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

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

Neuropathological characteristics of progression after prolonged response to bevacizumab in multifocal hemangioblastoma

Background: Antiangiogenic treatment has been explored in few patients with hemangioblastoma after failure of surgery and radiotherapy. Case Report: We present the first histopathological follow-up study of a bevacizumab-responsive hemangioblastoma that eventually progressed. For a period of 12 months, therapy with bevacizumab achieved a clinical response and radiological stabilization in a patient with progressive multifocal central nervous system (CNS) hemangioblastoma. Subsequently, selected tumor sites showed radiological progression, in particular, the formation of an intramedullary lesion of the initially predominantly leptomeningeal disease. Histology showed diffuse dural invasion by the hemangioblastoma accompanied with a relatively reduced cell density compared to the preserved vessel structures. Conclusion: The pattern of progression upon vascular endothelial growth factor (VEGF)-targeting antiangiogenic treatment in hemangioblastoma may involve increased tumor invasiveness. © 2014 S. Karger GmbH, Freiburg

Amino-acid PET versus MRI guided re-irradiation in patients with recurrent glioblastoma multiforme (GLIAA) – protocol of a randomized phase II trial (NOA 10/ARO 2013-1)

Background: The higher specificity of amino-acid positron emission tomography (AA-PET) in the diagnosis of gliomas, as well as in the differentiation between recurrence and treatment-related alterations, in comparison to contrast enhancement in T1-weighted MRI was demonstrated in many studies and is the rationale for their implementation into radiation oncology treatment planning. Several clinical trials have demonstrated the significant differences between AA-PET and standard MRI concerning the definition of the gross tumor volume (GTV). A small single-center non-randomized prospective study in patients with recurrent high grade gliomas treated with stereotactic fractionated radiotherapy (SFRT) showed a significant improvement in survival when AA-PET was integrated in target volume delineation, in comparison to patients treated based on CT/MRI alone. Methods: This protocol describes a prospective, open label, randomized, multi-center phase II trial designed to test if radiotherapy target volume delineation based on FET-PET leads to improvement in progression free survival (PFS) in patients with recurrent glioblastoma (GBM) treated with re-irradiation, compared to target volume delineation based on T1Gd-MRI. The target sample size is 200 randomized patients with a 1:1 allocation ratio to both arms. The primary endpoint (PFS) is determined by serial MRI scans, supplemented by AA-PET-scans and/or biopsy/surgery if suspicious of progression. Secondary endpoints include overall survival (OS), locally controlled survival (time to local progression or death), volumetric assessment of GTV delineated by either method, topography of progression in relation to MRIor PET-derived target volumes, rate of long term survivors (> 1 year), localization of necrosis after re-irradiation, quality of life (QoL) assessed by the EORTC QLQ-C15 PAL questionnaire, evaluation of safety of FET-application in AA-PET imaging and toxicity of re-irradiation. Discussion: This is a protocol of a randomized phase II trial designed to test a new strategy of radiotherapy target volume delineation for improving the outcome of patients with recurrent GBM. Moreover, the trial will help to develop a standardized methodology for the integration of AA-PET and other imaging biomarkers in radiation treatment planning. Trial registration: The GLIAA trial is registered with ClinicalTrials.gov (NCT01252459, registration date 02.12.2010), German Clinical Trials Registry (DRKS00000634, registration date 10.10.2014), and European Clinical Trials Database (EudraCT-No. 2012-001121-27, registration date 27.02.2012)

Molekulare Marker werden zunehmend wichtiger Therapieoptionen bei höhergradigen Gliomen

Die Histologie (Tumorresektion oder Biopsie) ist bei höhergradigen Gliomen essenziell zur Diagnosestellung sowie Evaluation von Prognose und Therapie. Molekulare Marker dienen als Ergänzung zur WHO-Klassifikation bezüglich des zu erwartenden Krankheitsverlaufs und Therapieansprechens auf alkylierende Chemotherapie. Die Standardtherapie für Patienten jünger als 65 bzw. 70 Jahre besteht aus kombinierter Strahlen- und Chemotherapie mit konkomitantem und adjuvantem Temozolomid (TMZ). Patienten über 65 bzw. 70 Jahre haben einen Überlebensvorteil bei einer Chemotherapie mit TMZ im Fall eines methylierten MGMT-Promotors; ohne methylierten MGMT-Promotor wird eine alleinige Strahlentherapie empfohlen. Bei anaplastischen Oligodendrogliomen und Oligoastrozytomen mit 1p/19q-Kodeletion besteht ein Überlebensvorteil im Fall einer frühen alkylierenden Chemotherapie (PCV oder TMZ)

Autocrine VEGFR1 and VEGFR2 signaling promotes survival in human glioblastoma models in vitro and in vivo

BACKGROUND Although the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) system has become a prime target for antiangiogenic treatment, its biological role in glioblastoma beyond angiogenesis has remained controversial. METHODS Using neutralizing antibodies to VEGF or placental growth factor (PlGF) or the tyrosine kinase inhibitor, cediranib, or lentiviral gene silencing, we delineated autocrine signaling in glioma cell lines. The in vivo effects of VEGFR1 and VEGFR2 depletion were evaluated in orthotopic glioma xenograft models. RESULTS VEGFR1 and VEGFR2 modulated glioma cell clonogenicity, viability, and invasiveness in vitro in an autocrine, cell-line-specific manner. VEGFR1 silencing promoted mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling, whereas VEGFR2 silencing resulted in cell-type dependent activation of the protein kinase B (PKB)/AKT and MAPK/ERK pathways. These responses may represent specific escape mechanisms from VEGFR inhibition. The survival of orthotopic glioma-bearing mice was prolonged upon VEGFR1 silencing in the LNT-229, LN-308, and U87MG models and upon VEGFR2 silencing in LN-308 and U87MG. Disruption of VEGFR1 and VEGFR2 signaling was associated with decreased tumor size, increased tumor necrosis, or loss of matrix metalloproteinase 9 (MMP9) immunoreactivity. Neutralizing VEGF and PlGF by specific antibodies was superior to either antibody treatment alone in the VEGFR1-dependent LNT-229 model. CONCLUSIONS Differential dependence on autocrine signaling through VEGFR1 and VEGFR2 suggests a need for biomarker-stratified VEGF(R)-based therapeutic approaches to glioblastoma

Neuropathological characteristics of progression after prolonged response to bevacizumab in multifocal hemangioblastoma

Background: Antiangiogenic treatment has been explored in few patients with hemangioblastoma after failure of surgery and radiotherapy. Case Report: We present the first histopathological follow-up study of a bevacizumab-responsive hemangioblastoma that eventually progressed. For a period of 12 months, therapy with bevacizumab achieved a clinical response and radiological stabilization in a patient with progressive multifocal central nervous system (CNS) hemangioblastoma. Subsequently, selected tumor sites showed radiological progression, in particular, the formation of an intramedullary lesion of the initially predominantly leptomeningeal disease. Histology showed diffuse dural invasion by the hemangioblastoma accompanied with a relatively reduced cell density compared to the preserved vessel structures. Conclusion: The pattern of progression upon vascular endothelial growth factor (VEGF)-targeting antiangiogenic treatment in hemangioblastoma may involve increased tumor invasiveness. © 2014 S. Karger GmbH, Freiburg

Limited role for transforming growth factor-β pathway activation-mediated escape from VEGF inhibition in murine glioma models

BACKGROUND The vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-β pathways regulate key biological features of glioblastoma. Here we explore whether the TGF-β pathway, which promotes angiogenesis, invasiveness, and immunosuppression, acts as an escape pathway from VEGF inhibition. METHODS The role of the TGF-β pathway in escape from VEGF inhibition was assessed in vitro and in vivo and by gene expression profiling in syngeneic mouse glioma models. RESULTS We found that TGF-β is an upstream regulator of VEGF, whereas VEGF pathway activity does not alter the TGF-β pathway in vitro. In vivo, single-agent activity was observed for the VEGF antibody B20-4.1.1 in 3 and for the TGF-β receptor 1 antagonist LY2157299 in 2 of 4 models. Reduction of tumor volume and blood vessel density, but not induction of hypoxia, correlated with benefit from B20-4.1.1. Reduction of phosphorylated (p)SMAD2 by LY2157299 was seen in all models but did not predict survival. Resistance to B20 was associated with anti-angiogenesis escape pathway gene expression, whereas resistance to LY2157299 was associated with different immune response gene signatures in SMA-497 and GL-261 on transcriptomic profiling. The combination of B20 with LY2157299 was ineffective in SMA-497 but provided prolongation of survival in GL-261, associated with early suppression of pSMAD2 in tumor and host immune cells, prolonged suppression of angiogenesis, and delayed accumulation of tumor infiltrating microglia/macrophages. CONCLUSIONS Our study highlights the biological heterogeneity of murine glioma models and illustrates that cotargeting of the VEGF and TGF-β pathways might lead to improved tumor control only in subsets of glioblastoma