A Novel Agent for Lung Cancer Prevention

Lung cancer is the leading cause of cancer-related deaths in the United States. Despite the identification of several preventive agents and strategies, optimal prevention of lung cancer, especially in smokers and ex-smokers, who are at high risk, has not been achieved. More effective agents are therefore required that would safely achieve prevention without drastic side effects. Novel compounds that are rational modifications of well-established chemopreventive agents and follow a similar mechanism of action, but with enhanced potency, reduced toxicity, and lower dose requirement, may be clinically more relevant. The long-term goal is to develop this rationally designed, effective, and safe agent for the prevention and interception of smoking-related lung cancer. We have developed one such agent, p-XS-Asp, which has shown promising lung cancer preventive properties in our preliminary animal studies. The specific objectives of this proposal are to (1) evaluate the efficacy of p-XS-Asp for inhibiting lung cancer development at different stages of NNK-induced carcinogenesis using the well-studied A/J mouse lung cancer model, (2) evaluate the pharmacological and biochemical mechanisms by conducting p-XS-Asp metabolism and comparing pharmacokinetics (PK)/bioavailability with p-XSC, and (3) elucidate mechanisms of action(s) of anti-initiation and anti-progression effects of p-XS-Asp. The Lung Cancer Research Program Area of Emphasis that this project would directly address is, 'Identify innovative strategies for prevention and treatment of lung cancer.' This study is highly significant and relevant, particularly to current smokers and ex-smokers, who are at high risk of developing lung cancer in their lifetime. The potential clinical relevance of this project is that the proposed studies will identify a novel small drug-like molecule with highly desirable oral bioavailability and PK features and negligible systemic toxicity for addressing lung cancer at its root cause through prevention of initiation and interception of disease progression. The dual ability for blocking carcinogen metabolism and increasing detoxification and for intercepting post-initiation progression is vital for risk reduction in both current smokers and ex-smokers who have already been exposed to tobacco carcinogens and borne precancerous lesions that can be regressed or delayed. At the completion of this project, we expect to have established the chemopreventive and intervention efficacy of p-XS-Asp with respect to stage-specificity and to have shed novel insights into the in vivo relevant mechanisms of action with respect to PK/PD knowledge. More preclinical studies would, however, be required before this preventive strategy could translate to humans. Such studies would include evaluation of chemopreventive efficacy in multiple established chemical and genetically modified mouse models of lung cancer, toxicity/safety, and the pharmacology of p-XS-Asp. The long-term impact would be filing an Investigational New Drug application with the Food and Drug Administration and eventually evaluating this new agent in high-risk individuals, e.g. smokers and ex-smokers. The projected time to achieve a clinically relevant outcome is expected to be 8-10 years. No effective preventive agents currently exist for lung cancer. Unfortunately, agents previously tested in clinical trials for lung cancer chemoprevention (including beta-carotene, isotretinoin, and a-tocopherol) have failed. Development of p-XS-Asp as a safe and effective lung cancer preventive agent would contribute to lowering lung cancer incidence, especially in smokers and ex-smokers. The use of cigarettes remains much higher (~32%) among military personnel compared to the general population (~21%) in the United States. Even after leaving the Service, as many as 27% of Veterans continue to smoke (during 2003 to 2007), and military smoking is strongly associated with increased lifelong ci