Targeting Signaling Vulnerabilities for Oral Cancer Prevention

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Abstract There is an urgent need to develop prevention strategies to halt progression of oral premalignant lesions (OPL) into head and neck squamous cell carcinoma (HNSCC), a disease that results in over 300,000 deaths each year worldwide. Our team discovered that activation of the PI3K/mTOR signaling network is the most frequently dysregulated cancer-driving signaling mechanism in HNSCC and OPLs and that, in turn, PI3K/mTOR inhibition exerts potent antitumor activity in experimental OPL and HNSCC models. These findings provided the foundation for our Phase II clinical trial (NCT01195922) exploring the antitumor activity mTOR blockade in HNSCC patients. More recently, we showed that repurposing metformin, a drug safely used by millions of type 2 diabetes (T2DM) patients, decreases mTOR signaling and displays potent chemopreventive activity in experimental OPL models. Based on these findings, and epidemiological data showing a significantly lower HNSCC incidence in T2DM patients on metformin, we conducted a Phase IIa trial in individuals with OPL to explore the potential of metformin to prevent oral cancer (M4OC-Prevent trial; NCT02581137). This represented the first study evaluating the chemopreventive potential of metformin in OPL. The histologic response rate was 60%, and we found a significant correlation between histological response and mTOR inhibition in OPL. These results provided the foundation for launching a multi-institutional NCI-funded Cancer Prevention Clinical Trial (M4OC-Prevent 2.0), a Phase IIb randomized, double-blind, placebo-controlled trial in current and former smokers with OPL to explore the potential of metformin for oral cancer prevention. However, we still have an incomplete understanding of the molecular determinants of the therapeutic response to metformin in OPL or in any other precancerous lesions. The overall objective of this project is to elucidate the molecular mechanisms by which metformin acts on OPL and HNSCC to (a) identify biomarkers for predicting and monitoring clinical response, (b) provide a rationale for mechanism-based multimodal precision chemoprevention strategies, and (c) prevent and overcome drug resistance. Leveraging the wealth of data from clinical, genetic, and tissue specimens from our M4OC-Prevent trial with our team’s expertise in decoding cancer promoting pathways, the long-term goal of our project is to define (1) mechanistic biomarkers predicting a response to metformin and (2) suitable multimodal therapeutic options to overcome drug resistance. Our planned studies will uncover new mechanistic and genetic determinants of metformin sensitivity to inform patient selection in future precision prevention trials, unveil novel mechanisms by which metformin induces histological response in OPL by the concomitant inhibition of mTOR and YAP1 signaling, and provide insights into novel a precision immune prevention strategy for metformin- resistant OPL lesions. By focusing on a cancer with a well-recognized premalignant state and readily accessible lesions for histological and molecular evaluation, our findings will have a broad impact, as they will enable the development of metformin as an effective, safe, and low-cost preventive agent for multiple malignancies.