Sustained VEGF Blockade Results in Microenvironmental Sequestration of VEGF by Tumors and Persistent VEGF Receptor-2 Activation

Kadenhe-Chiweshe, Angela; Papa, Joey; McCrudden, Kimberly W.; Frischer, Jason S.; Bae, Jae-O; Huang, Jianzhong; Fisher, Jason C.; Lefkowitch, Jay H.; Feirt, Nikki; Rudge, John S.; Holash, Jocelyn; Yancopouloš, George D.; Kandel, Jessica J.; Yamashiro, Darrell J.

doi:10.1158/1541-7786.mcr-07-0101

Cited by 63 publications

(50 citation statements)

References 31 publications

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“…Notably, VEGFA induces perlecan synthesis via activation of VEGFR2 in microvascular endothelial cells (51), indicating a positive feedback loop regulating VEGFA and perlecan biosynthesis. In contrast, sustained VEGFA blockade causes a marked up-regulation of perlecan in hepatoblastoma xenografts and sustained VEGFR2 activation (52). In agreement with these findings, perlecan knockdown attenuates the proliferative response to both VEGFA and FGF2 (53)(54)(55).…”

supporting

confidence: 78%

Endorepellin, the Angiostatic Module of Perlecan, Interacts with Both the α2β1 Integrin and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2)

Goyal

Pal

Concannon

et al. 2011

Journal of Biological Chemistry

104

136

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Endorepellin, the C-terminal module of perlecan, negatively regulates angiogenesis counter to its proangiogenic parental molecule. Endorepellin (the C-terminal domain V of perlecan) binds the ␣2␤1 integrin on endothelial cells and triggers a signaling cascade that leads to disruption of the actin cytoskeleton. Here, we show that both perlecan and endorepellin bind directly and with high affinity to both VEGF receptors 1 and 2, in a region that differs from VEGFA-binding site. In both human and porcine endothelial cells, this interaction evokes a physical down-regulation of both the ␣2␤1 integrin and VEGFR2, with concurrent activation of the tyrosine phosphatase SHP-1 and downstream attenuation of VEGFA transcription. We demonstrate that endorepellin requires both the ␣2␤1 integrin and VEGFR2 for its angiostatic activity. Endothelial cells that express ␣2␤1 integrin but lack VEGFR2, do not respond to endorepellin treatment. Thus, we provide a new paradigm for the activity of an antiangiogenic protein and mechanistically explain the specificity of endorepellin for endothelial cells, the only cells that simultaneously express both receptors. We hypothesize that a mechanism such as dual receptor antagonism could operate for other angiostatic fragments.

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supporting

confidence: 78%

Endorepellin, the Angiostatic Module of Perlecan, Interacts with Both the α2β1 Integrin and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2)

Goyal

Pal

Concannon

et al. 2011

Journal of Biological Chemistry

104

136

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“…Although in vivo response to aflibercept correlated with levels of VEGF-A produced by AML cells, inhibition of VEGF ligands secreted by marrow stromal and other microenvironment cells also likely play a significant role in the observed antileukemic effects. By immunohistochemical staining, we noted decreased vascularization, increased hypoxia, and VEGF sequestration in the local leukemia microenvironment following aflibercept therapy, consistent with this agent's previously described effects on solid tumor-associated angiogenesis (36). Because immunodeficient murine hosts were used for human AML engraftment, the effects of in vivo VEGF inhibition on VEGF/VEGFR-positive host immune cells, such as dendritic cells, macrophages, and monocytes, were not formally assessed here.…”

Section: Discussionsupporting

confidence: 76%

Aflibercept Exerts Antivascular Effects and Enhances Levels of Anthracycline ChemotherapyIn vivoin Human Acute Myeloid Leukemia Models

Lal

Park

Demock

et al. 2010

Molecular Cancer Therapeutics

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We examined whether potent vascular endothelial growth factor (VEGF) blockade mediated by aflibercept, a decoy VEGF receptor (VEGFR) 1/2 moiety with stronger affinity for VEGF than bevacizumab, resulted in antileukemia effects and enhanced the efficacy of systemic chemotherapy. The efficacy of aflibercept alone and in combination with doxorubicin was evaluated in human VEGF-expressing acute myeloid leukemia (AML) cell lines and primary cells xenotransplanted into immunodeficient mice. Aflibercept reduced primary VEGF/VEGFR-positive AML colony formation growth in vitro and inhibited AML xenograft growth up to 93% in association with antiangiogenic and antiproliferative effects, hypoxia, and VEGF sequestration in multiple models. High VEGF-A expression by AML cells promoted in vivo xenograft growth and aflibercept sensitivity. Aflibercept therapy slowed disease progression in two systemic human AML xenograft models and reduced peripheral leukemia disease in a primary relapsed AML model in NOD/SCID/IL2Rγnull mice. Combination aflibercept and doxorubicin enhanced antitumor effects in local xenograft models. Sequential aflibercept followed by doxorubicin resulted in progressive anthracycline accumulation in marrow and extramedullary AML sites and resulted in 2-fold higher drug levels 24 hours after administration. In contrast, tissues (tumor, plasma, marrow) treated with chemotherapy only showed progressive drug clearance over time. Combination aflibercept and doxorubicin also resulted in vascular narrowing, decreased vessel number, and perivascular apoptosis. These data suggest that inefficient drug delivery by leukemia-associated vasculature may mediate chemoresistance and support further clinical evaluation of combination aflibercept and anthracycline therapy in refractory/relapsed AML patients. Mol Cancer Ther; 9(10);

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“…However, the continuous production of VEGF by both tumor and host stromal cells and the local sequestration of VEGF by heparin binding matrix components (34) would suggest that prolonged and continuous inhibition might be necessary for most effective inhibition of tumor growth. To evaluate this, we conducted a number of preclinical studies in established xenograft tumors, comparing short-term anti-VEGF treatment with treatment for the entire duration of the study (end of study).…”

Section: Increased Efficacy Is Observed With Longer Duration Of Anti-mentioning

confidence: 99%

Effects of Anti-VEGF Treatment Duration on Tumor Growth, Tumor Regrowth, and Treatment Efficacy

Bagri¹,

Berry²,

Gunter³

et al. 2010

Clinical Cancer Research

127

102

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Purpose: Inhibition of the vascular endothelial growth factor (VEGF) axis is the basis of all currently approved antiangiogenic therapies. In preclinical models, anti-VEGF blocking antibodies have shown broad efficacy that is dependent on both tumor context and treatment duration. We aimed to characterize this activity and to evaluate the effects of discontinuation of treatment on the dynamics of tumor regrowth. Experimental Design: We evaluated the effects of anti-VEGF treatment on tumor growth and survival in 30 xenograft models and in genetic mouse models of cancer. Histologic analysis was used to evaluate the effects of treatment on tumor vasculature. We used a variety of treatment regimens to allow analysis of the effects of treatment duration and cessation on growth rate, survival, and vascular density. Results: Preclinical tumor models were characterized for their varied dependence on VEGF, thereby defining models for testing other agents that may complement or augment anti-VEGF therapy. We also found that longer exposure to anti-VEGF monoclonal antibodies delayed tumor growth and extended survival in established tumors from both cell transplants and genetic tumor models and prevented regrowth of a subset of residual tumors following cytoablative therapy. Discontinuation of anti-VEGF in established tumors resulted in regrowth at a rate slower than that in control-treated animals, with no evidence of accelerated tumor growth or rebound. However, more rapid regrowth was observed following discontinuation of certain chemotherapies. Concurrent administration of anti-VEGF seemed to normalize these accelerated growth rates. Conclusions: In diverse preclinical models, continuous VEGF suppression provides maximal benefit as a single agent, combined with chemotherapy, or as maintenance therapy once chemotherapy has been stopped. Clin Cancer Res; 16(15); 3887–900. ©2010 AACR.

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Sustained VEGF Blockade Results in Microenvironmental Sequestration of VEGF by Tumors and Persistent VEGF Receptor-2 Activation

Abstract: Vascular endothelial growth factor

Cited by 63 publications

References 31 publications

Endorepellin, the Angiostatic Module of Perlecan, Interacts with Both the α2β1 Integrin and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2)

Endorepellin, the Angiostatic Module of Perlecan, Interacts with Both the α2β1 Integrin and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2)

Aflibercept Exerts Antivascular Effects and Enhances Levels of Anthracycline ChemotherapyIn vivoin Human Acute Myeloid Leukemia Models

Effects of Anti-VEGF Treatment Duration on Tumor Growth, Tumor Regrowth, and Treatment Efficacy

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