Brief Report LYMPHOID NEOPLASIA ABT-199, a new Bcl-2–specific BH3 mimetic, has in vivo efficacy against aggressive Myc-driven mouse lymphomas without provoking thrombocytopenia

Whether cells live or die by apoptosis when confronted with diverse stresses, including radiation and chemotherapy, is determined by interactions between opposing factions of the Bcl-2 family of proteins. Bcl-2 prevents apoptosis, as do Bcl-xL, Bcl-w, Mcl-1, and A1, but other close relatives Bax and Bak instead provoke apoptosis. Stress signals induce distant relatives known as BH3-only proteins, which bind avidly to a hydrophobic groove on prosurvival proteins, preventing them from restraining any activated Bax or Bak molecules. Certain BH3-only proteins (Bim, cleaved Bid, and perhaps Puma, Noxa) can also bind weakly and transiently to Bax and/or Bak, triggering their conformational change and homo-oligomerization on the outer mitochondrial membrane. As a consequence, cytochrome c is released into the cytoplasm and provokes activation of the proteases (caspases) that demolish the cell. Chemical mimetics of BH3-only proteins represent an exciting new class of cancer therapeutic. The most promising thus far have been ABT-737 and the related orally available compound ABT-263 (navitoclax), which bind avidly to Bcl-2, Bcl-xL, and Bcl-w but not to Mcl-1 or A1. Both have significant efficacy against human tumor cell lines having high levels of Bcl-2 or Bcl-xL but little Mcl-1, particularly lymphoid malignancies and small cell lung carcinoma. However, because Bcl-xL is critical for the survival of platelets, ABT-737 and ABT-263 induced transient thrombocytopenia in preclinical trials, and the dose-limiting toxicity for navitoclax proved to be thrombocytopenia. Abbott Laboratories has recently developed a high-affinity Bcl-2– selective BH3 mimetic, ABT-199, which spared human platelets in vitro and dog platelets in vivo. Tumor regression was achieved for xenografts of human lymphoma cell lines and, excitingly, the first clinical tests for refractory chronic lymphocytic leukemia resulted in rapid tumor lysis in 3 of 3 patients. We have investigated the efficacy of ABT-199 in a preclinical model responsive to ABT-737: immunocompetent mice transplanted with lymphomyeloid progenitor cell tumors derived from Em-myc/ Em-bcl-2 (hereafter myc/bcl-2) transgenic mice. These lymphomas have high levels of Bim, which is thought to be critical for responsiveness. To test the requirement for Bim, we also generated and treated bim myc/bcl-2 tumors. In addition, we trialed combination therapy with ABT-737 and either the proteosome inhibitor bortezomib or the cyclin-dependent kinase (CDK) inhibitor purvalanol.