BH3-mimetic small molecule inhibits the growth and recurrence of adenoid cystic carcinoma

Objectives: To evaluate the anti-tumor effect of BM-1197, a new potent and highly specific small molecule inhibitor of Bcl-2/Bcl-x(L), in preclinical models of human adenoid cystic carcinoma (ACC). Methods: Low passage primary human adenoid cystic carcinoma cells (UM-HACC-2A,-2B,-5,-6) and patient-derived xenograft (PDX) models (UM-PDX-HACC) were developed from surgical specimens obtained from 4 patients. The effect of BM-1197 on cell viability and cell cycle were evaluated in vitro using this panel of low passage ACC cells. The effect of BM-1197 on tumor growth, recurrence and tumor cell apoptosis in vivo was evaluated with the PDX model of ACC (UM-PDX-HACC-5). Results: Exposure of low passage primary human ACC cells to BM-1197 mediated an IC50 of 0.92-2.82 mu M. This correlated with an increase in the fraction of apoptotic cells (p < 0.0001) and an increase in caspase-3 activity (p < 0.0001), but no noticeable differences in cell cycle (p > 0.05). In vivo, BM-1197 inhibited tumor growth (p = 0.0256) and induced tumor cell apoptosis (p = 0.0165) without causing significant systemic toxicities, as determined by mouse weight over time. Surprisingly, weekly BM-1197 decreased the incidence of tumor recurrence (p = 0.0297), as determined by Kaplan-Meier analysis. Conclusion: These data demonstrated that single agent BM-1197 induces apoptosis and inhibits tumor growth in preclinical models of adenoid cystic carcinoma. Notably, single agent BM-1197 inhibited tumor recurrence, which is considered a major clinical challenge in the clinical management of adenoid cystic carcinoma. Collectively, these results suggest that patients with adenoid cystic carcinoma might benefit from therapy with a BH3-mimetic small molecule. (C) 2015 Elsevier Ltd. All rights reserved.