Gerson A Acasigua1, Kristy A Warner2, Felipe Nör1, Joseph Helman3, Alexander T Pearson4, Anna C Fossati5, Shaomeng Wang6, Jacques E Nör7. 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.
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 humanadenoid cystic carcinoma (ACC). METHODS: Low passage primary humanadenoid 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.
Authors: Yangyang Hu; Lin Lu; Yang Xia; Xin Chen; Alfred E Chang; Robert E Hollingsworth; Elaine Hurt; John Owen; Jeffrey S Moyer; Mark E P Prince; Fu Dai; Yangyi Bao; Yi Wang; Joel Whitfield; Jian-Chuan Xia; Shiang Huang; Max S Wicha; Qiao Li Journal: Cancer Res Date: 2016-06-20 Impact factor: 12.701
Authors: Felipe Nör; Kristy A Warner; Zhaocheng Zhang; Gerson A Acasigua; Alexander T Pearson; Samuel A Kerk; Joseph I Helman; Manoel Sant'Ana Filho; Shaomeng Wang; Jacques E Nör Journal: Clin Cancer Res Date: 2016-08-22 Impact factor: 12.531
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