sFLT01: A Novel Fusion Protein with Antiangiogenic Activity

Kurtzberg, Leslie; Weber, William; Nguyen, Tri‐Hung; Roth, Stephanie; Krumbholz, Roy; Yao, Min; Richards, Brenda; Zhang, Mindy; Pecháň, Peter; Schmid, Steven M.; Scaria, Abraham; Kaplan, Johanne; Teicher, Beverly A.

doi:10.1158/1535-7163.mct-10-0813

Cited by 21 publications

(14 citation statements)

References 47 publications

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“…We have investigated whether a therapy that targets both VEGF and PlGF can be efficacious with a novel fusion protein, sFLT01 (33), which has a molecular weight of approximately 80 kDa and consists of the VEGF/PlGF binding domain of VEGFR-1/Flt-1 fused to the Fc portion of human IgG1 through a polyglycine linker (9Gly; ref. 34).…”

Section: Introductionmentioning

confidence: 99%

Placental Growth Factor Upregulation Is a Host Response to Antiangiogenic Therapy

Ren¹,

Weber²,

Yao³

et al. 2011

Clinical Cancer Research

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Purpose: Placental growth factor (PlGF) is an angiogenic protein. Upregulation of PlGF has been observed in the clinic following antiangiogenic regimens targeting the VEGF pathway. PlGF has been proposed as a therapeutic target for oncology. sFLT01 is a novel fusion protein that neutralizes mouse and human PlGF (mPlGF, hPlGF) and mouse and human VEGF-A (mVEGF-A, hVEGF-A). It was tested in syngeneic and xenograft tumor models to evaluate the effects of simultaneously neutralizing PlGF and VEGF-A and to investigate changes observed in the clinic in preclinical models. Experimental Design: Production of PlGF and VEGF-A by B16F10 and A673 cancer cells in vitro was assessed. Mice with subcutaneous B16F10 melanoma or A673 sarcoma tumors were treated with sFLT01. Tumor volumes and microvessel density (MVD) were measured to assess efficacy. Serum levels of hVEGF-A, hPlGF, and mPlGF at early and late time points were determined by ELISA. Results: Exposure of cancer cell lines to sFLT01 caused a decrease in VEGF secretion. sFLT01 inhibited tumor growth, prolonged survival, and decreased MVD. Analysis of serum collected from treated mice showed that sFLT01 administration caused a marked increase in circulating mPlGF but not hPlGF or hVEGF. sFLT01 treatment also increased circulating mPlGF levels in non–tumor-bearing mice. Conclusion: With the tumor cell lines and mouse models we used, antiangiogenic therapies that target both PlGF and VEGF may elicit a host response rather than, or in addition to, a malignant cell response that contribute to therapeutic resistance and tumor escape as suggested by others. Clin Cancer Res; 17(5); 976–88. ©2011 AACR.

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Section: Introductionmentioning

confidence: 99%

Placental Growth Factor Upregulation Is a Host Response to Antiangiogenic Therapy

Ren¹,

Weber²,

Yao³

et al. 2011

Clinical Cancer Research

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“…In a mouse tumor model of Ewing's sarcoma, soluble VEGFR-1 peptide-based inhibitor combined with cyclophosphamide had an enhanced effect on decreasing tumor size. 115 Combined inhibition of placental M Monographs growth factor (PlGF) using anti-PlGF and anti-VEGFR-2 or soluble VEGFR-2 peptide also showed a more pronounced inhibitory effect on tumor growth. 116 Combination therapy that includes DLL4 inhibition has also been proven to decrease tumor size.…”

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confidence: 99%

Notch Signaling in Developmental and Tumor Angiogenesis

et al. 2011

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The discovery that Notch, a key regulator of cell fate determination, is functional in the vasculature has greatly improved our understanding of differentiation and specialization of vessels. Notch signaling has been proven to be critical for arterial specification, sprouting angiogenesis, and vessel maturation. In newly forming vascular sprouts, Notch promotes the distinction between the leading "tip" endothelial cell and the growing "stalk" cell, the endothelial cells that eventually form a new capillary. Notch signaling has also been implicated in vessel stability by regulating vascular mural cell function. More recently, macrophages carrying an activated Notch have been implicated in shaping the course of new sprout formation. Tumor vessels abide by similar principles and use Notch signaling in similar ways. An exciting discovery, made by several researchers, shows that blocking Notch function in tumor vasculature provides a means by which to suppress tumor growth. The authors discuss the developmental and physiological role of Notch in the vasculature and apply this knowledge to an overview of how Notch targeting in the tumor environment can affect tumor angiogenesis and growth.

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“…Briefly, sFLT01 is a novel fusion protein which has a molecular weight of approximately 80 kDa and consists of the VEGF/ PlGF binding domain of VEGFR-1/Flt-1 fused to the Fc portion of human IgG1 through a polyglycine linker (9Gly) (33,34).…”

Section: Methodsmentioning

confidence: 99%

“…We have taken an innovative approach by selecting human choriocarcinoma cell lines to serve as PlGF-overexpressing models for preclinical studies. We utilized sFLT01, a novel fusion protein, as the PlGF-neutralizing agent (33,34). The production of PlGF and VEGF-A by BeWo, JAR, and JEG-3 cells in culture was quantified by ELISA and was altered upon exposure to sFLT01.…”

Section: Introductionmentioning

confidence: 99%

Human choriocarcinomas: Placental growth factor-dependent preclinical tumor models

Bagley

2011

Int J Oncol

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Abstract. Choriocarcinomas are a rare form of cancer that develops in the uterus from tissue which would normally become the placenta. Choriocarcinomas are a trophoblastic gestational disease and have been studied largely to investigate conditions related to pregnancy such as preeclampsia. Choriocarcinomas are highly angiogenic and produce high levels of placental growth factor (PlGF) to promote the development of blood vessels. Upregulation of PlGF expression also occurs during the development of other human malignancies such as breast cancer and melanoma. Both tumor specimens and plasma samples have higher levels of PlGF than normal tissues. Hence, PlGF has emerged as a valid target for anti-angiogenic therapy. The cell lines BeWo, JAR and JEG-3, derived from human choriocarcinomas, were investigated in vitro and in vivo for suitability as PlGF-dependent models. BeWo, JAR and JEG-3 cells were characterized in culture and were implanted into immunodeficient mice to generate subcutaneous tumors. The PlGF and VEGF angiogenic profiles of the choriocarcinoma cells and tumors were investigated by ELISA and by immunohistochemical methods. Double immunofluorescence methods were applied to choriocarcinoma xenograft sections to characterize the cellular components of the blood vessels. sFLT01, a fusion protein that neutralizes PlGF, was assessed in cell culture experiments and xenograft studies. The novel results presented here validate the importance of human choriocarcinoma cell lines and xenografts in further exploring the role of PlGF in tumor angiogenesis, for evaluating PlGF as an anti-angiogenic target, and for developing therapies that may provide clinical benefit.

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sFLT01: A Novel Fusion Protein with Antiangiogenic Activity

Cited by 21 publications

References 47 publications

Placental Growth Factor Upregulation Is a Host Response to Antiangiogenic Therapy

Placental Growth Factor Upregulation Is a Host Response to Antiangiogenic Therapy

Notch Signaling in Developmental and Tumor Angiogenesis

Human choriocarcinomas: Placental growth factor-dependent preclinical tumor models

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