Margie L. Clapper, PhD
Office Phone: 215-728-4301
1. Chemoprevention Intervention for Colorectal Cancer
Sporadic Colorectal Cancer
A unique strain of Multiple Intestinal Neoplasia (FCCC ApcMin/+) mice, a preclinical model of spontaneous colorectal cancer, has been established by this group. A thorough evaluation of lesions from these animals has revealed several unique features of this mouse strain. First, FCCC Min mice develop colorectal adenomas at a higher multiplicity (3.9 ± 0.3, mean ± SEM; range 0-27) than that reported by others for the C57BL/6J strain (1.1 ± 0.1). Immunohistochemical and molecular analyses of colonic lesions from these animals revealed loss of heterozygosity of Apc, nuclear translocation of β-catenin and overexpression of COX 2, suggesting that this mouse model closely approximates human colorectal cancer. In addition to the appreciable numbers of colorectal lesions available for study, the extended life span of the FCCC Min mice (200 days for the FCCC strain vs. 120 days for the conventional strain) provides a larger window of opportunity for chemopreventive/therapeutic intervention. Thus, this Min model represents an attractive and highly relevant system with which to test agents for their ability to inhibit colorectal cancer. This mouse model continues to serve as a unique resource with which to identify agents with chemopreventive activity against sporadic colorectal cancer.Top
Colitis-associated Colorectal Cancer
Inflammatory bowel disease, which includes ulcerative colitis, affects approximately one million individuals in the U.S. each year. Clinical studies have shown that patients with colitis have a 2−8-fold relative risk of developing colorectal cancer as compared to the general population. Similar to sporadic colorectal cancer, development of colitis-associated colorectal cancer is thought to occur in a stepwise manner, with the inflamed mucosa giving rise to dysplasia and ultimately cancer. Although dysplasia is a strong indicator of underlying carcinoma or neoplastic transformation, current surveillance programs often fail to detect early malignancies.
For the past decade, this team has focused on the development of a chemopreventive regimen for colitis patients using the dextran sulfate-sodium (DSS) model of induced colitis. This murine model represents a highly relevant system with which to evaluate chemopreventive agents. To date, we have identified at least two agents that can inhibit DSS-induced colitis-associated colorectal cancer. Chronic administration of the antischistosomal agent oltipraz to colitic mice caused complete inhibition of colitis-associated colorectal cancers. 5-aminosalicylic acid (5-ASA), the standard anti-inflammatory agent used to treat ulcerative colitis, decreased the multiplicity of colonic dysplasias by approximately 50%.
The goals of these chemopreventive intervention studies are to identify important drug targets, promising agents, and treatment combinations. Once an efficacious agent has been identified, significant effort is invested in exploring the associated pathology and molecular mechanism underlying tumor inhibition.Top
2. Tobacco Smoke Enhances Estrogen Metabolism in the Aerodigestive Tract
A new area of research has emerged in my laboratory over the past several years that focuses on the role of estrogen in smoking-related carcinogenesis. Rationale for this project is based on: 1) a 6-fold increase in lung cancer deaths in women in recent decades, 2) our discovery that tobacco smoke can modulate the expression of genes in the estrogen/androgen pathway, and 3) identification of cytochrome P450 1B1 (CYP1B1) as the gene whose expression is differentially regulated to the greatest extent in murine lung tissue following exposure to tobacco smoke. CYP1B1 catalyzes the conversion of both estrogen and tobacco smoke to mutagenic and carcinogenic intermediates. We hypothesize that induction of pulmonary CYP1B1, and other estrogen-metabolizing genes, by tobacco smoke leads to the increased production of both harmful estrogen metabolites (i.e., 4-hydroxyestradiol) and oxidative DNA adducts within the lung. Our data suggest that alterations in estrogen metabolism may contribute to smoke-induced lung cancer and raise concern about the contribution of hormonal therapies to lung cancer risk.
These preclinical hormonal data have been translated to humans using surgical specimens collected at Fox Chase Cancer Center (FCCC). Quantitative real-time PCR analyses of surgical specimens have confirmed that estrogen-metabolizing enzymes are expressed in human lung and head and neck tissues.Top
3. Multimodality Imaging: From Molecular Signaling to Target Organ
The availability of Min mice that uniquely develop multiple colorectal tumors has provided an opportunity to explore new strategies for the early detection of colorectal adenomas. Methods for the quantitative measurement of murine colon tumors in real time by MRI and endoscopy have been established in collaboration with Harvey Hensley, Ph.D., Director of the Small Animal Imaging Facility, and provide novel insight into the dynamics of colon tumor growth in vivo. These methods have recently been used to serially monitor colorectal tumors during chronic exposure to chemopreventive therapies.
Recent purchase of a Fluorescence Molecular Tomography system (VisEn Medical) allows the three-dimensional reconstruction
and spatial resolution of fluorescent signal in vivo. In collaboration with Harvey Hensley, PhD, pathologist Harry Cooper, MD, gastroenterologist Minh Nguyen, MD and biostatistician Karthik Devarajan, PhD, our lab has developed a reliable method for the early detection of colorectal tumors using near-infrared bioactivatable probes. Efforts to translate this image-based technique to a clinical setting have begun.Top