Selective Blockade of Vascular Endothelial Growth Factor Receptor 2 With an Antibody Against Tumor-Derived Vascular Endothelial Growth Factor Controls the Growth of Human Pancreatic Adenocarcinoma Xenografts

Holloway, Shane E.; Beck, Adam W.; Shivakumar, Latha; Shih, Jessica; Fleming, Jason B.; Brekken, Rolf A.

doi:10.1245/aso.2006.05.049

Cited by 27 publications

(27 citation statements)

References 36 publications

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“…1) or Avastin (data not shown) resulted in a detectable change in the level of VEGFR2 on tumor endothelium, suggesting that microbubbles targeted to VEGFR2 could potentially be used as a noninvasive marker of anti-VEGF activity. These results are consistent with previous observations made by our group and others showing that the number of VEGFR2-positive blood vessels in tumors from animals treated with anti-VEGF therapy decreases (30,31).…”

Section: Discussionsupporting

confidence: 94%

“…Because microbubbles are obligate intravascular tracers, we sought first to determine if antiangiogenic therapy affected the localization of microbubbles targeted to endothelial antigens known to be altered by antiangiogenic strategies. Blocking VEGF activity in solid tumors has been shown to decrease the expression of VEGFR2 on tumor endothelial cells (30,31). To show that microbubbles targeted to VEGFR2 could be used to noninvasively visualize this change, s.c. human pancreatic adenocarcinoma (MiaPaca-2) tumors were treated with the anti-VEGF mAb 2C3 or with a control IgG.…”

Section: Resultsmentioning

confidence: 99%

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Monitoring Response to Anticancer Therapy by Targeting Microbubbles to Tumor Vasculature

Korpanty¹,

Carbon²,

Grayburn

et al. 2007

Clinical Cancer Research

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233

171

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Purpose: New strategies to detect tumor angiogenesis and monitor response of tumor vasculature to therapy are needed. Contrast ultrasound imaging using microbubbles targeted to tumor endothelium offers a noninvasive method for monitoring and quantifying vascular effects of antitumor therapy.We investigated the use of targeted microbubbles to follow vascular response of therapy in a mouse model of pancreatic adenocarcinoma. Experimental Design: Microbubbles conjugated to monoclonal antibodies were used to image and quantify vascular effects of two different antitumor therapies in s.c. and orthotopic pancreatic tumors in mice. Tumor-bearing mice were treated with anti-vascular endothelial growth factor (VEGF) monoclonal antibodies and/or gemcitabine, and the localization of microbubbles to endoglin (CD105), VEGF receptor 2 (VEGFR2), or VEGF-activated blood vessels (the VEGF-VEGFR complex) was monitored by contrast ultrasound. Results: Targeted microbubbles showed significant enhancement of tumor vasculature when compared with untargeted or control IgG^targeted microbubbles.Video intensity from targeted microbubbles correlated with the level of expression of the target (CD105, VEGFR2, or the VEGF-VEGFR complex) and with microvessel density in tumors under antiangiogenic or cytotoxic therapy. Conclusions: We conclude that targeted microbubbles represent a novel and attractive tool for noninvasive, vascular-targeted molecular imaging of tumor angiogenesis and for monitoring vascular effects specific to antitumor therapy in vivo.

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Section: Discussionsupporting

confidence: 94%

Section: Resultsmentioning

confidence: 99%

Monitoring Response to Anticancer Therapy by Targeting Microbubbles to Tumor Vasculature

Korpanty¹,

Carbon²,

Grayburn

et al. 2007

Clinical Cancer Research

Self Cite

233

171

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“…Recently, bevacizumab has shown clinical effectiveness in the treatment of metastatic colorectal cancer (2,4,5). In our laboratory, we have characterized 2C3, a monoclonal antibody to human VEGF that, in contrast to bevacizumab, blocks VEGF interaction with VEGFR2 only (6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

“…We have previously shown 2C3 to be effective in controlling the growth of breast and pancreatic cancer in animal models (8)(9)(10). The antitumor effect of 2C3 treatment is due in part to the reduction in microvessel density seen in tumors after such treatment.…”

Section: Introductionmentioning

confidence: 99%

Vascular Endothelial Growth Factor Receptor 2 Mediates Macrophage Infiltration into Orthotopic Pancreatic Tumors in Mice

et al. 2008

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Macrophages are an abundant inflammatory cell type in the tumor microenvironment that can contribute to tumor growth and metastasis. Macrophage recruitment into tumors is mediated by multiple cytokines, including vascular endothelial growth factor (VEGF), which is thought to function primarily through VEGF receptor (VEGFR) 1 expressed on macrophages. Macrophage infiltration is affected by VEGF inhibition. We show that selective inhibition of VEGFR2 reduced macrophage infiltration into orthotopic pancreatic tumors. Our studies show that tumor-associated macrophages express VEGFR2. Furthermore, peritoneal macrophages from tumor-bearing animals express VEGFR2, whereas peritoneal macrophages from non-tumor-bearing animals do not. To our knowledge, this is the first time that tumor-associated macrophages have been shown to express VEGFR2. Additionally, we found that the cytokine pleiotrophin is sufficient to induce VEGFR2 expression on macrophages. Pleiotrophin has previously been shown to induce expression of endothelial cell markers on macrophages and was present in the microenvironment of orthotopic pancreatic tumors. Finally, we show that VEGFR2, when expressed by macrophages, is essential for VEGF-stimulated migration of tumor-associated macrophages. In summary, tumor-associated macrophages express VEGFR2, and selective inhibition of VEGFR2 reduces recruitment of macrophages into orthotopic pancreatic tumors. Our results show an underappreciated mechanism of action that may directly contribute to the antitumor activity of angiogenesis inhibitors that block the VEGFR2 pathway. [Cancer Res 2008;68(11):4340-6]

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“…103 Since its initial identification, 2C3 has been characterized in numerous tumor xenograft models as an effective inhibitor of tumor growth and angiogenesis and as a modulator of macrophage and immune cell infiltration. 60,[105][106][107][108] The success of 2C3 in preclinical models lead to the development of a phenotypically similar, fully human mAb, r84 (AT001, Affitech AS) that was generated by screening a human anti-VEGF single chain variable fragment library for specific 2C3-like properties. 2C3 and r84 cross-block each other in VEGF ELISA assays indicating that the epitope each mAb binds is very similar; however, the exact epitope on VEGF bound by each mAb has not been determined.…”

Section: C3 and R84 (At001 Affitech As)mentioning

confidence: 99%

The VEGF family in cancer and antibody-based strategies for their inhibition

Sullivan

Brekken²

2010

mAbs

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160

143

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Selective Blockade of Vascular Endothelial Growth Factor Receptor 2 With an Antibody Against Tumor-Derived Vascular Endothelial Growth Factor Controls the Growth of Human Pancreatic Adenocarcinoma Xenografts

Abstract: Blockade of VEGF receptor 2 activation by tumor-derived VEGF decreases tumor vessel function and growth of some human pancreatic adenocarcinoma cell lines in mice.

Cited by 27 publications

References 36 publications

Monitoring Response to Anticancer Therapy by Targeting Microbubbles to Tumor Vasculature

Monitoring Response to Anticancer Therapy by Targeting Microbubbles to Tumor Vasculature

Vascular Endothelial Growth Factor Receptor 2 Mediates Macrophage Infiltration into Orthotopic Pancreatic Tumors in Mice

The VEGF family in cancer and antibody-based strategies for their inhibition

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