Is there a world beyond bevacizumab in targeting angiogenesis in glioblastoma?

Abstract

INTRODUCTION: Antiangiogenic approaches are currently the dominating experimental therapeutic strategy in glioblastoma. First enthusiasm was provoked by promising radiological response rates and an apparent clinical benefit with some of these agents. Major limitations include the modest number of durable responses, the lack of cytotoxic antitumor activity, of synergy when combined with chemotherapy and of an overall survival benefit. AREAS COVERED: We review the rationale as well as preclinical and clinical evidence for the future development of antiangiogenic agents in glioblastoma. The most prominent approach targets VEGF and includes agents such as the VEGF antibody bevacizumab, the VEGF receptor fusion protein aflibercept or the tyrosine kinase inhibitors cediranib and XL-184. Inhibition of angiogenic pathways by small molecules, for example, enzastaurin, or anti-integrin-based approaches, for example, cilengitide, represent alternative strategies. EXPERT OPINION: Enzastaurin and cediranib failed in randomized Phase III trials in recurrent glioblastoma, aflibercept in Phase II. By contrast, bevacizumab was conditionally approved in many countries. Recently completed Phase III trials for bevacizumab and cilengitide in the first-line setting will define the future role of these agents. This intense clinical trial activity reflects the hope that antiangiogenic agents will become part of the limited therapeutic options for glioblastoma. Expert opinion: Enzastaurin and cediranib failed in randomized phase III trials in recurrent glioblastoma, aflibercept in phase II. In contrast, bevacizumab was conditionally approved in many countries. Recently completed phase III trials for bevacizumab and cilengitide in the first-line setting will define the future role of these agents. This intense clinical trial activity reflects the hope that antiangiogenic agents will become part of the limited therapeutic options for glioblastoma.

Biochanin A inhibits endothelial cell functions and proangiogenic pathways

“…Thus, the prognosis of patients with high-grade gliomas such as GBM is still poor despite the current treatment options available. Given the crucial importance of angiogenesis in the growth and survival of GBMs, many antiangiogenic therapies are being designed to target the disease [27]. Even though the resultant outcomes are encouraging, drug resistance developed by glioma remains one of the challenges faced in designing effective antiangiogenic therapies.…”

La niche des cellules souches tumorales dans le glioblastome : des aspects fondamentaux au ciblage thérapeutique

“…Jusqu'à présent, seul le bévacizumab a démontré une efficacité clinique au cours d'essais thérapeutiques et a été conditionnellement approuvé dans différents pays [39]. Enzastaurin, un inhibiteur de la protéine kinase C, n'a pas démontré de supériorité par rapport à la lomustine seule dans un essai thérapeutique de phase III sur les glioblastomes en récidive [40], malgré une bonne tolérance.…”

Angiogenesis and Invasion in Malignant Glioma: Friends or Foes?

“…Overall symptom burden and tumor and treatment-related symptoms were also worse. This also includes alteration of cognitive functions (Seystahl and Weller 2012 ). This underscores the necessity to improve the benefi t/risk ratio and to identify patient groups that are more likely to benefi t from anti-VEGF treatment.…”