Identification of Patients with Recurrent Glioblastoma Who May Benefit from Combined Bevacizumab and CCNU Therapy: A Report from the BELOB Trial

Erdem-Eraslan, Lale; Bent, Martin J. van den; Hoogstrate, Youri; Naz-Khan, Hina; Stubbs, Andrew; Spek, Peter van der; Böttcher, René; Gao, Yinjie; Wit, Maurice de; Taal, Walter; Oosterkamp, Hendrika M.; Walenkamp, Annemiek; Beerepoot, Laurens V.; Hanse, Monique C.J.; Buter, Jan; Honkoop, Aafke H.; Holt, Bronno van der; Vernhout, René M.; Smitt, Peter A.E. Sillevis; Kros, Johan M.; French, Pim J.

doi:10.1158/0008-5472.can-15-0776

Cited by 90 publications

(75 citation statements)

References 57 publications

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“…Analysis of AVAglio, a randomized phase III clinical study that investigated the addition of Bev to radiotherapy/TMZ, suggests that IDH1 WT proneural versus mesenchymal GBMs may benefit (Sandmann et al, 2015). In contrast, the BELOB trial with recurrent GBMs showed that the classical subtype was most responsive to Bev in combination with lomustine (Erdem-Eraslan et al, 2016). Thus, the GBM molecular subgroup may not be an adequate predictor of response to anti-angiogenic therapy and further criteria are needed.…”

Section: Discussionmentioning

confidence: 99%

A Glial Signature and Wnt7 Signaling Regulate Glioma-Vascular Interactions and Tumor Microenvironment

et al. 2018

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SUMMARY Gliomas comprise heterogeneous malignant glial and stromal cells. While blood vessel co-option is a potential mechanism to escape anti-angiogenic therapy, the relevance of glial phenotype in this process is unclear. We show that Olig2+ oligodendrocyte precursor-like glioma cells invade by single-cell vessel co-option and preserve the blood-brain barrier (BBB). Conversely, Olig2-negative glioma cells form dense perivascular collections and promote angiogenesis and BBB breakdown, leading to innate immune cell activation. Experimentally, Olig2 promotes Wnt7b expression, a finding that correlates in human glioma profiling. Targeted Wnt7a/7b deletion or pharmacologic Wnt inhibition blocks Olig2+ glioma single-cell vessel co-option and enhances responses to temozolomide. Finally, Olig2 and Wnt7 become upregulated after anti-VEGF treatment in preclinical models and patients. Thus, glial-encoded pathways regulate distinct glioma-vascular microenvironmental interactions.

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Section: Discussionmentioning

confidence: 99%

A Glial Signature and Wnt7 Signaling Regulate Glioma-Vascular Interactions and Tumor Microenvironment

et al. 2018

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“…Data were obtained from 115 patients included in the BELOB trial, which included glioblastoma-bearing patients at recurrence (35 treated with bevacizumab, 37 treated with lomustine and 43 with both) [27, 28]. Focusing on patients treated with lomustine or lomustine+bevacizumab, the association between treatment efficacy and CSF3 expression was determined in the BELOB cohort.…”

Section: Methodsmentioning

confidence: 99%

Blood baseline neutrophil count predicts bevacizumab efficacy in glioblastoma

et al. 2016

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Bevacizumab is used to treat glioblastoma; however, no current biomarker predicts its efficacy. We used an exploratory cohort of patients treated with the radiochemotherapy then bevacizumab or chemotherapy at recurrence (N = 265). Bevacizumab use increased median overall survival (OS) 18.7 vs 11.3 months, p = 0.0014). In multivariate analysis, age, initial surgery, neutrophil count, Karnofsky status >70% and bevacizumab administration were independent prognostic factors of survival. We found an interaction between bevacizumab use and baseline neutrophil count. The cut-off value for the neutrophil count was set at 6000/mm3. Only patients with a high neutrophil count benefited from the bevacizumab treatment (17.3 vs 8.8 months p < 0.0001). We validated this result using data from the TEMAVIR trial, which tested the efficacy of neoadjuvant bevacizumab plus irinotecan versus radiochemotherapy in the first-line treatment of glioblastoma. Transcriptomic data from TCGA underlined that CSF3 expression, the gene encoding G-CSF, the growth factor for neutrophils, correlated with VEGF-A-dependent angiogenesis. In another independent cohort (BELOB trial), which compared lomustine versus lomustine plus bevacizumab at recurrence, bevacizumab only benefited patients with high CSF3 expression in the tumor. These data suggest that only patients with a high peripheral neutrophil count before bevacizumab treatment benefited from this therapy.

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“…The IDH-wildtype proneural subclass shows the worst prognosis of all, which could speak for a particular relevance of bevacizumab for those patients who do not profit relevantly from the standard treatment today. Other published molecular biomarkers include a further analysis of the BELOB trial, where a particular gene expression signature that correlated more with the 'classical' glioblastoma subtype appeared to experience most clinical benefit from bevacizumab [32]. These discrepancies show that more work is needed for an unambiguous picture here, and, most importantly, a prospective validation of those biomarkers.…”

Section: Can We Better Select Patients With Biomarkers?mentioning

confidence: 99%

Anti-Angiogenics: Their Role in the Treatment of Glioblastoma

2018

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Angiogenesis is a hallmark of glioblastomas, but anti-angiogenic therapies have fallen short of the initial expectations to relevantly change the clinical course of the disease. Only one agent, the anti-vascular endothelial growth factor (VEGF)-A antibody bevacizumab, has shown meaningful efficacy in controlled clinical trials in glioblastoma, so far. In primary and recurrent glioblastoma, this efficacy is, however, limited to prolonging progression-free survival and to generating some additional palliative benefits, without affecting overall survival in the total population of glioblastoma patients. Here, we give an overview of the current status of anti-angiogenic therapy in glioblastoma, including how it is currently used in the clinic. Furthermore, we discuss avenues of biomarker research aiming to identify those glioblastoma patients with a higher likelihood of profiting from anti-VEGF-A therapies (and to identify those who will not). Together with novel anti-angiogenic treatment targets and combination regimens under development today, those might improve the current clinical benefits from this class of drugs in glioblastoma.

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Identification of Patients with Recurrent Glioblastoma Who May Benefit from Combined Bevacizumab and CCNU Therapy: A Report from the BELOB Trial

Abstract: The results from the randomized phase II BELOB trial pro-

Cited by 90 publications

References 57 publications

A Glial Signature and Wnt7 Signaling Regulate Glioma-Vascular Interactions and Tumor Microenvironment

A Glial Signature and Wnt7 Signaling Regulate Glioma-Vascular Interactions and Tumor Microenvironment

Blood baseline neutrophil count predicts bevacizumab efficacy in glioblastoma

Anti-Angiogenics: Their Role in the Treatment of Glioblastoma

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