abt-199 and Cell-Transformation--Neoplastic

Richter Transformation (RT) develops in CLL as an aggressive, therapy-resistant, diffuse large B cell lymphoma (RT-DLBCL), commonly clonally-related (CLR) to the concomitant CLL. Lack of available pre-clinical human models has hampered the development of novel therapies for RT-DLBCL. Here, we report the profiles of genetic alterations, chromatin accessibility and active enhancers, gene-expressions and anti-lymphoma drug-sensitivity of three newly established, patient-derived, xenograft (PDX) models of RT-DLBCLs, including CLR and clonally-unrelated (CLUR) to concomitant CLL. The CLR and CLUR RT-DLBCL cells display active enhancers, higher single-cell RNA-Seq-determined mRNA, and protein expressions of IRF4, TCF4, and BCL2, as well as increased sensitivity to BET protein inhibitors. CRISPR knockout of IRF4 attenuated c-Myc levels and increased sensitivity to a BET protein inhibitor. Co-treatment with BET inhibitor or BET-PROTAC and ibrutinib or venetoclax exerted synergistic in vitro lethality in the RT-DLBCL cells. Finally, as compared to each agent alone, combination therapy with BET-PROTAC and venetoclax significantly reduced lymphoma burden and improved survival of immune-depleted mice engrafted with CLR-RT-DLBCL. These findings highlight a novel, potentially effective therapy for RT-DLBCL.

Topics: Adenine; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Biomarkers, Tumor; Bridged Bicyclo Compounds, Heterocyclic; Cell Proliferation; Cell Transformation, Neoplastic; Gene Expression Regulation, Neoplastic; Humans; Lymphoma, Large B-Cell, Diffuse; Mice; Piperidines; Proteins; Proteolysis; Sulfonamides; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

BH3-only proteins trigger the stress apoptosis pathway and chemical mimetics have great potential for cancer therapy. BH3-only proteins inhibit antiapoptotic members of the Bcl-2 family. Promising BH3 mimetic ABT-737 and the related orally available compound ABT-263 (navitoclax) bind avidly to antiapoptotic Bcl-2, Bcl-xL, and Bcl-w. However, their interaction with Bcl-xL provokes thrombocytopenia, which has proven to be the dose-limiting toxicity. We have tested the efficacy of ABT-199, a new Bcl-2-specific BH3 mimetic, against aggressive progenitor cell lymphomas derived from bitransgenic myc/bcl-2 mice. As a single agent, ABT-199 was as effective as ABT-737 in prolonging survival of immunocompetent tumor-bearing mice without causing thrombocytopenia. Both drugs acted rapidly but, contrary to prevailing models, their apoptotic activity did not rely upon the BH3-only protein Bim. When ABT-737 was combined with the proteosome inhibitor bortezomib or CDK inhibitor purvalanol, many treated animals achieved long-term remission.

Topics: Animals; Antineoplastic Agents; Biomimetics; Bridged Bicyclo Compounds, Heterocyclic; Cell Transformation, Neoplastic; Genes, myc; Lymphoma; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neoplasm Invasiveness; Peptide Fragments; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Substrate Specificity; Sulfonamides; Survival Analysis; Thrombocytopenia; Treatment Outcome