Developing selective inhibitors of the b-catenin/BCL9 transcriptional complex for myeloma therapy
Ruben Carrasco
MD PhDDana-Farber Cancer Institute
Project Term: July 1, 2023 - June 30, 2026
The b-catenin/BCL9 transcriptional complex, is a novel dependency in multiple myeloma (MM). Disruption of this complex inhibits MM cell growth in culture and in MM xenograft models. Development of potent selective b-catenin/BCL9 inhibitors will provide valuable tools to further investigate their mechanism of MM inhibition. We have established a chemistry, structural biology, and molecular pathology platform to facilitate novel inhibitor development, and explore its translational potential in MM.
"Multiple myeloma (MM) is a cancer resulting from accumulation as multiple “omas” of malignant plasma cells in the bone marrow, the soft inner part of bones where new blood cells formation takes place. MM is the second most frequent human blood cancer, which remains incurable despite the advent of promising approaches such as CAR T-cell therapy. This is due, in part, to disease heterogeneity and clonal evolution underlying development of drug resistance and disease progression. Thus, there remains an urgent unmet medical need for innovative therapies, particularly for patients with advanced disease unresponsive to available therapies.
The Wnt/b-catenin system is a signaling pathway used by the tumor cells to communicate each other and with the tumor microenvironment. It conveys extracellular information from the cell surface to the nucleus where it enhances expression of genes involved in sustaining cancer stemness and promoting epithelial-to-mesenchymal transition and tumor immune evasion. Inappropriate activation of the Wnt/b-catenin pathway contributes to the initiation and progression of various human cancer types, including MM, and has emerged as a desirable, though challenging therapeutic target.
BCL9 is a critical co-activator of the Wnt/b-catenin pathway via direct binding to b-catenin. Data from our lab suggest that targeted disruption of the b-catenin/BCL9 heterodimeric complex is a possible therapeutic approach for MM based on the following findings: i) BCL9 is frequently over-expressed in MM cells but is absent in the normal plasma cells, providing a broad therapeutic window for targeting this complex; ii) The b-catenin/BCL9 complex serves multiple roles in MM pathogenesis and disease progression; iii) Deployment of a robust high-throughput screen assay with a small-molecule compound library allowed us to identify C-1 a “lead compound” that specifically disrupted formation of the b-catenin/BCL9 complex. C-1 treatment is associated with inhibition of cholesterol metabolism and anti-tumor activity in culture cells and in a murine model of MM. C-1 reduces MM tumor growth alone, but further reduces tumor burden when given in combination with other cholesterol lowering drugs or statins.
The finding that statin use is associated with reduced mortality among MM patients underscore the relevance of our findings and highlights the need for developing more effective C-1 derivatives and study their role in oncogenic Wnt/b-catenin activity, cholesterol metabolism and MM biology and therapy. With that purpose, we have inaugurated a close partnership that will bring together researchers with complementary expertise in structural biology (Dhe-Paganon lab), medicinal chemistry (Qi Lab), molecular pathology (Carrasco Lab), and clinical medicine (Anderson Lab) to facilitate novel inhibitor development, and explore its translational potential in MM."