Interrogating mitochondrial dysfunction for precision medicine in high-risk prostate cancer

The molecular mechanisms driving disparities in prostate cancer incidence and mortality remain largely unknown. Mitochondria are the powerhouses of the cell, integrating fuel metabolism to provide energy needed for function. There is increasing evidence that mitochondrial dysfunction propels prostate cancer progression, particularly in high-risk population groups. NKX3.1 is a key tumor suppressor gene in prostate cancer whose reduced expression contributes to disease aggressiveness, particularly in men of African descent. Co-occurrence of NKX3.1 loss and mitochondrial genome (mtDNA) mutations are associated with poorer prognosis in prostate cancer patients; however, whether there is functional link between these in driving prostate cancer is yet unknown. Dr. Alexandros Papachristodoulou is investigating the role of NKX3.1 in preserving mitochondrial function to suppress prostate cancer, and whether these mechanisms contribute to prostate cancer disparities in African American men. In this project, Dr. Papachristodoulou will define mediators of mitochondrial and metabolic dysfunction in prostate cancer, using mouse models based on loss of function of NKX3.1. Whether mitochondrial alterations are functionally linked with and can be a biomarker for more aggressive prostate cancer will be investigated, using data from patient cohorts including African American patients. Furthermore, whether mitochondrial vulnerabilities represent a therapeutic target for suppression of prostate cancer in high-risk groups will be determined. The role for metformin as an anti-cancer agent in this setting will be investigated. If successful, this project will determine the mechanisms by which mitochondrial dysfunction promotes tumor progression and uncover precision medicine strategies in men with high-risk prostate cancer. If pre-clinical data appear promising, the team anticipates setting up a clinical trial testing metformin in men undergoing active surveillance.