title: Therapeutic Inhibition of the MDM2-p53 Interaction Prevents Recurrence of Adenoid Cystic Carcinomas.
abstract: Purpose:Conventional chemotherapy has modest efficacy in advanced adenoid cystic carcinomas (ACC). Tumor recurrence is a major challenge in the management of ACC patients. Here, we evaluated the antitumor effect of a novel small-molecule inhibitor of the MDM2-p53 interaction (MI-773) combined with cisplatin in patient-derived xenograft (PDX) ACC tumors.Experimental Design:Therapeutic strategies with MI-773 and/or cisplatin were evaluated in SCID mice harboring PDX ACC tumors (UM-PDX-HACC-5) and in low passage primary human ACC cells (UM-HACC-2A, -2B, -5, -6)in vitroThe effect of therapy on the fraction of cancer stem cells (CSC) was determined by flow cytometry for ALDH activity and CD44 expression.Results:Combined therapy with MI-773 with cisplatin caused p53 activation, induction of apoptosis, and regression of ACC PDX tumors. Western blots revealed induction of MDM2, p53 and downstream p21 expression, and regulation of apoptosis-related proteins PUMA, BAX, Bcl-2, Bcl-xL, and active caspase-9 upon MI-773 treatment. Both single-agent MI-773 and MI-773 combined with cisplatin decreased the fraction of CSCs in PDX ACC tumors. Notably, neoadjuvant MI-773 and surgery eliminated tumor recurrences during a postsurgical follow-up of more than 300 days. In contrast, 62.5% of mice that received vehicle control presented with palpable tumor recurrences within this time period (P= 0.0097).Conclusions:Collectively, these data demonstrate that therapeutic inhibition of MDM2-p53 interaction by MI-773 decreased the CSC fraction, sensitized ACC xenograft tumors to cisplatin, and eliminated tumor recurrence. These results suggest that patients with ACC might benefit from the therapeutic inhibition of the MDM2-p53 interaction.Clin Cancer Res; 23(4); 1036-48. ©2016 AACR.
authors.affiliation: Department of Cariology, Restorative Sciences, and Endodontics, University of Michigan School of Dentistry, Ann Arbor, Michigan.|Department of Oral Pathology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
authors.forename: Felipe
authors.initials: F
authors.lastname: Nör
authors.affiliation: Department of Cariology, Restorative Sciences, and Endodontics, University of Michigan School of Dentistry, Ann Arbor, Michigan.
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, Michigan.
authors.forename: Zhaocheng
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Cariology, Restorative Sciences, and Endodontics, University of Michigan School of Dentistry, Ann Arbor, Michigan.|Department of Oral Pathology, Universidade Federal do Rio Grande do Sul, Porto Alegre, 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, Michigan.|Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan.
authors.forename: Alexander T
authors.initials: AT
authors.lastname: Pearson
authors.affiliation: Department of Cariology, Restorative Sciences, and Endodontics, University of Michigan School of Dentistry, Ann Arbor, Michigan.
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Kerk
authors.affiliation: Department of Oral and Maxillofacial Surgery, University of Michigan School of Dentistry, Ann Arbor, Michigan.|University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan, USA.
authors.forename: Joseph I
authors.initials: JI
authors.lastname: Helman
authors.affiliation: Department of Oral Pathology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
authors.forename: Manoel
authors.initials: M
authors.lastname: Sant'Ana Filho
authors.affiliation: Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan.|University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan, USA.|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.
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, Michigan. jenor@umich.edu.|University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan, USA.|Department of Otolaryngology, University of Michigan School of Medicine, Ann Arbor, Michigan.|Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, Michigan.
authors.forename: Jacques E
authors.initials: JE
authors.lastname: Nör
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D003528:Carcinoma, Adenoid Cystic / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics*; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D060066:Protein Interaction Maps / Q000187:drug effects*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics* / Q000378:metabolism; D013141:Spiro Compounds / Q000008:administration & dosage; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D009363:Neoplasm Proteins; D013141:Spiro Compounds; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D002945:Cisplatin