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Steven Belinsky, Ph.D.
Lovelace Respiratory Research Institute
Albuquerque, New Mexico
Dr. Steven Belinksy earned his Ph.D. in Toxicology from the University of North Carolina at Chapel Hill. He is currently a Senior Scientist at the Lovelace Respiratory Research Institute, where he directs the Lung Cancer Program. Dr. Belinsky also serves as the Deputy Director of the New Mexico NIEHS Center, and the Co-Director of the Cancer Epidemiology and Control Program for the University of New Mexico Cancer Center.
Dr. Belinsky’s research program is well-funded through grants from the National Institutes of Health, Department of Defense, Department of Energy, and various foundations. His work in the field of lung cancer has appeared in many prominent peer-reviewed journals, and he is frequently invited to speak at national and international conferences on cancer.
About the lecture
"Gene promoter hypermethylation: Biomarker for early lung cancer detection and target for therapy"
Lung cancer is the leading cause of cancer-related death in the U.S. and will soon reach epidemic levels worldwide. Mortality from this disease could be reduced through the development of an effective screening strategy for identifying persons with early stage disease and the implementation of chemopreventive strategies that can reverse or impede the progression of pre-malignant disease. Studies by our laboratory have evaluated genes inactivated by aberrant cytosine-guanosine (CpG) island methylation as candidate biomarkers for early detection of lung cancer. The specific hypothesis being evaluated is that methylation of genes detected in sputum can be used to identify early lung cancer in asymptomatic persons. We conducted the first study in collaboration with the Colorado Lung SPORE to prospectively evaluate a large panel of genes for their ability to predict lung cancer. This nested, case-control study of persons from the Colorado cohort revealed that a panel of genes could predict incident lung cancer 3-18 months prior to clinical diagnosis. Specifically, concomitant methylation of three or more of a six gene panel was associated with a 6.5-fold risk and a sensitivity and specificity of 64%. This same marker panel is now being used to evaluate methylation in sputum from prevalent Stage I lung cancer cases compared to the Lovelace Smokers Cohort, a second cohort of high-risk smokers. Methylation of 3 or more genes of an 8-gene panel revealed a sensitivity and specificity of 75% and 85%, respectively. In addition, evaluation of additional candidate biomarkers has identified other promising genes for inclusion in the penultimate panel for early detection of lung cancer. In two independent studies, gene methylation in sputum was also found to increase with lung cancer risk and to predict cancer recurrence in persons previously resected for early stage disease. Together these studies support advancing a methylation gene panel toward validation for early detection. The identification of determinants for the acquisition of gene methylation during lung cancer development could further aid the development of a molecular-based test. A functional double-strand break DNA repair capacity assay in lymphocytes demonstrated a striking difference in repair capacity (p < 0.001) between persons with 3 or more genes methylated in sputum compared to persons with 0 genes methylated. Studies to identify gene haplotypes that recapitulate the differences in DNA repair capacity phenotypes are underway.
The development of effective agents for prevention of lung cancer could greatly impact mortality from this disease. Rather than targeting single pathway alterations in cancer, epigenetic therapy using inhibitors of cytosine methylation and histone deacetylation may circumvent the problem of tumor heterogeneity by concomitantly inducing the re-expression of a large number of silenced tumor suppressor genes. An initial proof-of-concept study by our group showed that combined demethylation therapy can reduce the number of developing lung tumors in a murine model by > 50%. Subsequent studies are now developing a chemoprevention cocktail that also targets the PPAR-???Treatment of mice 42 wks after carcinogen exposure with this cocktail markedly blocked progression and inhibited growth of pre-invasive lesions. The refinement and validation of this prevention cocktail could lead to future clinical trials for primary and secondary lung cancer prevention.
Quoted from the 2006-2007 Loyd E. Harris Lecture Series Announcement Brochure