Resistance to Inhibitors of Angiogenesis

Dahan, Nili; Magidey, Ksenia; Shaked, Yuval

doi:10.1007/978-3-319-67932-7_9

Cited by 2 publications

(2 citation statements)

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“…Tumor‐associated endothelial cells in high‐metastatic tumors show higher VEGFR2 expression levels and resistance to paclitaxel than those in low‐metastatic tumors . These observations might at least partially explain the modest clinical benefits of anti‐VEGF therapies, that is, progression‐free survival and overall survival generally do not extend beyond a few months, and tumor relapse often results in metastasis . In this study, anti‐VEGFR2‐AF‐mediated targeting of VEGFR2 on tumor endothelium not only disrupts VEGF‐A‐induced signaling, but also triggers ADCC or CDC to directly kill the tumor‐associated endothelial cells and targeted cancer cells.…”

Section: Discussionmentioning

confidence: 78%

“…Therefore, tumor vessels should be less likely to acquire therapy‐induced mutations than cancer cells . There is a growing body of studies elucidating the mechanisms underlying acquired resistance to antiangiogenic therapy . In animal models, long‐term blockage of VEGF‐mediated signaling induced a compensatory response through upregulation of other angiogenic factors, such as hepatocyte growth factor, fibroblast growth factor‐2, and PlGF .…”

Section: Discussionmentioning

confidence: 99%

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Novel human Ab against vascular endothelial growth factor receptor 2 shows therapeutic potential for leukemia and prostate cancer

Chiu

Liu

et al. 2019

Cancer Science

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Vascular endothelial growth factor receptor 2 (VEGFR2) is highly expressed in tumorassociated endothelial cells, where it modulates tumor-promoting angiogenesis, and it is also found on the surface of tumor cells. Currently, there are no Ab therapeutics targeting VEGFR2 approved for the treatment of prostate cancer or leukemia.Therefore, development of novel efficacious anti-VEGFR2 Abs will benefit cancer patients. We used the Institute of Cellular and Organismic Biology human Ab library and affinity maturation to develop a fully human Ab, anti-VEGFR2-AF, which shows excellent VEGFR2 binding activity. Anti-VEGFR2-AF bound Ig-like domain 3 of VEGFR2 extracellular region to disrupt the interaction between VEGF-A and VEGFR2, neutralizing downstream signaling of the receptor. Moreover, anti-VEGFR2-AF inhibited capillary structure formation and exerted Ab-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity in vitro. We found that VEGFR2 is expressed in PC-3 human prostate cancer cell line and associated with malignancy and metastasis of human prostate cancer. In a PC-3 xenograft mouse model, treatment with anti-VEGFR2-AF repressed tumor growth and angiogenesis as effectively and safely as US FDA-approved anti-VEGFR2 therapeutic, ramucirumab. We also report for the first time that addition of anti-VEGFR2 Ab can enhance the efficacy of docetaxel in the treatment of a prostate cancer mouse model. In HL-60 human leukemiaxenografted mice, anti-VEGFR2-AF showed better efficacy than ramucirumab with prolonged survival and reduced metastasis of leukemia cells to ovaries and lymph nodes. Our findings suggest that anti-VEGFR2-AF has strong potential as a cancer therapy that could directly target VEGFR2-expressing tumor cells in addition to its anti-angiogenic action.

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Section: Discussionmentioning

confidence: 78%