The goal of precision prevention is to tailor interventions based on individualized patient cancer risk and likelihood of progression. This approach is particularly relevant for prostate cancer since it is characteristically indolent, and thus delaying disease progression can be highly advantageous for patients. Therefore, identifying molecular features predictive of cancer progression and response to specific interventions is vital to improve precision prevention in prostate cancer. In this regard, expression levels and localization of the tissue-specific homeobox protein, NKX3.1, helps distinguish men with high risk for developing more aggressive prostate cancer. Our recent study revealed a novel function for NKX3.1 in mitochondria, where it regulates aberrant mitochondrial oxidative stress to suppress prostate cancer initiation. Lower NKX3.1 expression levels at gene and protein levels are associated with poor outcome and higher risk for aggressive prostate cancer. We are now investigating the role of NKX3.1 as a prognostic marker and potential target for prostate cancer precision prevention interventions. Our new preliminary data indicate a role for metformin as a preventative intervention in contexts of reduced NKX3.1. Specifically, we have shown that metformin reduces oxidative stress and suppresses cancer initiation in the prostates of Nkx3.1 mutant mice. Moreover, studies in human prostate cancer cells as well as human prostate cancer organotypic assays revealed that metformin can indeed, restore mitochondrial function and inhibit tumorigenicity in the absence of NKX3.1. Although men on active surveillance for prostate cancer may benefit from metformin intervention, it has been unclear whether metformin is effective in delaying disease progression and, if so, whether specific patients are more likely to benefit. Our new data implicate NKX3.1 status as a predictor of response to metformin, suggesting that it can stratify high-risk prostate cancer patients most likely to benefit from such intervention during active surveillance.

Citation Format: Alexandros Papachristodoulou, Aditya Dutta, Cory Abate-Shen. NKX3.1 expression predicts response to metformin intervention in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1423.