Reducing toxicity from prostate cancer radiotherapy through genetics and technology

PROJECT SUMMARY/ABSTRACT There is an incredible need to find new biomarkers to improve our ability to personalize cancer therapy, to identify those that will have toxicity from treatment. This growing need has led to the request for proposals focusing on these problems and searching for solutions, entitled PAR-19-325 “Clinical Characterization of Cancer Therapy- Induced Adverse Sequelae and Mechanism-based Interventional Strategies.” Unfortunately, there are few biomarkers that have been identified that can predict toxicity radiation therapy (RT). RT is a cornerstone of cancer treatment and used to treat over 2/3 of cancer patients. This is particularly notable in the context of localized prostate cancer, which is an exceedingly common cancer for which RT is a standard of care treatment. Because survival is so high, late toxicity after RT and its impact on quality of life (QOL) is critical. In fact, prostate cancer patients have the highest cancer treatment–related years lived with disability worldwide, likely reflecting the high incidence and the high cure rates of modern therapy. RT-related adverse sequelae are related to the complex local host-specific response to therapy, indicating that germ-line biomarkers, that are present in all of a patient’s cells, will be the most likely place to find biomarkers predicting toxicity. Single nucleotide polymorphisms in microRNA, termed miR-SNPs, have been to be functional biomarkers that can identify patients with altered stress responses to therapy. However, most previous efforts studying germline DNA have largely ignored miR-SNPs, as these are not captured in most DNA evaluation platforms. Our prior work has identified a panel of these biomarkers predicting significant late genitourinary (GU) toxicity to RT for prostate cancer patients. The PROSTOX biomarker specifically predicts for late GU toxicity after stereotactic body radiotherapy (SBRT), an advanced form of RT that uses advanced technology to deliver high doses of radiation per treatment session, condensing the RT course to just 5 sessions. Our group has also shown, in a randomized trial, that increasing the physical precision of SBRT delivery reduces post-SBRT GU toxicity as well. In this proposal, the goal is to further validate the predictive power of PROSTOX in additional cohorts, to expand these biomarkers to predict those at risk of acute toxicity that can also lead to chronic toxicity in prostate cancer patients, to investigate the biological differences in the response to radiation for those that have these signatures, and finally, to evaluate whether cutting-edge adaptive radiotherapy can help reduce toxicity in patients by further increasing the precision of SBRT delivery. Results from this proposal will significantly advance our ability to prevent significant late adverse sequelae from radiation for prostate cancer patients, who are a large group of patients who currently suffer greatly from chronic toxicity from treatment.