title: Macitentan, a Dual Endothelin Receptor Antagonist, in Combination with Temozolomide Leads to Glioblastoma Regression and Long-term Survival in Mice.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.affiliation: Department of Cancer Biology, Metastasis Research Laboratory, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Sun-Jin
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Cancer Biology, Metastasis Research Laboratory, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ho Jeong
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Cancer Biology, Metastasis Research Laboratory, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Mark Seungwook
authors.initials: MS
authors.lastname: Kim
authors.affiliation: Department of Cancer Biology, Metastasis Research Laboratory, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Hyun Jin
authors.initials: HJ
authors.lastname: Choi
authors.affiliation: Department of Cancer Biology, Metastasis Research Laboratory, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Junqin
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Cancer Biology, Metastasis Research Laboratory, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Qiuyu
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Aldape
authors.affiliation: Department of Neurosurgery, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Weinberg
authors.affiliation: Department of Neuro-Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: W K Alfred
authors.initials: WK
authors.lastname: Yung
authors.affiliation: Department of Neuro-Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Conrad
authors.affiliation: Department of Cancer Biology, Metastasis Research Laboratory, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Robert R
authors.initials: RR
authors.lastname: Langley
authors.affiliation: Actelion Pharmaceuticals, Ltd., Allschwil, Switzerland.
authors.forename: François
authors.initials: F
authors.lastname: Lehembre
authors.affiliation: Actelion Pharmaceuticals, Ltd., Allschwil, Switzerland.
authors.forename: Urs
authors.initials: U
authors.lastname: Regenass
authors.affiliation: Department of Cancer Biology, Metastasis Research Laboratory, University of Texas MD Anderson Cancer Center, Houston, Texas. ifidler@mdanderson.org.
authors.forename: Isaiah J
authors.initials: IJ
authors.lastname: Fidler
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D065128:Endothelin Receptor Antagonists / Q000494:pharmacology*; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D005910:Glioma / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D011743:Pyrimidines / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D000077204:Temozolomide
chemical_list: D065128:Endothelin Receptor Antagonists; D011743:Pyrimidines; D013449:Sulfonamides; D003606:Dacarbazine; D000077204:Temozolomide; C533860:macitentan