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Abstract
Glioblastoma is the most aggressive primary brain tumor in adults. Consequently, new therapeutic strategies are needed. Tumor response to cytotoxic chemotherapy is heterogeneous across patients. Interestingly, predictive biomarkers of response to these classic chemotherapeutic agents have been identified in neuro-oncology (i.e., 1p/19q co-deletion, IDH mutation and O6-methylguanine DNA-methyltransferase promoter methylation). The most emblematic biomarker in glioblastoma is O6-methylguanine DNA-methyltransferase promoter methylation that predicts response to temozolomide. In parallel, innovative drugs are emerging. Some of these agents have shown some activity but in a limited number of glioblastoma patients. One of the major challenges is to identify molecular predictors of response to these smart drugs for an efficient personalized medicine. These novel agents have been tested in clinical trials enrolling glioblastoma patients. Although none of them has been validated prospectively in Phase III clinical trials, interesting molecular predictors of response to these drugs have been investigated and are presented in this review, which also reports more advanced biomarkers.
Financial & competing interests disclosure
The authors acknowledge funding from the program Investissements d’avenir ANR-10-IAIHU-06 and from SIRIC of Marseille, grant INCa-DGOS-INSERM 6038. A Idbaih has received honoraria from Roche and Novartis. A Idbaih has received research support funding from Intsel Chimos and Beta Innov. O Chinot has received an honorarium from Roche. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties
No writing assistance was utilized in the production of this manuscript.
Key issues
O6-methylguanine DNA-methyltransferase promoter methylation is not only a prognostic maker but also a predictive molecular biomarker of response to temozolomide and – with less strong evidence – to other alkylating chemotherapeutic agents.
Although its translation into clinical routine has been slow due to technical considerations and by limited therapeutic alternatives to cytotoxic alkylating agents, O6-methylguanine DNA-methyltransferase promoter methylation is close to being integrated in daily medical management of glioblastoma patients regardless of their age.
Promising novel therapeutic strategies including monoclonal antibodies, small molecules and vaccines emerging for glioblastoma treatment. These treatments target molecular abnormalities or disrupted cell functions in glioblastoma.
Several tumor and blood circulating molecular biomarkers have been correlated to tumor response to antiangiogenic drugs. Several biomarkers, including VEGF-A, matrix metalloproteinase 2, matrix metalloproteinase 9 and VEGFR, detected in tumor tissue or body fluids, have been linked to an increased benefit from antiangiogenic drugs, but these results remain preliminary and need further validating investigation.
EGFR pathway is one of the critical signaling pathways driving glioblastoma oncogenesis. However, anti-EGFR therapies have shown efficacy in a limited number of patients. The molecular specificities of these responding tumors need to be identified. EGFRvIII, PTEN or phospho-Akt statuses have been widely investigated in several studies with conflicting results.
EGFRvIII-expressing glioblastoma may respond to an EGFRvIII vaccine, but this needs to be confirmed by the ongoing Phase III clinical trial (NCT01480479) testing EGFRvIII vaccine in newly diagnosed glioblastoma patients.