Abstract 45: BTM-3528 potently induces G1/G0 cell cycle arrest and is efficacious in preclinical models of diffuse large B-cell lymphoma

Abstract

Abstract Aberrant regulation of cell cycle control, integration of signals from oncogenic signaling pathways, and cancer cell metabolism play a key role in the pathogenesis of multiple hematologic malignancies and solid tumors. BTM-3528 is an orally available compound that causes concentration-dependent cell cycle arrest in the G0/G1 phase of the cell cycle, rapidly decreases cellular glutathione levels, induces expression of p21, and decreases expression of Cyclin D 1/3. BTM-3528 has no significant biochemical activity against a panel of known drug targets such as kinases (including cyclin-dependent kinases), G-protein coupled receptors, ion channels, and histone deacetylases. For the described study, the activity of BTM-3528 was evaluated in in vitro and in vivo models of diffuse large B-cell lymphoma (DLBCL). Profiling of BTM-3528 across a panel of hematologic and solid tumor cancer cell lines demonstrated potent antiproliferative activity against a select set of cancer cell types without effect on normal human cells. These included multiple DLBCL cell lines notably of germinal center B-cell (GCB) subtype. The majority of the DLBCL cell lines tested were characterized by Myc and Bcl-2 gene rearrangements or amplifications. Cell proliferation was 100% inhibited with IC50s ranging from 0.14 to 0.52 μM in these DLBCL cell lines. BTM-3528 induced apoptosis with caspase 3/7 activation and decreased Mcl1 protein expression at concentrations associated with cell growth inhibition. In vivo pharmacokinetic studies showed that BTM-3528 has excellent oral bioavailability with a murine t ½ of 6 hours. BTM-3528 was tested in a human subcutaneous DLBCL xenograft model (BJAB). Post tumor implantation, animals with tumors ≥ 250 mm3 were treated with BTM-3528 at the maximum tolerated dose of 75 mg/kg once daily orally for 14 days. Significant antitumor activity was observed after 3 days of treatment followed by sustained tumor regressions. Furthermore, following discontinuation of BTM-3528 after 14 days of treatment, sustained complete tumor regressions were maintained in 50% of the treated animals. Preliminary toxicology evaluation of BTM-3528 showed no adverse effect on hematopoiesis or hepatic function. Conclusion: BTM-3528 is a novel orally bioavailable compound with a unique mechanism of action based on G1/G0 cell cycle arrest and modulation of cancer cell metabolism. It shows significant activity and a favorable toxicity profile in in vitro and in vivo models of DLBCL. These results support the clinical development potential of BTM-3528 for the treatment of DLBCL. Citation Format: Matthew Kostura, Jedd Levine, Vibha Oza, Alan Cooper, Meztli Arguello, Peter W. White, Stephane Ciblat, Anthony Regina, Edith Bellavance, Martine Brault, Arshad Siddiqui, Michael Luther. BTM-3528 potently induces G1/G0 cell cycle arrest and is efficacious in preclinical models of diffuse large B-cell lymphoma [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr 45.