Approximately 90% of sporadic colorectal cancers contain mutations in components of the Wnt/β-catenin signaling pathway. These mutations are found in the earliest neoplasms, suggesting that this pathway is a critical gatekeeper to prevent colorectal carcinogenesis.
Colorectal Cancer
Small Molecule Therapeutics
Globally, colorectal cancer (CRC) is the third most common type, making up about 10% of all cases. Approximately 90% of sporadic CRCs contain mutations in components of the Wnt/β-catenin signaling pathway. These mutations are found in the earliest neoplasms, suggesting that this pathway is a critical gatekeeper to prevent colorectal carcinogenesis. Most tumors contain a mutation in a single component of the signaling pathway. However, recent cancer genome atlas consortium data indicates that mutations in multiple components can co-occur. Most mutations, some 85%, map to 'hotspots' within APC and often lead to the expression of a truncated APC protein from this allele. This truncated protein is incapable of incorporating into a function β-catenin destruction complex. Thus, when the wild-type APC is inactivated by mutations or lost through loss of heterozygosity, β-catenin levels inappropriately accumulate in the cell, leading to an aberrant expression of Wnt/β-catenin targeting genes and the development of benign adenomas.
At MD2, we specifically target β-catenin-directly to treat WT and mutant cancer cells with our small molecule drugs. Our direct β-catenin inhibitors target β-catenin in the cytoplasm, thus reducing the nucleus's burden. It represents a first-in-class approach to treating β-catenin driven CRC.