Pioglitazone-Metformin Combination Treatment for High Risk Oral Preneoplasia

With stagnant cure rates, there is a severe unmet need for strategies to improve oral and all other types of aerodigestive cancer survival. There are no robust chemoprevention drugs or other treatments for high risk oral precancerous conditions or field carcinogenesis despite 40 years of clinical trial research. High risk oral precancerous conditions (such as leukoplakia) represent a standard target for chemoprevention interventions. Type II anti-diabetic agents, including pioglitazone and metformin, are promising cancer prevention drugs for oral cavity preneoplasia that we have used in NCI sponsored clinical trials. They have adequate safety and moderate efficacy in human trials, however, individually are likely not sufficient to advance to large scale clinical trials. These agents have differing mechanisms of action which each attack different events in oral carcinogenesis. In this project, we propose to conduct a phase IIa 12 week clinical trial with combination BID pioglitazone-metformin (15mg-500mg) in oral preneoplasia patients. We have assembled a consortium of clinics in Minneapolis/St. Paul MN for efficient accrual to this trial. We will examine pharmacodynamic endpoints in specimens based on both the mechanisms of the agents and how they may affect T cell subsets before and after treatment. Further, we will also analyze leukoplakia specimens and adjacent normal mucosa specimens by RNA-Seq before and after treatment, which will shed light on effects of the drugs as well as any putative “off target” effects. At the completion of this project, we will have a better understanding of pioglitazone and metformin effects on oral carcinogenesis, as well as, an early stage clinical trial which could be expanded to larger randomized trials with a promising cancer prevention strategy for oral preneoplasia or other tobacco-associated malignancies.