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SFRP2 supersedes VEGF as an age-related driver of angiogenesis in melanoma, affecting response to anti-VEGF therapy in older patients
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Fane, M., Ecker, B., Kaur, A., Marino, G., Alicea, G., Douglass, S., Webstr, M., Marshall, A. (Andrea), Colling, R., Espinosa, O., Coupe, N., Campo, L., Maroo, N., Middleton, M., Corrie, P., Xu, X., Karakousis, G. and Weeraratna, A. (2020) SFRP2 supersedes VEGF as an age-related driver of angiogenesis in melanoma, affecting response to anti-VEGF therapy in older patients. Clinical Cancer Research, 26 (21). pp. 5709-5719. doi:10.1158/1078-0432.CCR-20-0446 ISSN 1078-0432.
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WRAP-SFRP2-supersedes-VEGF-driver-angiogenesis-melanoma-patients-Marshall-2020.pdf - Accepted Version - Requires a PDF viewer. Download (10Mb) | Preview |
Official URL: https://doi.org/10.1158/1078-0432.CCR-20-0446
Abstract
Purpose: Angiogenesis is thought to be critical for tumor metastasis. However, inhibiting angiogenesis using antibodies such as bevacizumab (Avastin), has had little impact on melanoma patient survival. We have demonstrated that both angiogenesis and metastasis are increased in older individuals, and therefore sought to investigate whether there was an age-related difference in response to bevacizumab, and if so, what the underlying mechanism could be.
Experimental Design: We analyzed data from the AVAST-M trial of 1,343 patients with melanoma treated with bevacizumab to determine whether there is an age-dependent response to bevacizumab. We also examined the age-dependent expression of VEGF and its cognate receptors in patients with melanoma, while using syngeneic melanoma animal models to target VEGF in young versus old mice. We also examined the age-related proangiogenic factor secreted frizzled-related protein 2 (sFRP2) and whether it could modulate response to anti-VEGF therapy.
Results: We show that older patients respond poorly to bevacizumab, whereas younger patients show improvement in both disease-free survival and overall survival. We find that targeting VEGF does not ablate angiogenesis in an aged mouse model, while sFRP2 promotes angiogenesis in vitro and in young mice. Targeting sFRP2 in aged mice successfully ablates angiogenesis, while the effects of targeting VEGF in young mice can be overcome by increasing sFRP2.
Conclusions: VEGF is decreased during aging, thereby reducing response to bevacizumab. Despite the decrease in VEGF, angiogenesis is increased because of an increase in sFRP2 in the aged tumor microenvironment. These results stress the importance of considering age as a factor for designing targeted therapies.
Item Type: | Journal Article | ||||||||
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Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Clinical Trials Unit Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Health Sciences Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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Journal or Publication Title: | Clinical Cancer Research | ||||||||
Publisher: | American Association for Cancer Research | ||||||||
ISSN: | 1078-0432 | ||||||||
Official Date: | November 2020 | ||||||||
Dates: |
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Volume: | 26 | ||||||||
Number: | 21 | ||||||||
Page Range: | pp. 5709-5719 | ||||||||
DOI: | 10.1158/1078-0432.CCR-20-0446 | ||||||||
Status: | Peer Reviewed | ||||||||
Publication Status: | Published | ||||||||
Access rights to Published version: | Restricted or Subscription Access | ||||||||
Copyright Holders: | ©2020 American Association for Cancer Research | ||||||||
Date of first compliant deposit: | 16 September 2020 | ||||||||
Date of first compliant Open Access: | 23 October 2021 | ||||||||
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