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

Oral Oncol. 2015 Sep;51(9):839-47. doi: 10.1016/j.oraloncology.2015.06.004. Epub 2015 Jun 26.


Objectives: To 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).

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 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.

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.

Keywords: Apoptosis; Bcl-2; Bcl-x(L); Resistance to therapy; Salivary gland cancer; Targeted therapy; Tumor recurrence.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aniline Compounds / pharmacology*
  • Animals
  • Apoptosis / drug effects
  • Carcinoma, Adenoid Cystic / drug therapy*
  • Caspase 3 / drug effects
  • Caspase 3 / metabolism
  • Cell Cycle / drug effects
  • Female
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Mice
  • Middle Aged
  • Neoplasm Recurrence, Local / prevention & control*
  • Neoplasms, Experimental
  • Salivary Gland Neoplasms / drug therapy*
  • Sulfonamides / pharmacology*
  • Treatment Outcome


  • Aniline Compounds
  • BM-1197
  • Sulfonamides
  • Caspase 3