Targeting mitochondria in prostate cancer with novel a Gold (Au)-based therapeutic compound to improve radiation treatment (RPA Pilot / Seed Project)

Radiation therapy (RT) is a primary curative option for localized prostate cancer (PCa), yet many patients experience biochemical recurrence, progressing to metastatic castration-resistant prostate cancer (mCRPC) with bone metastases and a median survival of about three years due to high tumor heterogeneity and therapy resistance. While RT is effective in many cases, mechanisms underlying radioresistance, particularly involving non-genetic mitochondrial variability, remain poorly understood. Variability in mitochondrial reactive oxygen species (mtROS), electron transport chain composition, and membrane potential may drive recurrence. Our preliminary data show that mitochondrial biogenesis, regulated by transcription factor A, mitochondrial (TFAM), is upregulated in recurrent PCa, and radioresistant PCa cells exhibit increased mitochondrial metabolism and mtROS, indicating that mitochondrial redox regulation contributes to radioresistance. We identified gold (Au)-based compounds, particularly Au-Tri-C5, as potential therapeutics. Au-Tri-C5 accumulates selectively in PCa cell mitochondria, disrupting mitochondrial function, generating mtROS, and inhibiting proteins involved in resistance. Our research aims to evaluate Au-Tri-C5 in two specific areas: Aim 1 assesses its ability to enhance RT efficacy in radioresistant PCa models by overloading mitochondrial ROS to sensitize cancer cells to radiation; Aim 2 evaluates whether Au-Tri-C5 can prevent PCa invasion and bone resorption by inhibiting TFAM-driven mitochondrial biogenesis in PCa and suppressing osteoclast differentiation through the RANKL pathway. By simultaneously targeting mitochondrial biogenesis and bone resorption, Au-Tri-C5 holds promise for improving mCRPC outcomes and quality of life. If successful, this project could establish Au-based compounds as novel mCRPC therapies that integrate well with existing treatments, potentially reducing recurrence and skeletal-related complications.