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Macitentan, a Dual Endothelin Receptor Antagonist, in Combination with Temozolomide Leads to Glioblastoma Regression
Sun-Jin Kim1, Ho Jeong Lee1, Mark Seungwook Kim1
1Department of Cancer Biology, Metastasis Research Laboratory, University of Texas MD Anderson Cancer Center, Houston, Texas.
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.
Insights
Dual endothelin receptor antagonist macitentan combined with temozolomide chemotherapy shows high efficacy against glioblastoma. This combination therapy effectively eliminates glioma cells, even resistant types, warranting clinical trials.
Area of Science:
- Neuro-oncology
- Pharmacology
- Cancer Biology
Background:
- Astrocytes and brain endothelial cells can protect glioma cells from temozolomide treatment.
- Endothelin signaling pathways are implicated in this protective mechanism.
Purpose of the Study:
- To investigate if astrocytes and brain endothelial cells protect glioma cells from temozolomide via an endothelin-dependent pathway.
- To evaluate the efficacy of macitentan, a dual endothelin receptor antagonist, in preclinical glioblastoma models.
Main Methods:
- Chemoprotection assays were used to assess endothelin receptor antagonists' ability to inhibit protection.
- Orthotopic models of human glioblastoma (including temozolomide-resistant variants) were treated with macitentan, temozolomide, or both.
- Tumor burden, cell division, apoptosis, vasculature, and survival pathways were analyzed.
Main Results:
- Dual endothelin receptor antagonism was the only method to abolish protection of glioma cells from temozolomide.
- 96% of mice treated with macitentan plus temozolomide showed no evidence of disease, outperforming other treatment groups.
- Macitentan downregulated survival proteins in glioma and endothelial cells, increasing temozolomide sensitivity.
Conclusions:
- Macitentan combined with temozolomide is well-tolerated and achieves durable responses in glioblastoma models.
- This combination therapy demonstrates significant potential and warrants clinical evaluation for glioblastoma patients.
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