Targeting Cell Powerhouses -Mitochondria- to Enhance Radiation Treatment Outcomes

Abstract Prostate cancer is a slow progressive disease in which advancement to aggressive cancer is highly unpredictable. Patients may be diagnosed with localized prostate cancer several years prior to development into metastasizing prostate cancer. Radiation therapy is commonly used as a standard treatment for localized prostate cancer. However, the subset of cancer cells within a tumor and the frequency of recurrence cancer, after radiation therapy, indicate that a good fraction of cancer are survived and contributing to the re-growth of prostate cancer. Therefore, understanding the molecular events that cause radiation resistance in prostate cancer is an urgent needed that will enable us to design combination treatments to enhance radiation therapy efficacy. Clinical data from recurrent prostate cancer patients at Markey Cancer Center, identified a strong association of mitochondria (cell powerhouses) and radiation resistance. The rises of mitochondria, including the increase in mitochondrial size and mitochondrial number, are caused by radiation during time of treatment (radiation-induced new mitochondria). This phenomenal obviously cannot be detected prior to treatment; thus, making it problematic to prevent beforehand. We recently screened FDA-approved drugs in search of compounds that could simultaneously kill pre-existing mitochondria and inhibit a process of radiation-induced making new mitochondria in prostate cancer cells, without being toxic to normal prostate cells. We identified antibiotic Azithromycin (AZM), also known as Z-pack, to be the most effective prototype compound that contains those properties. We further demonstrated that when combining AZM with radiation, they enhance the death of prostate cancer cells including those that are survived the radiation treatment. These data are robust and promising. Accordingly, the ongoing studies in my laboratory are aimed to 1) establish the underlying mechanism of how mitochondria contribution to the survival of radioresistance prostate cancer, and 2) determine if targeting mitochondria, including utilizing AZM, can overcome radioresistance prostate cancer cells, without being toxic to the normal prostate cells. Our application challenges the traditional view of targeting mitochondria in cancers, instead of targeting one mitochondrial population, we propose to target both pre-existing mitochondria and radiation-induced new mitochondria. From the translation point of view, since AZM is already being used clinically, this novel property of AZM as anti-mitochondrial agent will lead to the rapid using AZM as an enhancer of radiation treatment. Knowing that mitochondria is associated with radioresistance prostate cancer, physicians, health care providers, and patients could use this information to identify those who are most likely to respond to radiation or receive such treatments for enhancing efficacy of radiation. If successful, this project will establish a new and significant therapeutic platform for overcome radioresistance, not only in prostate cancer and also in other cancers that use radiation as the standard therapy.