Nuclear-Mitochondrial DNA Interplay During Prostate Cancer Clonal Evolution
Abstract
Prostate cancer (PCa) is the most common cancer in men in the United States, after skin cancer. It is the second leading cause of death from cancer in men, with more than 26,000 deaths per year in the United States. The current protocols for PCa diagnosis are based on prostate-specific antigen (PSA) blood testing and digital rectal examination; however, none of the tools are able to distinguish between indolent and aggressive disease. Therefore, there is an urgent need for clinicians and patients to identify which key features in PCa lead to a metastatic and lethal disease. We know of the importance of changes in the metabolic machinery when cancer cells leave the prostate because they need to constantly adapt to completely new environments. The main guardian of metabolism in the cell is the mitochondrion, a bacterial sized structure inside the cell, which importantly contains its own genes that are termed mitochondrial DNA or mtDNA. Intriguingly, mtDNA changes are what allowed scientists to define the patterns of human migration and people s adaptation to entirely new environments as they colonized all of earth s continents between 70,000 to 20,000 years ago. Furthermore, mtDNA mutations have been found to be associated with different tumors including PCa. In the same way, I aim to study the mitochondrial changes that occur when cancer cells escape from prostate and colonize metastatic sites that present them with entirely different environments. I will explore this process in the new RapidCaP mouse model system. It was developed by my mentor and is unique in recapitulating natively growing metastatic PCa. If my approach is successful, it will deliver candidate biomarkers for the ability to separate the many men with PCa that will never develop life-threatening disease from those that do. After that, the validation of my results in human is expected to take 2 years of collaboration with our clinical partners. A second potential outcome of my research is the identification of mitochondrial drug targets that help PCa patients. For an already existing drug, translation to patient benefit could take as few as 2 years. PCa trials with the mitochondrial drug Metformin are a great example for this. For new drugs, the process would take between 5 and 10 years. With this project, I have the opportunity to be part of a multidisciplinary research group consisting of mentoring experts in both cancer and metabolism in the outstanding environment of the Cold Spring Harbor Laboratory. My research approach will give me unique expertise, which in the long term will form the basis of my own original program for a career in PCa research.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710408
Entities
People
- Irene Casanova-Salas
Organizations
- Cold Spring Harbor Laboratory
- United States Army