Antiangiogenic compounds interfere with chemotherapy of brain tumors due to vessel normalization

Claes, An; Wesseling, Pieter; Jeuken, Judith; Maass, Cathy; Heerschap, Arend; Leenders, William P. J.

doi:10.1158/1535-7163.mct-07-0552

Cited by 98 publications

(86 citation statements)

References 22 publications

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“…This led the authors to conclude that "Vessel normalization has an antagonizing rather than a synergistic or additive effect." 27 Vandetanib is a tyrosine kinase inhibitor with specificity toward epidermal growth factor receptor and VEGF receptor 2, 28 while bevacizumab blocks signaling through VEGF receptor 1 as well as VEGF receptor 2.…”

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confidence: 99%

The paradoxical effect of bevacizumab in the therapy of malignant gliomas

2011

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One rationale behind the use of agents that inhibit vascular endothelial growth factor in the therapy of primary CNS malignancies is based upon the concept that normalization of tumor vasculature with a decrease in tumor interstitial pressure will improve access of cytoreductive drugs and improve radiotherapy efficacy due to increased oxygen delivery. However, several studies have raised the concern that these agents may both rapidly restore the low permeability characteristics of the blood-brain barrier and counteract the beneficial effect of pseudoprogression. The result may be decreased therapeutic efficacy while increasing infiltration by co-opting normal vessels. In this discussion, we examine both histologic and radiographic tumor progression in the context of antiangiogenic agents. Issues dealing with the safety of bevacizumab (Avastin ® , Genentech, South San Francisco, CA) and its potential to decrease efficacy of standard radiochemotherapy when used to treat patients with newly diagnosed malignant glioma are emphasized. Bevacizumab is a recombinant humanized monoclonal immunoglobulin G (IgG)1 antibody that binds to vascular endothelial growth factor (VEGF) and prevents the proliferation of endothelial cells and formation of new blood vessels. 1 VEGF has a role in endothelial cell survival, proliferation, invasion, and migration, which all affect tumor progression and angiogenesis.2 Treatment with bevacizumab was quickly implemented for salvage therapy in progressive malignant gliomas after its efficacy was demonstrated in metastatic colon cancer 3 and in non-small-cell lung cancer. 4 Multiple groups using bevacizumab plus chemotherapy 2,5-12 and 2 phase II trials using bevacizumab alone 13,14 have demonstrated impressive imaging responses with increased overall survival (OS) and progression-free survival (PFS) in recurrent glioma patients relative to historical data in patients who received chemotherapy alone. 15,16 The results of the phase II trials were so compelling that in May 2009, the US Food and Drug Administration granted approval for the use of bevacizumab for the second-line treatment of glioblastoma multiforme (GBM).17 Additionally, 2 recent phase II trials explored the use of bevacizumab plus chemotherapy as initial therapy for newly diagnosed GBM 18,19 and several other centers are enrolling patients in 2 large phase III trials of temozolomide and radiation with and without bevacizumab for the treatment of newly diagnosed GBM. 20,21VESSEL NORMALIZATION The general rationale behind using bevacizumab in combination with chemotherapy for malignant gliomas is twofold. First, bevacizumab normalizes vessels in the CNS by a mechanism similar to that of solid tumors outside the CNS. Bevacizumab decreases the abnormal morphology and organization of tumor-related vasculature that causes inefficient transport of oxygen and therapeutic drugs to

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confidence: 99%

The paradoxical effect of bevacizumab in the therapy of malignant gliomas

2011

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“…[5][6][7][8][9][10][11]29,30 Although gliomas are certainly at the extreme end of a spectrum with respect to infiltrative growth, it was recently shown that targeting of the angiogenic pathway also in subcutaneous xenografts leads to enhanced invasive growth and metastases. 31,32 Such adverse effects are not expected to occur when directing therapy against the existing tumor vasculature.…”

Section: Discussionmentioning

confidence: 99%

“…However, a number of phase II studies have now revealed that, despite inducing a radiological response, these inhibitors do not prolong overall survival and allow disease progression, 5,6 likely because diffuse infiltrative growth is angiogenesis independent and provides a mechanism of escape from anti-angiogenic therapies. [4][5][6][7][8][9][10][11] The phenotypic differences that exist in GBM are reflected in the vasculature, which is highly heterogeneous. 12 Vessels may be angiogenic as well as more mature or co-opted, and the latter ones may be unsusceptible to anti-angiogenic therapy.…”

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Isolation of targeting nanobodies against co-opted tumor vasculature

Roodink

Franssen

Zuidscherwoude

et al. 2010

Laboratory Investigation

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Tumor vasculature is in general highly heterogeneous. This characteristic is most prominent in high-grade gliomas, which present with areas of angiogenic growth, next to large areas of diffuse infiltrative growth in which tumor cells thrive on pre-existent brain vasculature. This limits the effectiveness of anti-angiogenic compounds as these will not affect more matured and co-opted vessels. Therefore, additional destruction of existing tumor vasculature may be a promising alternative avenue to effectively deprive tumors from blood. This approach requires the identification of novel tumor vascular targeting agents, which have broad tumor vessel specificities, ie are not restricted to newly formed vessels. Here, we describe the generation of a phage library displaying nanobodies that were cloned from lymphocytes of a Llama which had been immunized with clinical glioma tissue. In vivo biopanning with this library in the orthotopic glioma xenograft models E98 and E434 resulted in the selection of various nanobodies which specifically recognized glioma vessels in corresponding glioma xenografts. Importantly, also nanobodies were isolated which discriminated incorporated pre-existent vessels in highly infiltrative cerebral E434 xenografts from normal brain vessels. Our results suggest that the generation of nanobody-displaying immune phage libraries and subsequent in vivo biopanning in appropriate animal models is a promising approach for the identification of novel vascular targeting agents.

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“…It has often been used as a human glioma model (Claes et al, 2008;Nakatsu et al, 1997). The tumor line expresses several ABC transporters such as P-gp and MRP1 (Rittierodt et al, 2004;Perek et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…In a rat model, normalizing the tumor blood vessel increased topotecan delivery to neuroblastoma (Dickson et al, 2007). However the same strategy (normalizing the tumor blood vessel) does not seem to work for CNS tumor (Devineni et al, 1996b;Claes et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Factors Influencing Topotecan CNS Penetration in Mouse Models

Shen¹

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Antiangiogenic compounds interfere with chemotherapy of brain tumors due to vessel normalization

Cited by 98 publications

References 22 publications

The paradoxical effect of bevacizumab in the therapy of malignant gliomas

The paradoxical effect of bevacizumab in the therapy of malignant gliomas

Isolation of targeting nanobodies against co-opted tumor vasculature

Factors Influencing Topotecan CNS Penetration in Mouse Models

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