Program 1

Targeting a unique cancer genetic vulnerability

Adenomatous polyposis coli (APC) is a tumor suppressor gene that plays an important role in the regulation of the Wnt/β-Catenin pathway, a central mechanism that drives the initiation and progression of colorectal cancer (CRC) and pre-cancerous conditions such as familial adenomatous polyposis (FAP). The APC gene product binds to beta-catenin, axin and glycogen synthase kinase 3 to form a large protein complex that breaks down beta-catenin, resulting in negative regulation of the Wnt/β-Catenin signaling pathway, which plays a critical role in cell proliferation and homeostasis. APC mutation is the driving factor behind colorectal pre-cancer and cancer. APC is mutated in 100% of FAP patients and over 80% of colorectal cancer patients.

Paradoxically, APC mutation leading to Wnt/β-Catenin hyperactivation is also a genetic vulnerability for colorectal pre-cancer and cancer. Like APC, GSK3 and other components of the beta catenin destruction complex inhibit Wnt/β-Catenin. Therefore, a GSK3 inhibitor increases Wnt/β-Catenin signaling and further activates Wnt/β-Catenin signaling pathway in APC mutant cells. GSK3 inhibition specifically kills APC mutant cells.

Our GSK3 inhibitor program is in pre-clinical development. We plan to file an IND in 2026 for colorectal cancer.