Surgery Plus Sulindac or Surgery Alone for Advanced Colorectal Cancer

* Despite strong evidence for a causative role of inflammatory mediators in intestinal cancer, the underlying mechanisms remain obscure. Established evidence indicates activation of the Wnt/beta-catenin pathway is an early step in the malignant transformation of colorectal adenomas with persistent activation in 90% of colorectal cancers. Activation of this pathway ultimately effects transcription of the S100A4 gene. * S100A4 transcript serum levels have been shown to correlate with risk of recurrence in colorectal cancer and patients with systemic metastases are found to have increased S100A4 transcript expression. * S100A4 may be a novel prognostic biomarker in colorectal cancer. * Cyclooxygenase-2 is a key enzyme involved in the inflammatory response and is a key target of molecular chemoprevention in colorectal adenoma prevention trials. * Recent studies demonstrate mitigation of Wnt/beta-catenin signaling by COX-2 inhibition via administration of the non-steroidal anti-inflammatory drug (NSAID) sulindac using in vitro and in vivo animal models. * We hypothesize that sulindac administration will abrogate Wnt/beta-catenin mediated signaling and thus decrease S100A4 activity in patients with colorectal metastases. * We propose to define the benefit of sulindac administration to patients with colorectal metastases following resection and validate the use of circulating S100A4 transcripts as a novel biomarker for disease recurrence.