Macitentan, a Dual Endothelin Receptor Antagonist, in Combination with Temozolomide Leads to Glioblastoma Regression and Long-term Survival in Mice.

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-229(Res) and D54(Res)) 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.

• Authors: 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
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 21 Issue 20 Pg. 4630-41 (Oct 15 2015) ISSN: 1557-3265 [Electronic] United States
• PMID: 26106074 (Publication Type: Journal Article)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Endothelin Receptor Antagonists
• Pyrimidines
• Sulfonamides
• Dacarbazine
• Temozolomide
• macitentan

Topics

• Animals
• Cell Division (drug effects)
• Cell Line
• Cell Line, Tumor
• Dacarbazine (analogs & derivatives, pharmacology)
• Down-Regulation (drug effects)
• Endothelial Cells (drug effects, pathology)
• Endothelin Receptor Antagonists (pharmacology)
• Female
• Glioblastoma (drug therapy, pathology)
• Glioma (drug therapy, pathology)
• Humans
• Mice
• Mice, Nude
• NIH 3T3 Cells
• Pyrimidines (pharmacology)
• Sulfonamides (pharmacology)
• Temozolomide