Margie L. Clapper, PhD

Prevention of Heritable and Colitis-associated Colorectal Cancer. A major interest of the lab is to improve our ability to detect colorectal tumors early and establish regimens for the prevention of colorectal cancer in both subjects with known genetic risk and patients with ulcerative colitis. Scientific advances have been facilitated by the generation of genetically-engineered and chemically-induced mouse models that recapitulate the human disease. A novel strain of Apc^+/Min-FCCC mice uniquely develop spontaneous colorectal tumors at a high multiplicity. This model has been used extensively to test agents for their cancer preventive activity and develop image-based probes for the detection of early neoplastic colorectal lesions. Several mouse models of colitis-associated colorectal cancer have also been established by this group. Their extensive characterization has not only confirmed their clinical relevance, but provided new insight into the pathogenesis of inflammation-associated disease progression. Analyses of the molecular mechanisms underlying colitis-associated neoplasia have led to the discovery that morphological subtypes of dysplasia arise via distinct genetic pathways and respond differently to therapeutic intervention. State-of-the-art genomic approaches are being used to elucidate the molecular events (e.g., microRNA expression) that accompany disease initiation and progression and could serve as early biomarkers of the development of colitis-associated colorectal lesions. Specific projects follow:

Preventive Regimen for Patients with Lynch Syndrome. Lynch Syndrome is one of the most common hereditary cancer syndromes, characterized by a heritable mutation in a mismatch repair gene. Mutation carriers have a high lifetime risk of developing colorectal cancer (£ 80%), with the majority diagnosed before age 50. Preclinical data generated by this group indicate that the preventive activity of agents varies depending on the point of intervention. Atorvastatin (Lipitor) dramatically decreases colorectal adenomas when administered to naïve Apc^+/Min-FCCC mice before the formation of endoscopically detectable adenomas. In contrast, use of an NSAID in combination with atorvastatin is needed to reduce the multiplicity of colorectal adenomas in mice with existing tumors at treatment initiation. These promising data have been used to design a biomarker prevention trial in high-risk subjects with Lynch Syndrome that is currently in progress at Fox Chase.

Impact of Folic Acid Supplementation on Risk of Colitis-associated Colorectal Dysplasia. The fortification of foods with folic acid in the US, when combined with the routine use of supplements, has led to the intake of folic acid at unprecedented high levels. Published reports suggest that: 1) supraphysiological levels may increase the risk for colorectal cancer; and 2) delaying folic acid supplementation until after lesions are established may promote colon tumorigenesis. Patients with chronic ulcerative colitis not only have a strong underlying predisposition to colorectal cancer, but frequently require folic acid supplementation. The goal of this study is to assess the effect of varying doses of folic acid on the development of colitis-associated neoplasia and DNA methylation in the clinically relevant mouse model of carcinogen azoxymethane/dextran sulfate-sodium (DSS)-induced colitis. Preliminary findings indicate folic acid enhances colitis‑associated colorectal dysplasia and impacts DNA methylation in a dose-dependent manner.

Contribution of Estrogen to Lung Cancer Among Never Smokers. The incidence of non-small cell lung cancer (NSCLC) among those without a history of tobacco use is increasing rapidly, highlighting the critical need to better elucidate its biology and the factors contributing to its rise in recent years. The etiology of NSCLC in never-smokers remains unexplained, although the predominance of females affected by this disease has prompted an investigation of the contribution of hormones to lung tumorigenesis. This group is the first to report that: 1) the murine and human lung can extensively metabolize estrogen; 2) metabolite levels are higher in human lung tumors, as compared with adjacent normal tissue, and in women vs. men; and 3) estrogen metabolism varies with race among postmenopausal women.   

Non-Small Cell Lung Cancer among Never-smokers. A multidisciplinary team of basic researchers and thoracic oncologists has been assembled to investigate the mechanism by which estrogen may promote NSCLC in never-smokers, as well as the basis for elevated levels of specific catechol metabolites in some patients. Mechanistic in vitro studies are being complimented by experimentation in genetically-engineered mouse models of EGFR- and Kras- mutated lung cancer. Findings from these studies are anticipated to greatly enhance our understanding of the manner in which estrogen metabolism is regulated in humans, as well as the mechanisms by which estrogen derivatives may damage the normal lung.

       A sensitive UPLC-MS/MS assay for quantifying estrogen metabolites in biosamples has been established recently by this group. Analysis of the urinary estrogen metabolite profile of never-smoking NSCLC patients revealed significant heterogeneity, with overproduction of specific metabolites detected in a subset of patients vs. cancer-free controls. Elucidation of the regulatory mechanisms and the clinical factors that impact the activity of estrogen metabolizing enzymes will allow identification of never-smokers with detrimental profiles who may benefit from targeted therapeutic intervention. Rapid translation of preclinical findings to patients facilitated by the recent establishment of a Clinic for Never‑smokers with NSCLC, the first on the East Coast, by thoracic oncologists Drs. Joseph Treat and Nick Bodor at Fox Chase Cancer Center.