Repurposing Metformin and Aspirin for Prostate Cancer Prevention and Control

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 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.