ABLATION IN PREVENTION OF ESOPHAGUS ADENOCARCINOMA

University Of Arizona, Tucson AZ

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Abstract

DESCRIPTION (provided by applicant): Barrett?s Esophagus (BE), a known precursor to esophageal adenocarcinoma, is an excellent model for the study of carcinogenesis in vivo. BE is a condition where columnar, metaplastic epithelium replaces the normal squamous epithelium and is associated with increased risk of cancer. Because approximately 1 percent of U.S. adults are estimated to have BE, the affected population is approximately 2 to 3 million adults. One of the latest treatments for BE utilizes techniques to ablate or reverse this lesion back to squamous epithelium. While the use of ablation techniques is rapidly increasing in the US, a question that has never been answered is whether the cancer risk is reduced by these procedures. Our group was the first, to raise this question and has published early data indicating that complete reversal, ie. with no signs of Barrett?s columnar epithelium left behind, results in a lesion indistinguishable from normal squamous esophagus. On the other hand, partial reversal, where areas of columnar, metaplastic epithelium co-exist with squamous, produces regions of epithelium that appear quite abnormal and may indeed result in increased cancer risk. Incomplete ablation occurs in 22-57 percent of subjects, when they are endoscoped six months after the procedure. A compelling way to show an increased cancer risk would be a clinical trial, but this is not a practical undertaking, as is often the situation in premalignant diseases. Consequently, our approach has been to study biomarkers and their expression in BE tissue biopsies. Our preliminary data indicates that the post-ablation partially-reversed tissue has increased cyclooxygenase-2 (COX-2) expression. COX-2 overexpression contributes to apoptosis resistance, a situation that increases genomic instability resulting in mutations, some of which are carcinogenic. We have also found that the BE epithelial cells are resistant to apoptosis. We plan to evaluate the expression of COX-2 land other redox-associated proteins (eg. NF-kB, NOS2, bcl-2) that we have shown to be anti-apoptotic in the colon, for their upregulation in partially-reversed BE tissue. We also plan to evaluate the down-regulation of pro-apoptotic DNA damage response/repair proteins (eg. BRCA1, GADD153, PARP, p53) as risk factors for cancer in the esophagus. The long-term goals of our studies are to develop new biomarkers for assessing risk of cancer in BE patients, especially those undergoing ablation, and identify new intervention strategies to reduce this risk.