Safer Approaches to CRC Chemoprevention

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Project Summary The major purpose of this proposed research is to develop mechanistically based, effective, and safer agents for colorectal cancer (CRC) chemoprevention. Every year, about 150,000 Americans are diagnosed with colorectal cancer (CRC), the second leading cause of cancer-related mortality in the US. About 1.35 million new CRC cases are diagnosed worldwide, highlighting that CRC is a major health problem. Evidence from our group and others suggests that NSAIDs and select COX-2 inhibitors show significant inhibitory effects in preclinical models and patients with CRC, but these inhibitors are also associated with gastrointestinal (GI) toxicity and cardiovascular (CV) risk. Reasons for these risks include increased 5-LOX metabolites and reduced PGI2 synthesis. Thus, selectively targeting microsomal PG Synthase-1 (mPGES-1) and 5-LOX would block the protumorigenic PGE2/prothrombotic LTs, but spare the PGI2. This approach is ideal for developing efficient and safer CRC chemopreventive agents. Toward this end, through high-throughput and enzyme kinetics assays and short- term in vivo efficacy studies, we have discovered a novel dual mPGES-1 /5-LOX inhibitor, CDPDPA. In this proposal, we seek to further develop CDPDPA for CRC chemoprevention. We have designed the research strategies to assess the pharmaco-dynamic dose-response efficacy, understand the role of mPGES-1/5- LOX, improve efficacy and safety through combinatorial approaches, and evaluate CV risk, if any, of CDPDPA compared with COX-2 inhibitor. We have assembled a team with expertise in CRC chemoprevention and cardivascular research to undertake following aims. 1). Determine whether targeting both mPGES-1 and 5-LOX with CDPDPA is efficacious in AOM-induced rat colon adenocarcinoma treatment; 2) Determine the source and relative contribution of mPGES-1 and 5-LOX to colon tumor developmen;t 3). Determine whether combinational targeting of mPGES-1/5-LOX with statin would improve the colon tumor inhibition efficacy and reduce cardiovascular side effects compared with celecoxib, and; 4). Determine the potential CV risk, if any, of long-term administration of CDPDPA compared with Celecoxib in LDLr-/-ApoB100/100 mice. The completion of this project will significantly improve the safety and efficacy of this novel drug for the prevention and treatment of CRC.