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 vitro The 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: 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: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 23 Issue 4 Pg. 1036-1048 (Feb 15 2017) ISSN: 1557-3265 [Electronic] United States
• PMID: 27550999 (Publication Type: Journal Article)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• Neoplasm Proteins
• Spiro Compounds
• TP53 protein, human
• Tumor Suppressor Protein p53
• MDM2 protein, human
• Proto-Oncogene Proteins c-mdm2
• Cisplatin

Topics

• Animals
• Apoptosis (drug effects)
• Carcinoma, Adenoid Cystic (drug therapy, genetics, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cisplatin (administration & dosage)
• Female
• Humans
• Male
• Mice
• Neoplasm Proteins (genetics)
• Neoplasm Recurrence, Local (genetics, pathology, prevention & control)
• Protein Interaction Maps (drug effects)
• Proto-Oncogene Proteins c-mdm2 (genetics, metabolism)
• Spiro Compounds (administration & dosage)
• Tumor Suppressor Protein p53 (genetics, metabolism)
• Xenograft Model Antitumor Assays