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Clin Cancer Res. 2016 Jul 15;22(14):3550-9. doi: 10.1158/1078-0432.CCR-15-1698. Epub 2016 Mar 2.

Targeting MDM2 for Treatment of Adenoid Cystic Carcinoma.

Author information

1
Department of Cariology, Restorative Sciences, Endodontics, University of Michigan School of Dentistry, Ann Arbor, Michigan.
2
Department of Cariology, Restorative Sciences, Endodontics, University of Michigan School of Dentistry, Ann Arbor, Michigan. Department of Oral Pathology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
3
Department of Oral Pathology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil. Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan.
4
Department of Otolaryngology, University of Michigan School of Medicine, Ann Arbor, Michigan. University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan.
5
Department of Otolaryngology, University of Toronto, Ontario, Canada.
6
University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan. Department of Oral and Maxillofacial Surgery, University of Michigan School of Dentistry, Ann Arbor, Michigan.
7
South Texas Accelerated Research Therapeutics, San Antonio, Texas.
8
Department of Pathology, University of Virginia, Charlottesville, Virginia.
9
Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan.
10
Department of Cariology, Restorative Sciences, Endodontics, University of Michigan School of Dentistry, Ann Arbor, Michigan. University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan. Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan.
11
University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan. Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan. Department of Pharmacology, University of Michigan School of Medicine, Ann Arbor, Michigan. Department of Medicinal Chemistry, University of Michigan College of Pharmacy, Ann Arbor, Michigan.
12
Department of Cariology, Restorative Sciences, Endodontics, University of Michigan School of Dentistry, Ann Arbor, Michigan. Department of Otolaryngology, University of Michigan School of Medicine, Ann Arbor, Michigan. University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan. Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, Michigan. jenor@umich.edu.

Abstract

PURPOSE:

There are no effective treatment options for patients with advanced adenoid cystic carcinoma (ACC). Here, we evaluated the effect of a new small molecule inhibitor of the MDM2-p53 interaction (MI-773) in preclinical models of ACC.

EXPERIMENTAL DESIGN:

To evaluate the anti-tumor effect of MI-773, we administered it to mice harboring three different patient-derived xenograft (PDX) models of ACC expressing functional p53. The effect of MI-773 on MDM2, p53, phospho-p53, and p21 was examined by Western blots in 5 low passage primary human ACC cell lines and in MI-773-treated PDX tumors.

RESULTS:

Single-agent MI-773 caused tumor regression in the 3 PDX models of ACC studied here. For example, we observed a tumor growth inhibition index of 127% in UM-PDX-HACC-5 tumors that was associated with an increase in the fraction of apoptotic cells (P = 0.015). The number of p53-positive cells was increased in MI-773-treated PDX tumors (P < 0.001), with a correspondent shift in p53 localization from the nucleus to the cytoplasm. Western blots demonstrated that MI-773 potently induced expression of p53 and its downstream targets p21, MDM2, and induced phosphorylation of p53 (serine 392) in low passage primary human ACC cells. Notably, MI-773 induced a dose-dependent increase in the fraction of apoptotic ACC cells and in the fraction of cells in the G1 phase of cell cycle (P < 0.05).

CONCLUSIONS:

Collectively, these data demonstrate that therapeutic inhibition of the MDM2-p53 interaction with MI-773 activates downstream effectors of apoptosis and causes robust tumor regression in preclinical models of ACC. Clin Cancer Res; 22(14); 3550-9. ©2016 AACR.

PMID:
26936915
PMCID:
PMC4947417
DOI:
10.1158/1078-0432.CCR-15-1698
[Indexed for MEDLINE]
Free PMC Article

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