Lung cancer is responsible for nearly one-third of all cancer-related death in the U.S., and the cure ratesremain low. Thus, there is a need to develop compounds that can prevent the disease in individuals at risk.Cigarette smoking, obstructive pulmonary disease, and age are the overwhelming risk factors. Persons thathave quit smoking remain at an increased risk for lung cancer for lifetime that is proportional to the amountof cigarettes smoked. Former smokers are a particularly attractive target population for chemopreventionwith pharmacological agents. A number of compounds have been tested but trials to date have not resultedin a decrease of lung cancer incidence. In fact, two large-scale chemoprevention trials, which evaluatedbeta-carotene in current and former smokers, resulted in an increase of incidence and mortality from lungcancer. Subgroup analyses of these studies and other related published reports suggest that the clinicaland biologic responses to chemopreventive agents differ between active and former smokers. Nationally,the focus of lung cancer chemoprevention is on inhibitors of inflammatory response pathways and growthfactor signaling pathways and the use of intermediate biomarkers as primary trial endpoints. A novel agentwith antiproliferative, proapoptotic, and minimal toxic effects is enzastaurin (LY317615). It is an oral proteinkinase C (PKC) inhibitor currently undergoing clinical efficacy testing in phase II and III trials in patients witha variety of malignancies. To test the clinical utility of this agent in lung cancer prevention, we will conduct adouble-blind, placebo-controlled, randomized phase lib trial in former smokers. A surrogate marker of lungcancer risk, the proliferation marker Ki-67, will be used as the primary endpoint. Other markers previouslyand currently investigated by us and others, in particular components of the DMA replication origin licensingcomplex, will also be explored as surrogate trial endpoints. The data generated by these investigations willnot only determine the efficacy of enzastaurin as a chemopreventive agent for lung cancer, but also provideimportant analytical leads for future studies.
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