Multi-omic Evaluation of the mTOR pathway in Radiotherapy-Related Fatigue

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PROJECT SUMMARY/ABSTRACT Cancer-related fatigue is one of the most debilitating, distressing, and commonly reported side effects of cancer treatment, with up to 71% of prostate cancer (PC) patients complaining of fatigue during radiation therapy (RT). While the etiology and associated mechanisms of the fatigue responses to RT treatment remain elusive, the candidate recently found evidence that changes in gene expression of both MTOR and p70S6K were associated with changes in fatigue during RT. The proposed study will explore the network of interactions among the biomolecules present in mTOR signaling pathways at the systems level, which could shift existing symptom management paradigm as it relates to fatigue by offering an understanding of how the mTOR biological functions are regulated and how the fatigue may emerge from its dysregulation. The proposed research is guided by a model of dysregulation of the mTOR pathway and RT-related fatigue. The training plan was designed to allow the candidate to build on her post-doctoral experience to receive the necessary training to become an independent investigator, proficient in genomics, other “omics”, and bioinformatics as they relate to symptom science. An experienced team of scientists will provide career mentoring and training with the following objectives: (1) enhance knowledge of “omics” (i.e., transcriptomics, epigenomics), and the science related to mechanisms of symptoms; (2) gain additional expertise in the characterization of fatigue phenotypes and in relation to patient biological and clinical data; (3) attain bioinformatics proficiency (via didactic coursework and comprehensive hands-on training) in the analysis of transcriptomic, epigenomic, and protein data, and interpretation of the findings; and (4) improve scientific writing skills and build collaborations with experts in the fields of bio-behavioral, symptom management, and omic research that will allow for successful publications in high-impact, peer-reviewed journals, and submission of competitive NIH R-Series grant. The training plan is for thirty-six months and includes six core areas: didactic; interdisciplinary seminars; mentorship; laboratory training; research; and dissemination. There are 3 specific aims proposed. Aim 1: Identify mTOR pathway and activity- related genes associated with changes in fatigue scores from pre, end, and 1 month after stereotactic body radiation therapy (SBRT) in a sample of men with PC. Aim 2: Investigate the relationships between epigenetic regulation of mTOR pathway genes associated with changes in fatigue scores from pre, end, and 1 month after SBRT in a sample of men with PC. Aim 3: Determine the associations between changes in mTOR signaling pathway and activity-related proteins with changes in fatigue scores from pre, end, and 1 month after SBRT in a sample of men with PC. This study identifies a novel area for exploration and aligns well with the NINR Strategic Plan calling for studies on symptom science with a focus on Promoting Personalized Medicine, by understanding the mechanisms underlying the symptom of fatigue through symptom science research.