Familial adenomatous polyposis (FAP) is a devastating rare genetic disorder with no effective drug; all patients develop cancer unless the colon is surgically removed at an early age. Celecoxib, an FDA-approved selective COX-2 (cyclooxygenase 2) inhibitor, was once approved for the treatment of FAP. Unfortunately, this indication was withdrawn because chronic use of celecoxib, which is needed to inhibit polyp growth in patients with FAP, causes rare but serious cardiovascular toxicities, including death. The problem is, therefore, not the lack of a validated drug target, but identifying drugs to treat FAP patients without toxicity. To overcome this problem, we propose the development of loca...

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Familial adenomatous polyposis (FAP) is a devastating rare genetic disorder with no effective drug; all patients develop cancer unless the colon is surgically removed at an early age. Celecoxib, an FDA-approved selective COX-2 (cyclooxygenase 2) inhibitor, was once approved for the treatment of FAP. Unfortunately, this indication was withdrawn because chronic use of celecoxib, which is needed to inhibit polyp growth in patients with FAP, causes rare but serious cardiovascular toxicities, including death. The problem is, therefore, not the lack of a validated drug target, but identifying drugs to treat FAP patients without toxicity. To overcome this problem, we propose the development of locally bioavailable (i.e., no systemic exposure and toxicities) selective COX-2 inhibitors that are only available in the colon to suppress colonic COX-2 expression and reduce prostaglandin E2 levels, which is known to promote tumor growth. Locally bioavailable selective COX-2 inhibitors will be designed to take advantage of the normal metabolic process of the human body by 1) being slowly metabolized in the colon but rapidly metabolized in the liver via a process called glucuronidation and 2) undergoing recycling back to the colon, minimizing systemic exposure. Our lead compound LBD-01 already possesses these metabolic properties, but its anti-COX-2 activity is lower than that of celecoxib (positive control). Hence, our research goal is to obtain more active compounds (similar or more active than celecoxib) while maintaining their local bioavailability in the colon. This innovative project will be co-led by three contributing investigators with complementary expertise from the University of Houston and Baylor College of Medicine. Dr. Eduardo Vilar Sanchez, a clinician who treats patients with FAP at the M.D. Anderson Cancer Center, is also part of the team. Our project holds great promise for patients with FAP by providing a new treatment paradigm that would be safe and effective.

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