Repurposing Pyrvinium as an Orphan Drug for Familial Adenomatous Polyposis

Orton, Darren

Abstract

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.