Abstract C183: Targeted disruption of the BCL9/b-catenin complex inhibits oncogenic WNT signaling.

Abstract

Abstract Deregulated Wnt/β-catenin signaling underlies the pathogenesis of a broad range of human cancers yet the development of targeted therapies to disrupt the pathway has remained a formidable challenge due to the toxicities associated with disrupting the pathway's homeostatic functions and the large protein interaction surfaces involved. BCL9 is an important co-activator for β-catenin-mediated transcription and is highly expressed in tumors but not in the cells of origin, presenting an opportunity to selectively block pathologic β-catenin activity. BCL9 drives β-catenin signaling through a direct binding interaction mediated by its α-helical homology domain-2. We report the development of a Stabilized Alpha-Helix of BCL9 (SAH-BCL9) that targets β-catenin, dissociates native β-catenin/BCL9 complexes, selectively suppresses Wnt transcription, and elicits mechanism-based anti-tumor responses. The clinical translation potential of this approach is underscored by the capacity of SAH-BCL9 to effectively suppress the growth, angiogenesis, invasion, and metastasis of Wnt-dependent colorectal cancer and multiple myeloma in vivo. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C183. Citation Format: Ruben D. Carrasco, Loren Walensky. Targeted disruption of the BCL9/b-catenin complex inhibits oncogenic WNT signaling. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C183.