Predicting response to mTOR inhibitors in oral cancer

The use of “mammalian target of rapamycin” (mTOR) inhibitors for prevention and treatment of oral cancer is an exciting new prospect in the field of cancer prevention. The application to oral cancer, a cancer whose primary risk factors include tobacco and alcohol use, comes at an important time when there is high prevalence but relatively few therapeutic options, resulting in a five-year survival rate of 50 percent. In several studies, mTOR inhibition was able to prevent progression of pre-cancerous lesions to oral cancer and even stopped tumor growth. Despite the promise of this new therapeutic, resistance to mTOR inhibition limits the full potential of this targeted therapy. The goal of this proposal is to use genome-wide approaches to identify predictive biomarkers of sensitivity to mTOR inhibition, especially metformin, in both oral premalignant lesions (OPL) and Oral Squamous Cell Carcinoma (OSCC). In this work, mTOR inhibition will be studied in a reverse engineering approach, first removing genes, or activating pathways, treating with mTOR inhibitors and then studying the response. As well as in a forward direction, by first treating cells, OSCC or OPL with mTOR inhibitors then studying the effect of the therapy. By characterizing resistance to mTOR inhibition in oral cancer and identifying biomarkers, this work will increase the precision of this promising new chemopreventive therapy.