Repurposing Pyrvinium as an Orphan Drug for Familial Adenomatous Polyposis

DESCRIPTION provided by applicant The tumor suppressor Adenomatous Polyposis Coli APC directs degradation of catenin a central signaling protein in the WNT pathway Germline loss of function mutations in APC activate WNT signaling and underlie the inherited colorectal cancer predisposition syndrome Familial Adenomatous Polyposis FAP an orphan disease while somatic mutations lead to sporadic colorectal cancer CRC Current treatment for FAP includes colectomy as well as relatively ineffective medical management aimed at inhibiting further polyp formation Thus there is a compelling unmet need for effective medical therapies for patients with FAP with effective therapies also having potential for chemoprevention against sporadic CRC as well We have demonstrated that pyrvinium an FDA approved antihelminthic drug attenuates WNT signaling Within we show that pyrvinium inhibits polyp formation in the intestinal epithelium of a mutant APC driven mouse model for FAP APC min mice via attenuation of WNT signaling We hypothesize that pyrvinium driven inhibition of WNT signaling will improve survival in FAP We propose preclinical studies enabling us to repurpose pyrvinium through the orphan drug program to treat FAP patients Because FAP patients will be taking pyrvinium chronically we will identify the minimum dose of pyrvinium required to attenuate WNT signaling in FAP mice We will then treat cohorts of FAP mice monitoring responses including survival intestinal pathology and WNT biomarkers in short and long term treatments Successful completion enables us to complete requirements to file for Orphan Drug Designation for pyrvinium PUBLIC HEALTH RELEVANCE Familial Adenomatous Polyposis is a precancerous disease driven by WNT signaling that occurs in young adults with no effective treatment options Patients develop hundreds of polyps in their colon and subsequently require the removal of their colon We propose to develop a Wnt Inhibitor pyrvinium under the orphan drug program to treat this disease