响，从细胞培养系统到遗传修饰的小鼠模型和原理验证的随机临床试验，以便为未来的临床研究提供结果。该项目的结果不仅将阐明二甲双胍和阿司匹林在调节前列腺进展中的作用机制，而且将为化学预防策略的发展提供信息，特别是对于PSA水平升高的肥胖PCa患者。

 DESCRIPTION (provided by applicant): Prostate cancer (PCa) continues to be the most commonly diagnosed cancer and the second leading cause of cancer-related deaths in American men. Although the association between obesity (body mass index, BMI ≥30) and PCa incidence is controversial, obesity has been consistently associated with increased risk of more aggressive forms of PCa and mortality. However, there are currently no established recommendations forprevention of obesity-related PCa progression using pharmacological \ agents. Approximately 25-33% of PCa patients treated with surgery or radiation experience biological recurrence manifested as a rising PSA level in their blood. It is my goal as a scientist to find novel and effective approaches that will be used to reduce theincidence and mortality of PCa, especially in obese PCa patients with a rising PSA level. This K07 CareerDevelopment Award is the most effective means for me to begin accomplishing these objectives and become aproductive translational cancer prevention researcher. To accomplish this goal, I will receive extensive didactic training in clinical/translational research, clinical outcomes, clinical trial management and methodology, and biostatistics. As part of my career development plan, I have assembled an interdisciplinary team of outstandingmentors in PCa outcomes research, translational research, mouse studies, and randomized clinical trials. I will have regular interactions with my mentors and will attend AACR conferences, meetings for the PCa programproject grant and seminars in cancer prevention and control. The technologically well-equipped and intellectually-rich environment of the Rutgers Cancer Institute of New Jersey and the Center for Cancer Prevention Research in Ernest Mario School of Pharmacy at Rutgers provide me with unique and valuabletools for furthering my training and accomplishing my goals.Scientifically, this K07 award will help me to evaluate the potential synergistic effects of metformin and aspirin on the inhibition of inflammation and insulin/mTOR signaling pathways, thus providing a mechanism for preventing obesity-related PCa progression. Metformin has recently gained attention as an anti-cancer drug and/or a chemoprevention agent because of its effects on inhibiting mTOR, lowering hyperinsulinemia, modulating inflammatory responses, and selectively killing cancer stem cells. However, the underlying mechanistic aspects of metformin on inhibition of prostate tumorigenesis have not been established. Aspirin has also been evaluated as a promising chemoprevention agent for the treatment and/or prevention of cancer, including PCa. However, whether aspirin may contribute to improving inhibitory effects of metformin on obesity related prostate progression has been unexplored. The insulin-lowering effects of metformin and anti-inflammatory properties of aspirin have been suggested as the important mechanisms mediating their antitumor efficacy, respectively. We hypothesize that metformin alone or in combination with aspirin willdelay obesity-related PCa progression through inhibition of insulin/mTOR signaling and inflammation pathways. To test our hypothesis, two integrated Specific Aims are proposed. Aim 1) To determine in vivoefficacy of treatment with metformin alone or in combination with aspirin on the development of prostatic tumor in prostate-specific Pten knock-out (Ptenpc-/-) mice with high-fat diet induced obesity. We will first determinewhether metformin suppresses prostate tumor development (i.e. tumor incidence, size, and weight) and/ordelays the progression to invasive carcinoma in mice, and whether aspirin enhances its effects. Then, we will elucidate the major targets or pathways that are affected by metformin and aspirin and their potentialsynergistic effects on obesity-related prostate progression. Aim 2) To assess the clinical benefit of metformin and aspirin stratified by obesity in a randomized placebo-controlled clinical trial in men with rising prostatespecific antigen (PSA) values following prostatectomy or radiation therapy for PCa. This project willsystematically evaluate the effects of metformin and aspirin on PCa progression from cell culture systems to agenetically modified mouse model and a proof-of-principle randomized clinic trial in order to inform translationof the results for future clinical investigation. Results of ths project will not only shed light on the mechanisms of metformin and aspirin action in modulating prostate progression, but will inform the development of chemoprevention strategies, especially for obese PCa patients with a rising PSA level.