Development of an Oral WNT inhibitor

ABSTRACT Colorectal cancerCRCrepresents the fourth most commonly diagnosed cancer withnew cases each yearUnfortunatelyCRC results in a disproportionate number of deathsprojected indue to advanced stage at diagnosisthe aggressive phenotype of the disease and lack of effective therapeuticsGreater thanof CRC patients possess activating mutations in the WNT signaling pathwayWNT pathway activation is a critical step in the initiation of CRC tumorigenesisCurrentlythere are no FDA approved drugs or drugs in late stage clinical trials that target the WNT pathwayAs a resultthere is an urgent need for the development of inhibitors of the WNT pathway to treat not only CRCbut other WNT driven cancersStemSynergy Therapeutics IncSSTIis a biopharmaceutical company focused on the discoverydevelopment and commercialization of novel therapeutic approaches to target critical cancer stem cellsincluding WNTHedgehog and NotchSSTI has identified a class of small molecules that regulate WNT signaling via activation of Casein KinaseIn this applicationwe describe detailed characterization of mechanism of actiondemonstrate SSTfunctions downstream of activating mutations found in CRC to produce excellent in vitro potency in a range of CRC cell lines and provide significant in vivo efficacy data using various genetic and xenograft models in miceSignificantlySSTdoes NOT affect normal GI architecturewhich is in contrast to two other major classes of WNT inhibitors currently being developed where GI toxicity is dose limitingThis Phase I application outlines the development of SSTas an orally bioavailable drug for dosing in humans that would complement or supersede the formulation that we are progressing through preclinical development and into clinical trials for metastatic CRCThe WNT pathway plays a role in many different cancer subtypes and because there are no drugs on the market that target the WNT pathwayby continuing to move SSTthrough the oncology development pipelineSSTI has the potential to improve and prolong the lives of millions of cancer patients worldwideThe multi disciplinary Randamp D team at SSTI has strong credentials and experience in all relevant areasenabling us to complete the key science and business aspects of the development PROJECT NARRATIVE Colorectal cancer is usually an aggressive and deadly disease with limited treatment optionsThe Wnt pathway is a major growth pathway that plays a critical role in andgtof all cases and there are currently no inhibitors in the clinicWe intend to perform formulation studies to allow ORAL dosing in human clinical trials for a treatment of colorectal cancer