Macitentan, a dual endothelin receptor antagonist, in combination with temozolomide leads to glioblastoma regression and long-term survival in mice

Sun Jin Kim, Ho Jeong Lee, Mark Seungwook Kim, Hyun Jin Choi, Junqin He, Qiuyu Wu, Kenneth Aldape, Jeffrey S. Weinberg, W. K.Alfred Yung, Charles A. Conrad, Robert R. Langley, François Lehembre, Urs Regenass, Isaiah J. Fidler

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

Abstract

Purpose: The objective of the study was to determine whether astrocytes and brain endothelial cells protect glioma cells from temozolomide through an endothelin-dependent signaling mechanism and to examine the therapeutic efficacy of the dual endothelin receptor antagonist, macitentan, in orthotopic models of human glioblastoma. Experimental Design: We evaluated several endothelin receptor antagonists for their ability to inhibit astrocyte- and brain endothelial cell-induced protection of glioma cells from temozolomide in chemoprotection assays. We compared survival in nude mice bearing orthotopically implanted LN-229 glioblastomas or temozolomide-resistant (LN-229Res and D54Res) glioblastomas that were treated with macitentan, temozolomide, or both. Tumor burden was monitored weekly with bioluminescence imaging. The effect of therapy on cell division, apoptosis, tumor-associated vasculature, and pathways associated with cell survival was assessed by immunofluorescent microscopy. Results: Only dual endothelin receptor antagonism abolished astrocyte- and brain endothelial cell-mediated protection of glioma cells from temozolomide. In five independent survival studies, including temozolomide-resistant glioblastomas, 46 of 48 (96%) mice treated with macitentan plus temozolomide had no evidence of disease (P < 0.0001), whereas all mice in other groups died. In another analysis, macitentan plus temozolomide therapy was stopped in 16 mice after other groups had died. Only 3 of 16 mice eventually developed recurrent disease, 2 of which responded to additional cycles of macitentan plus temozolomide. Macitentan downregulated proteins associated with cell division and survival in glioma cells and associated endothelial cells, which enhanced their sensitivity to temozolomide. Conclusions: Macitentan plus temozolomide are well tolerated, produce durable responses, and warrant clinical evaluation in glioblastoma patients.

Original languageEnglish (US)
Pages (from-to)4630-4641
Number of pages12
JournalClinical Cancer Research
Volume21
Issue number20
DOIs
StatePublished - Oct 15 2015

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

MD Anderson CCSG core facilities

  • Advanced Technology Genomics Core
  • Research Animal Support Facility
  • Small Animal Imaging Facility
  • Cytogenetics and Cell Authentication Core

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