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Margie L. Clapper, PhD

Margie L. Clapper, PhD
About

Deputy Scientific Director

Professor and Co-Leader, Cancer Prevention and Control Program

Samuel M.V. Hamilton Chair in Cancer Prevention

Adjunct Faculty, Lewis Katz School of Medicine, Temple University

Research Program

Lab Overview

This program, established more than 20 years ago, is one of the first basic research programs nationally to focus on the development of strategies for the prevention of cancer. Its overall goal is to develop novel, efficacious preventive regimens for those individuals who are at highest risk for cancer, based on predisposing genetic and environmental factors. All research is highly translational, with experimentation spanning from cultured cells and genetically-defined animal models to the analysis of human tissues and conduct of clinical trials. Innovative use of state-of-the-art genomic and image-based technologies continues to provide unique insight into the molecular basis for cancer susceptibility and inform the design of promising strategies for early tumor inhibition. As a Prime Contractor of the Division of Cancer Prevention, NCI for the past two decades, the group has evaluated the ability of numerous promising agents to inhibit tumor formation in preclinical animal models and comprehensively investigated the associated mechanisms of drug action. Specific research interests include the establishment of regimens for the prevention of colorectal cancer in high‑risk subjects with ulcerative colitis or predisposing genetic factors, the improved detection of early colorectal tumors, and the contribution of hormones to the development of lung cancer among never-smokers. In many cases, findings from preclinical efficacy and mechanistic studies have led to the conduct of biomarker trials in humans with promising cancer preventive agents. The laboratory has been funded continuously by grants from the National Cancer Institute, NIH since its initiation and has a long track record of mentoring talented physician scientists, and pre- and postdoctoral trainees.

 

As Deputy Scientific Director at Fox Chase Cancer Center, Dr. Clapper is responsible for fostering collaborations with faculty in the area of population science and identifying opportunities to enhance research interactions and funding across Fox Chase's scientific programs.

A professor and longtime faculty member at Fox Chase, Dr. Clapper also serves as co-leader of the Center's Cancer Prevention and Control Program. In 1991, she created one of the first basic research programs nationally to focus on developing strategies to reduce cancer risk among high-risk individuals and promote early detection and prevention. At the time, the idea of preventing a disease like cancer was not widely accepted. The program has since grown under her direction and has broadened its work to include prevention research focused on colorectal cancer as well as lung cancer, with a strong interest in and pursuit of translational opportunities.

First report that the lung can metabolize estrogen extensively. Its conversion to 4-hydroxyestrogen, a putative carcinogen, is accelerated in mice exposed to tobacco smoke.
Early detection of colorectal tumors in Apc+/Min-FCCC mice using endoscopic examinations (panel A) and infrared bioactivatable probes specific for matrix metalloproteinases (panel B) has provided new insight into the growth characteristics of preneoplastic colorectal lesions.
The presence vs. loss of p53 drives the formation of polypoid and flat colitis-associated colorectal neoplasms, respectively. The morphological subtypes also vary in their response to therapeutic intervention; a critical factor for consideration during chemopreventive agent development.
Colorectal Adenomas in FCCC ApcMin/+ Mice
Colitis-associated Colorectal Neoplasia in Mice treated with AOM/DSS
Education and Training

Educational Background

  • PhD, Genetics/Cell Biology, University of Connecticut at Storrs, CT, 1986
  • BS, Biology, State Univ. College of New York at Oneonta, NY, 1980

Memberships

  • NCI IRG Subcommittee A for Review of Cancer Centers, 2012-2017
  • Prime Contractor, Division of Cancer Prevention, NCI
  • External Advisory Board, O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, 2019-present

Honors & Awards

  • Alumni of Distinction, 125th Anniversary of the State University of New York, Oneonta, NY, 2014
Research Profile

Research Program

Research Interests

  • Genetic mechanisms underlying the development of spontaneous and colitis-associated colorectal cancer
  • Contribution of hormones to lung cancer among never-smokers and gender-based differences in lung cancer susceptibility
  • Characterization of promising nutritional and therapeutic cancer preventive agents and their mechanisms of action in tumor prone mouse models
  • Novel image-based strategies and biomarkers for the earliest detection of neoplasia

Lab Description

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.

Lab Staff

Wen-Chi Chang, PhD

Associate Research Professor

Room: P2161
215-728-5368

Mariana Fragoso, PhD

Postdoctoral Associate

Room: P2161
215-728-4302

Kristen Harvey, BS

Scientific Technician I

Room: P2161
215-728-4302

Daniel Krzizike, PhD

Postdoctoral Associate

Room: P3117
215-728-3558

Rodrigo Macedo, MD, MSc

Scientific Associate

Room: P3138
215-214-4274

Lisa Vanderveer, BS

Scientific Associate

Room: P2161
215-214-3980

Mark Yulis, PhD

Postdoctoral Associate

Room: P2157
215-728-5275

Darlene Curran

Administrative Assistant

Room: P3048
215-214-1643
Publications

Selected Publications

Leystra A.A., Clapper M.L., Gut microbiota influences experimental outcomes in mouse models of colorectal cancer. Genes (Basel). 10(11)2019. PMC6895921. 3.331

Chang W.L., Jackson C., Riel S., Cooper H.S., Devarajan K., Hensley H.H., Zhou Y., Vanderveer L.A., Nguyen M.T., Clapper M.L., Differential preventive activity of sulindac and atorvastatin in Apc(+/Min-FCCC) mice with or without colorectal adenomas. Gut. 67(7): 1290-1298, 2018. PMC6031273. 17.943

Hensley H., Cooper H.S., Chang W.L., Clapper M.L., Imaging matrix metalloproteases in spontaneous colon tumors: Validation by correlation with histopathology. Methods Mol Biol. 1579: 245-255, 2017.

Xu J, Cortellino S, Tricarico R, Chang WC, Scher G, Devarajan K, Slifker M, Moore R, Bassi MR, Caretti E, Clapper M, Cooper H, Bellacosa A. Thymine DNA Glycosylase (TDG) is involved in the pathogenesis of intestinal tumors with reduced APC expression. Oncotarget, 8(52):89988-97, 2017. PMC5685726

Salaün, M, Peng J, Hensley HH, Roder N, Flieder DB, Houlle-Crépin S, Abramovici-Roels O, Sabourin J-C, Thiberville L, Clapper ML. MMP-13 in-vivo molecular imaging reveals early expression in lung adenocarcinoma. PLoS One. 2015 Jul20;10(7):e0132960.  PubMed PMID: 26193700 PubMed Central PMCID: PMC4508003. PubMed

Chang WC, Zenser TV, Cooper HS, Clapper ML. Differential response of flat and polypoid colitis-associated colorectal neoplasias to chemopreventive agents and heterocyclic amines. Cancer Lett. 2013 Jun 28;334(1):62-8. PubMed PMID: 23415736; PubMed Central PMCID: PMC3770752. PubMed

Peng J, Xu X, Mace BE, Vanderveer LA, Workman LR, Slifker MJ, Sullivan PM, Veenstra TD, Clapper ML.  Estrogen metabolism within the lung and its modulation by tobacco smoke. Carcinogenesis. 2013 Apr;34(4):909-15. PubMed PMID: 23276798; PubMed Central PMCID: PMC3616670. PubMed

Clapper ML, Hensley HH, Chang W-C, Devarajan K, Nguyen MT, Cooper HS. Detection of colorectal adenomas using a bioactivatable probe specific for matrix metalloproteinase activity. Neoplasia. 2011 Aug;13(8):685-91. PubMed PMID: 21847360; PubMed Central PMCID: PMC3156659. PubMed

Shatalova EG, Klein-Szanto AJ, Devarajan K, Cukierman E, Clapper ML. Estrogen and cytochrome P450 1B1 contribute to both early- and late-stage head and neck carcinogenesis. Cancer Prev Res (Phila). 2011 Jan;4(1):107-15. PubMed PMID: 21205741; PubMed Central PMCID: PMC3043603. PubMed

Meireles SI, Esteves GH, Hirata R Jr, Peri S, Devarajan K, Slifker M, Mosier SL, Peng J, Vadhanam MV, Hurst HE, Neves EJ, Reis LF, Gairola CG, Gupta RC, Clapper ML.  Early changes in gene expression induced by tobacco smoke: Evidence for the importance of estrogen within lung tissue. Cancer Prev Res (Phila). 2010 Jun;3(6):707-17. PubMed PMID: 20515954; PubMed Central PMCID: PMC2896420. PubMed

Hensley HH, Merkel CE, Chang WC, Devarajan K, Cooper HS, Clapper ML. Endoscopic imaging and size estimation of colorectal adenomas in the multiple intestinal neoplasia mouse. Gastrointest Endosc. 2009 Mar;69(3 Pt 2):742-9. PubMed PMID: 19251020; PubMed Central PMCID: PMC2821747. PubMed

Egleston, BL, Meireles SI, Flieder DB, and Clapper ML.  Population-based trends in lung cancer incidence in women.  Seminars in Oncology. 2009 36: 506-515.  (Lead article in an edition devoted to lung cancer in women.) PubMed PMID: 19995642; PubMed Central PMCID: PMC2846780. PubMed

Clapper, ML, Gary MA, Coudry RA, Litwin S, Chang W-C L, Devarajan K, Lubet RA, Cooper HS.  5‑aminosalicylic acid inhibits colitis-associated colorectal dysplasias in the mouse model of azoxymethane/dextran sulfate sodium-induced colitis.  Inflamm. Bowel Dis. 2008 14:1341-1347. PubMed PMID: 18452197. PubMed

Cooper HS, Chang WC, Coudry R, Gary MA, Everley L, Spittle CS, Wang H, Litwin S, Clapper ML. Generation of a unique strain of multiple intestinal neoplasia (Apc+/Min-FCCC) mice with significantly increased numbers of colorectal adenomas. Mol Carcinog. 2005 Sep;44(1):31-41. PubMed PMID: 15937958. PubMed

Hensley HH, Chang WC, Clapper ML. Detection and volume determination of colonic tumors in Min mice by magnetic resonance micro-imaging. Magn Reson Med. 2004 PubMed

 

Additional Publications

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