Investigating the molecular changes that lead to the development of lung cancer and define its biologic properties is of great importance. It is anticipated that identification of molecular targets that play a role in lung cancer progression will lead to rational design of a new generation of trials in lung cancer prevention, screening, and treatment.
As Thoracic Oncology Program Leader, Dr. Bepler has focused the program on somatic genetic alterations in lung cancer and premalignant lesions of the lung. These alterations have been investigated in cell lines, short-term cell cultures, freshly resected lung cancers, and pathologic specimens by using a variety of cytogenetic and molecular genetic techniques. These efforts have identified a region on chromosome segment 11p15.5 with a frequent aberration called LOH11A. Molecular alterations are found in approximately 60% of primary lung cancers, and many other carcinomas arising in adults, including those of the breast, ovary, esophagus, stomach, and others, have frequent alterations in or near the LOH11A region. Loss of heterozygosity in this region is an independent predictor of poor survival for patients with stage I lung cancer.
Because of its location at the site of maximal allele loss, the RRM1 gene has been investigated as a potential suppressor activity. No inactivating mutations were identified in this gene; however, three silent single nucleotide polymorphisms were identified in the open reading frame and two in the promoter region. When cells lines representing cancers of the lung, breast, colon, and prostate were transfected with a mammalian expression vector containing RRM1, the resulting minimal overexpression of the transgene yielded dramatic phenotypic changes, including cell cycle arrest, apoptosis, and inhibition of migration, invasion, and metastasis. The mechanism responsible for these changes is being investigated.
About 75% of patients with non-small cell lung cancer (NSCLC) present in advanced stages, when the disease is incurable and the median survival duration is 9-11 months. In stage IV disease, combination chemotherapy is palliative and produces measurable responses in approximately 30-40% of patients; complete responses are rare and eventual progression inevitable. In the last decade, several new drugs have been developed that have shown promising activity in advanced NSCLC. Multiple recent trials have shown, however, that the best currently available therapy is a two-drug platinum-based combination regimen. The Thoracic Oncology Program is focusing on development of therapeutic approaches to molecular targets expressed in these tumors.
Because cure rates for lung cancer are low (~14%) and chemotherapeutic intervention prolongs survival only marginally, there is an urgent need to develop compounds that can prevent the disease in individuals who are at increased risk because of exposure to carcinogens in tobacco smoke or other factors. The program has obtained support for a chemoprevention trial with exisulind (Aptosyn), the first in the class of proapoptotic agents. Exisulind has shown promise in chemoprevention of colon cancer by reducing adenomatous polyps in humans. In animal studies, this agent reduced the incidence of carcinogen-induced lung cancer. To test the clinical utility of this agent in lung cancer prevention in individuals at high risk for the disease, the program will conduct a double-blind, placebo-controlled, randomized trial in former smokers with obstructive airway disease. A surrogate marker of lung cancer, the proliferation marker Ki-67, will be used as the primary endpoint. Other markers such as MCM2, cytokine response profiles, genetic alterations, and apoptosis index will be explored as surrogate trial endpoints.