Deregulated Wnt/β-catenin signaling underlies the pathogenesis of a broad range of human cancers, yet the development of targeted therapies to disrupt the aberrant transcription has proven difficult because the pathway incorporates large protein interaction surfaces and regulates many homeostatic functions. Therefore, we have directed our efforts toward blocking the interaction with BCL9, a co-activator for β-catenin-mediated transcription that is highly expressed in tumors but not in the cells of origin. BCL9 drives β-catenin signaling through direct binding mediated by its α-helical homology domain-2. We developed a Stabilized Alpha-Helix of BCL9 (SAH-BCL9), which we show targets β-catenin, dissociates native β-catenin/BCL9 complexes, selectively suppresses Wnt transcription, and exhibits mechanism-based anti-tumor effects. SAH-BCL9 also suppresses tumor growth, angiogenesis, invasion, and metastasis in mouse xenograft models of Colo-320 colorectal carcinoma and INA-6 multiple myeloma. By inhibiting the BCL9/β-catenin interaction and selectively suppressing oncogenic Wnt transcription, SAH-BCL9 may serve as a novel prototype therapy for cancers driven by deregulated Wnt signaling.

Wnt/β-catenin signaling underlies the pathogenesis of a broad range of human cancers, including the deadly plasma cell cancer multiple myeloma (MM). In this study, we report that downregulation of the tumor suppressor microRNA miR-30-5p is a frequent pathogenetic event in MM. Evidence was developed that miR-30-5p downregulation occurs as a result of interaction between MM cells and bone marrow stromal cells, which in turn enhances expression of BCL9, a transcriptional co-activator of the Wnt signaling pathway known to promote MM cell proliferation, survival, migration, drug resistance and formation of MM cancer stem cells. The potential for clinical translation of strategies to re-express miR-30-5p as a therapeutic approach was further encouraged by the capacity of miR-30c and miR-30mix to reduce tumor burden and metastatic potential in vivo, in three murine xenograft models of human MM, without adversely affecting associated bone disease. Together, our findings offer a preclinical rationale to explore miR-30-5p delivery as an effective therapeutic strategy to eradicate MM cells in vivo.