Antiangiogenic therapies for high-grade glioma

Norden, Andrew D.; Drappatz, Jan; Wen, Patrick Y.

doi:10.1038/nrneurol.2009.159

Cited by 237 publications

(207 citation statements)

References 109 publications

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“…1 J-L). This is in full agreement with reported clinical data (4,17,18). In summary, these data indicate that, in our xenograft model derived from patient tumor material, bev induces a slight reduction in tumor progression during the treatment period and strongly reduces leakage of contrast agent from the blood vessels.…”

Section: Marked Decrease In Contrast Agent Leakage After Bevacizumabsupporting

confidence: 81%

“…There is, however, a controversy regarding treatment efficacy in terms of patient survival and the validity of radiological response rates as a surrogate endpoint for clinical benefit (9,27,28). Furthermore, it is currently not clear whether radiotherapy, which is dependent on the oxygenation level of the tumor, and/or systemic drug delivery, which is influenced by vessel permeability and blood flow, should benefit from antiangiogenic treatment or not (17). To address these questions, a better understanding of the biological effects of anti-VEGF treatment is mandatory.…”

Section: Discussionmentioning

confidence: 99%

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Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma

Keunen

Johansson

Oudin

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

552

467

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Bevacizumab, an antibody against vascular endothelial growth factor (VEGF), is a promising, yet controversial, drug in human glioblastoma treatment (GBM). Its effects on tumor burden, recurrence, and vascular physiology are unclear. We therefore determined the tumor response to bevacizumab at the phenotypic, physiological, and molecular level in a clinically relevant intracranial GBM xenograft model derived from patient tumor spheroids. Using anatomical and physiological magnetic resonance imaging (MRI), we show that bevacizumab causes a strong decrease in contrast enhancement while having only a marginal effect on tumor growth. Interestingly, dynamic contrast-enhanced MRI revealed a significant reduction of the vascular supply, as evidenced by a decrease in intratumoral blood flow and volume and, at the morphological level, by a strong reduction of large-and medium-sized blood vessels. Electron microscopy revealed fewer mitochondria in the treated tumor cells. Importantly, this was accompanied by a 68% increase in infiltrating tumor cells in the brain parenchyma. At the molecular level we observed an increase in lactate and alanine metabolites, together with an induction of hypoxia-inducible factor 1α and an activation of the phosphatidyl-inositol-3-kinase pathway. These data strongly suggest that vascular remodeling induced by anti-VEGF treatment leads to a more hypoxic tumor microenvironment. This favors a metabolic change in the tumor cells toward glycolysis, which leads to enhanced tumor cell invasion into the normal brain. The present work underlines the need to combine anti-angiogenic treatment in GBMs with drugs targeting specific signaling or metabolic pathways linked to the glycolytic phenotype.angiogenesis | glioma | metabolism | perfusion G lioblastomas (GBMs) are highly vascularized brain tumors and are therefore attractive targets for anti-angiogenic therapies (1). In particular, vascular endothelial growth factor (VEGF) has been identified as a critical regulator of angiogenesis, and currently a number of clinical trials targeting the VEGFsignaling pathways are under development (2, 3). Bevacizumab (bev), a humanized anti-VEGF antibody, has shown promising results in exploratory phase II trials of recurrent GBM. Alone or in combination with irinotecan, it is well tolerated and shows a high radiological response rate and possibly an increase in median progression-free survival compared with historical controls (4-7), although no impact on overall survival has been reported (8). However, these results are based on small patient cohorts and, because anti-angiogenic agents directly affect vessel permeability, the imaging response assessment based on contrast enhancement (CE) is highly ambiguous (9). Indeed, a direct antitumor effect of bev has remained elusive and the infiltrative part of the tumor may even increase (10,11). In addition to a lack of robust clinical data, the cellular and molecular consequences of anti-VEGF treatment have not been outlined (12). Detailed information on how bev affects ...

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Section: Marked Decrease In Contrast Agent Leakage After Bevacizumabsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma

Keunen

Johansson

Oudin

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

552

467

View full text Add to dashboard Cite

show abstract

“…VEGF can promote tumorigenesis and angiogenesis of human glioblastoma stem cells, and VEGF expression is significantly increased in high-grade astrocytomas compared with low-grade astrocytomas (19). Various anti-VEGF therapies are in development, and an anti-VEGF monoclonal antibody, Avastin (bevacizumab), was recently approved for treatment of glioblastoma (20).…”

Section: Discussionmentioning

confidence: 99%

Identification of blood protein biomarkers that aid in the clinical assessment of patients with malignant glioma

Gowda

et al. 2012

Int J Oncol

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Abstract. Analyzing molecular biomarkers using blood is an important approach for clinical assessment of malignant glioma. We investigated a molecular proteomic biomarkerbased approach for glioblastoma using patients' blood samples. The expression levels of a list of candidate proteins were quantified in plasma and serum samples from two different cohorts of patients with malignant glioma and normal controls. The biological function was studied for one of the identified markers. Additionally, the prognostic significance of protein marker expression was measured by survival analysis. As a result, protein biomarkers associated with malignant glioma were identified from the blood specimens and five of the protein biomarkers were common to both cohorts. Immunohistochemical analysis demonstrated that many of the protein biomarkers identified in peripheral blood specimens were expressed in malignant gliomas. Staining levels for one of the biomarkers, MIP-1α, was found to correlate with WHO grade among invasive gliomas, and we demonstrate that MIP-1α promotes human glioblastoma cell proliferation and migration. Additionally, four prognostic protein biomarkers were identified. In conclusion, we demonstrate that both peripheral blood plasma and serum specimens are highly valuable and complementary to each other in the quest for protein biomarkers of malignant glioma. Sets of novel protein biomarkers were identified that may aid in the diagnosis and prognosis of patients with malignant glioma.

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“…Bevacizumab is currently involved in a broad development program with more than 100 ongoing clinical trials in various indications and has been approved by the Food and Drug Administration (FDA) for treatment of recurrent glioblastoma [34]. Bevacizumab prolongs progression-free survival and controls peritumoral edema, but its effects on overall survival remain to be determined.…”

Section: The Controversial Effect Of Vascular Normalization In the Trmentioning

confidence: 99%

Vascular normalization: a real benefit?

Ribatti

2011

Cancer Chemother Pharmacol

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Abstract. It is well established that antibodies to vascular endothelial growth factor (VEGF) in combination with chemotherapeutic agents produce synergistic cytotoxicity in a range of cancer. In this review article it has been analyzed if the so called "vascular normalization" of abnormal tumor blood vessels as an effect of VEGF inhibition in association with chemotherapeutic agents in the treatment of tumors, produces a real benefit. Literature data show that the process of normalization of the structure of tumor blood vessels is not always accompained with a real benefit. In fact as in the case of cerebral tumors, the process of normalization may induce a re-establishment of the low permeability characteristics of normal brain microvasculature, preventing the delivery of chemotherapeutics.

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Antiangiogenic therapies for high-grade glioma

Cited by 237 publications

References 109 publications

Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma

Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma

Identification of blood protein biomarkers that aid in the clinical assessment of patients with malignant glioma

Vascular normalization: a real benefit?

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