title: BH3-mimetic small molecule inhibits the growth and recurrence of adenoid cystic carcinoma.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Gerson A
authors.initials: GA
authors.lastname: Acasigua
authors.affiliation: Department of Cariology, Restorative Sciences and Endodontics, University of Michigan School of Dentistry, Ann Arbor, MI 48109-1078, United States.
authors.forename: Kristy A
authors.initials: KA
authors.lastname: Warner
authors.affiliation: 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.
authors.forename: Felipe
authors.initials: F
authors.lastname: Nör
authors.affiliation: 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.
authors.forename: Joseph
authors.initials: J
authors.lastname: Helman
authors.affiliation: 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.
authors.forename: Alexander T
authors.initials: AT
authors.lastname: Pearson
authors.affiliation: Department of Morphological Sciences, Federal University of Rio Grande do Sul, Brazil.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Fossati
authors.affiliation: 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.
authors.forename: Shaomeng
authors.initials: S
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Jacques E
authors.initials: JE
authors.lastname: Nör
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D003528:Carcinoma, Adenoid Cystic / Q000188:drug therapy*; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control*; D009374:Neoplasms, Experimental; D012468:Salivary Gland Neoplasms / Q000188:drug therapy*; D013449:Sulfonamides / Q000494:pharmacology*; D016896:Treatment Outcome
chemical_list: D000814:Aniline Compounds; C000600257:BM-1197; D013449:Sulfonamides; D053148:Caspase 3
keywords: Apoptosis; Bcl-2; Bcl-x(L); Resistance to therapy; Salivary gland cancer; Targeted therapy; Tumor recurrence