Targeting mTOR with Metformin for Oral Cancer Prevention

In spite of the strong rationale for the use of PI3K and mTOR inhibitors for HNSCC in the clinic, their potential immunosuppressive activity and other undesirable side effects may raise safety concerns regarding their long term use as chemopreventive agents (Cohen et al. 2012). This is of particular relevance to patients diagnosed with potential premalignant oral lesions (OPL), such as hyperplasia and dysplasia that may undergo variable progression to malignancy over a period of years, thus requiring extended therapy (Warnakulasuriya et al. 2008). OPL often present as leukoplakia or erythroplakia (white or red patches, respectively) that have variable rates of progression to cancer, ranging from 11 to 36% for leukoplakia to >50% for erythroplakia (Lee et al. 2000; Reichart and Philipsen 2005). Long-term surveillance for progression is frequently the choice for non-resectable OPL patient management. Furthermore, even adequate surgical resection with negative margins has a relatively high rate (15-40%) of progression to oral squamous cell carcinoma (Arnaoutakis et al. 2013). This reinforces the concept that the presence of OPL represents a risk for malignant transformation due to occult clonal premalignant cells that may demonstrate normal histology (Braakhuis et al. 2005).

Metformin is an oral biguanide that is currently the drug of choice for the treatment of Type 2 Diabetes, and is being prescribed to at least 120 million people worldwide (Viollet et al. 2012). Hence, metformin’s safety profile for long-term use and the management of its potential side effects are all well documented. Compelling evidence demonstrates metformin exerts anticancer effects in various cancers, including the breast (Fan et al. 2015), endometrium, colon, thyroid and esophagus (Moon and Mantzoros 2014), pancreas (Gou et al. 2013; Karnevi et al.

2013), stomach (Kato et al. 2012) and prostate (Kato et al. 2015) by reducing tumor cell growth in part by reducing the activity of mTOR as part of its complex mTORC1 (Pollak 2010; Quinn et al. 2013; Pollak 2012; Pierotti et al. 2013). Therefore, we can hypothesize that in malignancies where the mTORC1 pathway is frequently hyperactivated, such as HNSCC, targeting mTOR with metformin may represent an effective, safe, and low cost therapeutic strategy for cancer prevention.

Metformin showed a striking impact in tumor progression by a significant decrease the number of low and high grade dysplasia in premalignant oral cancer mouse model induced by chemical carcinogen 4NQO (Vitale-Cross et al. 2012). We also found that metformin decreases mTOR activity and HNSCC progression by acting on HNSCC-initiating cells directly (Madera et al. 2015). This result was achieved with metformin concentrations in blood similar to that reported for diabetic patients taking metformin for type 2 diabetes (Balan et al. 2001; Sambol et al. 1996). Remarkably, aligned with our findings two recent large retrospective population case-control cohort studies involving together more than 300,000 diabetic patients demonstrated a decreased OSCC risk in patients on metformin (Tseng 2016; Yen et al. 2015).

Collectively, our findings and the emerging epidemiological data have provided a strong rationale for the future implementation of molecular-targeted chemopre- ventive trials in HNSCC, using agents impinging on the mTOR pathway with a better safety profile than direct mTOR inhibitors. Indeed, our team has developed a multi institutional phase IIa single-arm, open-label trial (metformin for oral cancer prevention, M4OC-Prevent) in individuals with OPL (NCT02581137; Table 7.2). We hope that the outcome of this first study evaluating the chemopreventive potential of metformin in OPL will pave the way for future mechanism-based precision therapies for HNSCC prevention in at risk patient populations, as well as for the treatment of HNSCC associated with traditional risk factors and the increasing incidence of HPV-associated oropharyngeal HNSCC. Overall, we can expect that the elucidation of the molecular mechanisms driving the growth, survival, and invasive potential of HNSCC cells will provide an opportunity for precision medicine approaches to prevent HNSCC from arising from its potential premalignant precursors and to halt the progression HNSCC lesions, thus increasing the quality of life and life expectancy of HNSCC patients.

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