Every year 150,000 Americans are diagnosed with colorectal cancer (CRC), the second leading cause of cancer-related mortality in the US and is a major health problem among the Veterans. Approximately 4,000 veterans being diagnosed with the CRC each year within VA facilities. CRC development is mostly due to high smoking, unhealthy dietary habits, high alcohol consumption and exposure to hazardous agents, commonly seen in veterans. A significant risk of relapse for post-resection primary CRC or drug resistance after chemotherapy is commonly observed in CRC patients. Thus, to reduce the risk of CRC development in high-risk individuals and improve relapse and survival rates for veterans requires early intervention with safer and novel drugs are warranted. Project hypothesis to be tested: NSAIDs and select COX-2 inhibitors show significant inhibitory effects in CRC patients, but they are also associated with GI toxicity and cardiovascular (CV) risk. Reasons for this risks are an increase in 5-LOX metabolites and reduced synthesis of PGI2 levels. Thus, selective targeting of microsomal PG Synthase-1 (mPGES-1) and 5-LOX would block the protumorigenic PGE2/prothrombotic leukotrienes (LTs) but spare the PGI2, is considered to be an ideal approach to developing efficient and safer colon cancer chemo preventive agents. Toward this end, we have discovered a novel dual mPGES- 1 and 5-LOX inhibitor, LFA-9 by high-throughput and enzyme kinetics assays, and short-term in vivo efficacy studies support further development for CRC prevention/treatment. First series of experiments will focus on: A) Determine the optimal dose, efficacy, dose-response effects of LFA-9 on azoxymethane (AOM)-induced colon cancer in male and female F344 rats. B) Assess the cardiovascular risk/toxicity and prothrombotic events for short-term and long term administration of LFA-9. C) Evaluate the key biomarkers and its correlation with colon tumor inhibition. D) Determine the efficacy of LFA-9 in CRC Patients derived xenograft (PDX) mice model to assess any possible therapeutic benefits. Second series of experiments will be performed with genetically deficient mice (mPGES1-/- - 5-LOX-/-) to assess the relative relevance of mPGES-1 and 5-LOX in colon tumor development. Also, we will determine the role of macrophage specific mPGES-1 and 5-LOX in colon tumor development. To test this, CD11b- DTR mice will be depleted of its macrophages and also macrophages isolated from bone marrow of compound (mPGES1-/- - 5-LOX-/-) mice will be adoptively transferred into CD11b-DTR. CD11b-DTR mice will be used to test AOM/DSS-induced colon tumor formation in the presence of mPGES1-/- - 5-LOX-/- macrophages. A comprehensive and competitive team has been assembled with expertise in the field of colorectal cancer, cancer drug development, understanding mechanisms. The accomplishment of this project will significantly improve the safety and efficacious drugs for the prevention and treatment of CRC patients.
Every year 150,000 Americans are diagnosed with colorectal cancer (CRC), the second leading cause of cancer-related mortality in the US and is a major health problem among the Veterans. Approximately 4,000 veterans being diagnosed with the CRC each year within VA facilities. NSAIDs are promising CRC preventive agents. However, Veterans, as a group on NSAIDs therapy, are at high risk for both gastrointestinal and cardiovascular NSAID-induced complications. Therefore, to reduce the risk of CRC in Veterans, potential early intervention with novel and safer drugs for prevention are warranted. In this project we propose to develop a novel drug with efficacious and safe profile for the high-risk CRC patients. Toward this end, we have discovered a novel drug with promising CRC preventive effects. Further development of this drug in this project will significantly improve clinical and translational research towards prevention and treatment of VA-CRC patients.