Aspirin-PC for Chemoprevention of Colorectal Cancer

摘要

ABSTRACT Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in the U.S. Based on numerous epidemiological studies and recent prospective clinical trials, the use of daily aspirin is associated with a significant reduction in CRC incidence, deaths and metastatic spread. However, the chronic use of this drug is limited due to the side-effects of gastrointestinal bleeding/ulceration in susceptible subjects. The main goal of this revised STTR Phase II proposal, developed by the PI, Lenard M. Lichtenberger, PhD, (Professor of Integrative Biology & Pharmacology, The University of Texas Health Science Center at Houston) and the small business, PLx Pharma Inc, based upon our encouraging results in Phase I, is to use cell culture studies and rodent colorectal cancer models to evaluate the chemopreventive activity of a recently approved novel aspirin drug, PL2200 (a phosphatidylcholine (PC)-associated aspirin; NDA issued to PLx Pharma in 01/ 2013), that has been documented in clinical trials to be safer to the GI mucosa than traditional aspirin. We will initially evaluate PL2200 (vs unmodified aspirin) alone on proliferation and apoptosis of mouse and human isogenic CRC cell culture lines. Studies to be performed in collaboration with Dr. Vinod Vijayan from Baylor College of Medicine (BCM), an expert on platelet function, will study the role of platelets in promoting growth, invasive activity and Epithelial-Mesenchymal Transition (EMT) in colon cancer cells and how these platelet-induced pro- carcinogenic changes are inhibited by Aspirin-PC via irreversible COX-1 inhibition. To gain insight into the mechanism of action of Aspirin-PC/PL2200 we will compare the COX-1 and COX-2 inhibitory activity of the test formulations on platelet aggregation/ thromboxane generation and PGE2 concentration of CRC tissue/lower gut epithelium, respectively. This will be followed by evaluating our test drugs ability to affect the dysplastic growth of colonic mucosa of APCMin/+ mice and APC-deficient rats challenged with dextran sodium sulfate (DSS) to induce colonic adenomas and genetic engineered mouse (GEM) models of CRC - to be performed in the laboratory of our collaborators, Drs Kopetz and Menter, at MD Anderson Cancer Center. The GI toxicity of the test-drugs will routinely be monitored in the above animal models. We will also study the role of PIK3CA mutation (which occurs in ~20% of CRC patients and enhances the patient's sensitivity to aspirin) on the chemopreventive efficacy of Aspirin-PC, using the isogenic CRC cell lines where the gene mutation is selectively expressed. Based upon these pre-clinical studies, PLx Pharma Inc will perform a pilot manufacturing run of low-dose (81mg) PL2200 and develop a strategy in consultation with the PI and our colleagues at MDACC to design a future clinical trial to evaluate the chronic use of low-dose PL2200 (81 mg/day) on “at-risk” CRC patients and develop an IND package.