New targets for cancer prevention: Where do we go from here?

Proc Amer Assoc Cancer Res, Volume 46, 2005 SY25-3 Progress in cancer prevention is predicated on understanding the biology of cancers arising at different organ sites and on identifying strategies that interrupt the process of carcinogenesis without undue side effects. Maintaining the balance between efficacy and toxicity of interventions is critical to long term successful application of chemoprevention to high-risk populations. In the setting of tobacco-related malignancies such as lung or head and neck cancer, identifying the population at the highest risk for subsequent cancer remains a priority so that prevention strategies can appropriately focus on those who are most likely to benefit from them. An expanding understanding of the contribution of inflammation to cancer development has identified key enzymes involved in the metabolism of arachidonic acid (AA) as potential targets for the prevention of a variety of epithelial cancers. AA is generated from phospholipids by the phospholipase A2 (PLA2) enzyme family and is ultimately metabolized by cyclooxygenases (the constitutive COX-1 and inducible COX-2 enzymes) and lipoxygenases (various LOX enzymes) to form a variety of bioactive metabolites involved in inflammatory and other homeostatic processes. Animal carcinogenesis studies provide strong evidence that inhibitors of AA metabolism interrupt lung adenocarcinogenesis. Both systemic and inhaled glucocorticoids, which inhibit PLA2, are particularly effective in inhibiting adenoma and adenocarcinoma formation in carcinogen treated mice. However, a recent phase IIb study of inhaled budesonide did not show any efficacy in regressing or preventing bronchial dysplastic lesions, which are precursors to squamous cell carcinoma. Budesonide treatment did, however, result in a small but significant decrease in peripheral nodules identified by spiral CT, raising the possibility of efficacy in adenocarcinoma prevention analogous to that seen in animal models. The availability of spiral CT to examine the peripheral lung (the site of adenocarcinoma development) may allow, for the first time, the design of clinical trials to specifically address cancer prevention in the peripheral lung compartment. Other agents that are currently being studied include downstream inhibitors of AA metabolism such as the non-steroidal anti-inflammatory agents and the 5-lipoxygenase inhibitor zileuton. Since inhibition of both COX and LOX pathways appears to be promising, new dual function COX-LOX inhibitors offer an intriguing alternative to combination treatment. Ligands of the peroxisome proliferator-activated receptor gamma (PPARγ), which include the anti-diabetic thiazolidinedione drugs, induce maturation in lung cancer cell lines and inhibit tumorigenesis in a variety of epithelial cell types. These agents are currently being tested and show promise in the treatment of oral cancer premalignant lesions. The need to maintain the balance between drug-associated side effects and risk of disease has prevented many of the newer molecularly targeted agents such as farnesyltransferase inhibitors (which are also potent inhibitors of tumorigenesis after carcinogen exposure in mice) from entering clinical trials for lung cancer prevention. A better understanding of the mechanisms of lung carcinogenesis is crucial to the development of targeted therapies for prevention of lung cancer. Equally important is the development of novel clinical trial designs to appropriately test new agents in a timely fashion. Recent progress in both of these areas provides hope for progress in prevention of lung cancer.