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Curtis C. Harris, M.D.
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Our continuing research projects utilize an integrative biology and translational strategy that addresses facets of the NCI strategic objectives: (a) Understand the causes and mechanisms of cancer; (b) Improve early detection and diagnosis; (c) Understand the factors that influence cancer outcomes; and (d) Overcome cancer health disparities. (The NCI Strategic Objectives; the Nation's Investment in Cancer Research, FY2009) As described in the overview of LHC, our strategy and strength is to conduct laboratory-epidemiological investigations and to mentor young investigators.
Project 1: Molecular Epidemiology of Human Cancer and Clinical Biomarkers of Cancer Diagnosis, Prognosis, and Therapeutic Outcome. Gene-environment interaction is a seminal concept in the molecular epidemiology of human cancer. Our case-control (using hospital- and population-based controls) studies focus on lung cancer, a tobacco-related cancer, and colon, a cancer type more associated with chronic inflammation. These studies require the integration of data from genetic association studies, analysis of carcinogen exposure, rapidly developing technologies, bioinformatics, social-ethical concerns, and epidemiological study-design methods and the hypothesis, aims, and demographic characteristics of study subjects of multiple investigations. We also validate our results with independent cohorts, e.g., The NCI Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, Mayo Clinic Never Smoker Lung Cancer cohort (P. Yang), Black Women Health Study (J. Palmer and L. Adams-Campbell), and Hong Kong Colon Cancer cohort (S.Y. Leung), and contribute data to the large multi-institutional International Lung Cancer Consortium, e.g., replication of susceptibility loci identified in Genome-Wide Association Studies. For example, we discovered from 2 independent cohorts that childhood exposure to secondhand smoke and a hyperactive innate immune system is associated with an increased the lung cancer risk in never smokers. Our studies have also provided genetic and biological evidence of racial health disparity of lung and colon cancer in African Americans: common genetic variations in TP53 are associated with increased lung cancer risk and poor prognosis; a less efficient G2/M cell cycle checkpoint is associated with increased lung cancer risk; and an increased risk and/or poor survival of colon cancer are associated with either specific microRNA expression or SNPs in the MBL2 gene. Cancer cases were also utilized to develop clinical biomarkers. For example, microRNAs and selected inflammatory cytokines were found to be diagnostic and prognostic biomarkers of human lung, esophageal, and colon cancer in their early TNM stages. Some of these biomarkers are also associated with therapeutic outcome. We continue to focus on tobacco-related cancer, inflammation-associated cancer, and cancer-related health disparities.
Project 2: p53 and Cancer. The p53 pathway is an intrinsic monitor and response pathway of telomeric attrition involved in cellular aging and senescence. Cellular senescence is a tumor suppressive mechanism that can be activated by p53 in cancer cells. We are currently studying the molecular mechanisms of cellular senescence in normal human cells and the role of the telometric multiprotein complex, shelterin, that includes TRF2 and POT1 in aging and carcinogenesis.
Project 3: Inflammation and Cancer. Chronic inflammation can increase cancer risk. We are investigating the interaction between nitric oxide (NO) and p53 as a crucial pathway in inflammatory-mediated carcinogenesis. We have shown that NO induces ATM- and ATR-dependent p53 posttranslational modifications leading to a p53 stress response in human cells in vitro, in an admixture of activated macrophages and human cells in vitro, and in colon tissue from patients with ulcerative colitis or Crohn's, both of which are cancer prone, chronic inflammatory diseases. Furthermore, NO can suppress or enhance tumorigenesis in an animal model of the Li- Fraumeni Syndrome, depending on NO concentration.
This page was last updated on 6/7/2013.