Repurposing metformin in early-stage high risk prostate cancer to avoid ADT-induced cardiovascular toxicity

Abstract Prostate cancer is the second most common cause of cancer-related deaths in American men. About 20-40% of patients with localized castration-sensitive prostate cancer (CSPC) eventually progress, requiring androgen deprivation therapy (ADT). However ADT inevitably fails, giving rise to castration-resistant prostate cancer (CRPC), which is incurable and fatal. A significant fraction of patients undergoing ADT die of treatment-accelerated cardiovascular disease. Pre-existing metabolic dysfunction has been implicated in PC disease incidence, higher rates of prostatectomy failure, and accelerated progression to CRPC. Thus, there is an unmet need to counter the adverse sequelae of ADT through alternative CSPC treatments that do not exacerbate metabolic syndrome but prevent PC progression. Few studies have evaluated whether targeting the metabolic dysfunction associated with early-stage PC can prevent progression and thus the need for ADT. In a recent clinical trial spearheaded by Dr. Bilusic, metformin, an affordable and well-tolerated insulin-sensitizing diabetes drug, has recently shown promise as monotherapy in biologically-recurrent CSPC, preventing PSA rise in about 40% of high-risk patients. To identify the molecular mechanisms and biomarkers of positive response to metformin in PC patients, we performed preliminary cytokine profiling of responder vs non-responder patient sera. We found that mitigation of inflammatory factors implicated in cardiovascular disease as well as markers of pro-apoptotic response are associated with positive metformin response. We also found that metformin responders exhibited pre-treatment cytokine signatures associated with inflammatory metabolic diseases, including diabetes and hyperinsulinemia, which are conditions known to benefit from metformin treatment. We have been able to model the variability of metformin treatment response in two well-characterized CSPC cell lines, LNCaP (highly responsive) and LAPC4 (minimally responsive). Metformin induced cell death in LNCaP but not in LAPC4, which possesses mutant p53 and high Bcl-2 levels. LAPC4 instead showed markers of senescence, which is associated with an inflammatory phenotype. Metformin also elevated levels of damaging high-potency (short-lived) ROS in LNCaP to a greater extent than in LAPC4. LAPC4 instead exhibited elevated levels of hydrogen peroxide upon metformin treatment, a ROS associated with inflammation. Thus the cell models show congruence with factors of positive response seen in patients. Our findings shed light on the potential mechanism of positive response to metformin in CSPC patients, and lay the groundwork for further investigation, while insight into biomarkers predicting positive response could be immediately useful in the clinic. Citation Format: Philip Gregory, Beatriz Mateo-Victoriano, Ling Zhang, Cassie Due, Marijo Bilusic, Priyamvada Rai. Repurposing metformin in early-stage high risk prostate cancer to avoid ADT-induced cardiovascular toxicity. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4335.