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

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

Author information

1
Department of Cariology, Restorative Sciences and Endodontics, University of Michigan School of Dentistry, Ann Arbor, MI 48109-1078, United States; Department of Morphological Sciences, Federal University of Rio Grande do Sul, Brazil.
2
Department of Cariology, Restorative Sciences and Endodontics, University of Michigan School of Dentistry, Ann Arbor, MI 48109-1078, United States.
3
Department of Oral and Maxillofacial Surgery, University of Michigan School of Dentistry, United States; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, United States.
4
Department of Cariology, Restorative Sciences and Endodontics, University of Michigan School of Dentistry, Ann Arbor, MI 48109-1078, United States; Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI, United States.
5
Department of Morphological Sciences, Federal University of Rio Grande do Sul, Brazil.
6
Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI, United States; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, United States.
7
Department of Cariology, Restorative Sciences and Endodontics, University of Michigan School of Dentistry, Ann Arbor, MI 48109-1078, United States; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, United States; Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI, United States; Department of Otolaryngology, University of Michigan School of Medicine, Ann Arbor, MI, United States. Electronic address: jenor@umich.edu.

Abstract

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

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