Acting as intercellular signals, Wnt proteins regulate the proliferation of cells. Wnt signals are active in numerous contexts, initially in early development and later during the growth and maintenance of various tissues. Wnt signaling is often implicated in stem cell control, as a proliferative and self-renewal signal. Mutations in Wnt genes or Wnt pathway components lead to specific developmental defects, as well as various human diseases, including cancer.
One such pathway, known as the canonical Wnt signaling pathway, has historically been considered an “undruggable” cancer target, as small molecule approaches have proven ineffective or toxic. Activating mutations in the Wnt/β-catenin signaling pathway are responsible for many solid tumors and hematological malignancies, including colorectal, breast, and lung cancers, hepatocellular and ovarian carcinomas, glioblastoma, and hematological malignancies such as chronic lymphocytic leukemia and mantle cell lymphoma. Wnt/β-catenin signaling drives cancer initiation and contributes to tumor growth, angiogenesis and metastasis. Disruption of the BCL9/β-Catenin interaction suppresses transcription of Wnt target genes regulating proliferation, migration, invasion, and the metastatic potential of tumor cells.
Sapience has generated a panel of β-catenin antagonist peptides specifically designed to inhibit its interaction with BCL9, which is essential for its oncogenic activity but should not impact its homeostatic functions. Initial in vitro and in vivo data sets are promising, with highly potent cell kill against 3-dimensional patient-derived breast cancer xenograft tumoroids and tumor regressions/growth delays in multiple models of disease. We anticipate moving this program into IND-enabling studies in mid-2021.