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

• BM-1197 is a new, potent, BH3 mimetics small molecule inhibitor of Bcl-2/Bcl-xL
• BM-1197 potently induces caspase-3 and apoptosis of adenoid cystic carcinoma cells.
• BM-1197 slows down tumor growth in PDX models of adenoid cystic carcinoma.
• BM-1197 prevents local recurrence of PDX tumors.
• These data unveil therapeutic potential of BH3-mimetics in adenoid cystic carcinoma.

SummaryObjectivesTo evaluate the anti-tumor effect of BM-1197, a new potent and highly specific small molecule inhibitor of Bcl-2/Bcl-xL, in preclinical models of human adenoid cystic carcinoma (ACC).MethodsLow 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).ResultsExposure of low passage primary human ACC cells to BM-1197 mediated an IC50 of 0.92–2.82 μM. 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.ConclusionThese 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.