MOLECULAR PROFILING OF RECTAL CANCERS TO EVALUATE THE ROLE OF COX-2

Vanderbilt University, Nashville TN

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Abstract

DESCRIPTION (provided by applicant): Adjuvant chemotherapy and radiation therapy have had a modest effect on recurrence rates and survival for patients with node positive or transmural (stage II/III) rectal cancer, but approximately half of these patients will suffer a recurrence and most of the patients who recur will die of their cancer. Following surgical resection, a small but significant minority of patients with early stage rectal cancer experience lethal recurrences of their tumors. For this subset of patients, adjuvant therapy has, to date, shown no significant benefit. Increased expression of cyclooxygenase-2 (COX-2) occurs in ~80 percent of colorectal cancers, and several lines of evidence suggest that this increased COX-2 expression may promote tumor progression through increased tumor cell survival, increased invasiveness and increased tumor-associated angiogenesis. COX-2 inhibitors have shown promise in the prevention of the progression of colorectal polyps. In addition to a chemopreventive role, results of preclinical studies with selective COX-2 inhibitors also suggest that these new and nontoxic pharmaceuticals may have a role in the treatment of colorectal cancer. Experimental studies have also suggested that COX-2 inhibitors appear to enhance the effects of radiation therapy selectively on those tissues that express COX-2. The effect of treatment with COX-2 inhibitors on human colorectal cancer cells in vivo is unknown, as are the effects of these agents in combination with standard chemotherapy and radiation therapy. This project aims to examine the biological responses to a COX-2 inhibitor and the combination of a COX-2 inhibitor with chemoradiation in the treatment of rectal cancer. Rectal cancer was selected as a target tissue in this study because of the accessibility of the tumor tissue for repeated biopsy during a simple proctoscopic procedure that does not require sedation or mechanical bowel preparation beyond a pre-procedure enema. Specific Aim 1: To determine VEGF expression and eicosanoid levels in tumors and in normal rectal tissues and to assess the effects of COX-2 inhibition on (1) Eicosanoid metabolism in both normal and tumor tissue, (2) VEGF expression and (3) Microvascular density. Specific Aim 2: To assess the effects of COX-2 inhibition on surrogate markers of eicosanoid expression. Specific Aim 3: To evaluate protein and RNA expression profiles pre and post administration of Celecoxib. Specific Aim 4: To determine whether changes in COX-2 expression, eicosanoid production (tissue/urine), gene and protein expression following celecoxib and celecoxib/RT can be used to predict clinical outcome in Stage Il/III rectal cancer.