Abstract CN04-02: PPARgamma in aerodigestive cancer prevention

The development of agents to prevent cancer requires an iterative process of target identification, preclinical testing, and early and late phase clinical trials to establish efficacy and safety. Appropriate target selection is based on efficacy assessment as well as the potential negative effects of impacting the target. Indications of effectiveness fall into several major categories: knowledge of mechanisms, in vitro and animal in vivo experimental data, epidemiological case-control and cohort studies, and data from clinical trials, either early phase prevention trials or secondary endpoint analysis from trials performed for other indications. Given that the history of cancer prevention clinical trials includes multiple examples of unintended harms from the tested agents (e.g., beta carotene increased rather than decreased the risk of lung cancer; rofecoxib and celecoxib were associated with cardiovascular risks despite reducing colorectal polyp recurrence), the current research emphasis is on obtaining a better understanding of the process of lung carcinogenesis and on careful selection of agents whose short and long term side effect profile are well understood. The peroxisome proliferator-activated receptor gamma (PPARγ) is a member of the nuclear hormone receptor superfamily and is a key regulator of adipogenesis. It is the target of the thiazolidinedione class of oral agents, two of which are currently approved by the FDA to treat type II diabetes mellitus (pioglitazone and rosiglitazone). Abundant cell line studies show that ligands of PPARγ inhibit cell proliferation of a variety of cancer cell types by promoting differentiation and/or apoptosis. Several xenograft studies confirm these effects in breast, lung, and colon cancer models, among others. However, pilot clinical trials of PPARγ ligands in patients with advanced breast or colon cancer who have received multiple lines of chemotherapy have shown no activity. The suggestion that PPARγ ligands may be useful for the prevention of lung and upper aerodigestive (head and neck) carcinogenesis comes from three lines of evidence. First, two epidemiologic studies focusing on a large VA database show that diabetics who used PPARγ ligands compared to those who used other oral agents or insulin had a 30-50% reduced risk of lung or head and neck cancer. Second, multiple mouse carcinogenesis studies suggest that PPARγ ligands may be useful for the prevention of different types of cancer. PPARγ overexpression in mouse lung protects against carcinogen-induced lung tumors. Similarly, PPARγ ligand treatment potently reduces tumor burden in mouse models of lung adenomas/adenocarcinomas and squamous cell carcinomas, and in rat models of oral squamous cell carcinomas. Finally, a pilot clinical trial of the PPARγ ligand pioglitazone in subjects with oral premalignancy showed a high clinical response rate, with only minor side effects. Taken together, these data provide a strong justification for further clinical trials, which are currently ongoing to explore the role of pioglitazone in the prevention of lung and head and neck malignancies. Citation Information: Cancer Prev Res 2010;3(12 Suppl):CN04-02.