TY - JOUR
T1 - sFRP2 Supersedes VEGF as an age-related driver of angiogenesis in melanoma, affecting response to anti-VEGF therapy in older patients
AU - Fane, Mitchell E.
AU - Ecker, Brett L.
AU - Kaur, Amanpreet
AU - Marino, Gloria E.
AU - Alicea, Gretchen M.
AU - Douglass, Stephen M.
AU - Chhabra, Yash
AU - Webster, Marie R.
AU - Marshall, Andrea
AU - Colling, Richard
AU - Espinosa, Olivia
AU - Coupe, Nicholas
AU - Maroo, Neera
AU - Campo, Leticia
AU - Middleton, Mark R.
AU - Corrie, Pippa
AU - Xu, Xiaowei
AU - Karakousis, Giorgos C.
AU - Weeraratna, Ashani T.
N1 - Funding Information:
A.T. Weeraratna, G. Alicea, and G.E. Marino are supported by R01CA174746, and A.T. Weeraratna, M. Fane, and S.M. Douglass are supported by R01CA207935. X. Xu and A.T. Weeraratna are supported by P01 CA114046. X. Xu, G.C. Karakousis, and A.T. Weeraratna are also supported by P50 CA174523. M.R. Webster is supported by R00 CA208012-01. A.T. Weeraratna is also supported by R01CA232256, a Melanoma Research Alliance/L’Oréal Paris-USA Women in Science Team Science Award, the Wistar Science Discovery Fund, the E.V. McCollum Chair, and a Bloomberg Distinguished Professorship. Core facilities used in this grant are supported by P30CA010815 and P30CA006973. The AVAST-M study was funded by grants from Cancer Research UK (reference:
Funding Information:
A.T. Weeraratna, G. Alicea, and G.E. Marino are supported by R01CA174746, and A.T. Weeraratna, M. Fane, and S.M. Douglass are supported by R01CA207935. X. Xu and A.T. Weeraratna are supported by P01 CA114046. X. Xu, G.C. Karakousis, and A.T. Weeraratna are also supported by P50 CA174523. M.R. Webster is supported by R00 CA208012-01. A.T. Weeraratna is also supported by R01CA232256, a Melanoma Research Alliance/L'Oreal Paris-USA Women in Science Team Science Award, the Wistar Science Discovery Fund, the E.V. McCollum Chair, and a Bloomberg Distinguished Professorship. Core facilities used in this grant are supported by P30CA010815 and P30CA006973. The AVAST-M study was funded by grants from Cancer Research UK (reference: C7535/A6408 and C2195/A8466). M.R. Middleton is supported by the NIHR Oxford Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health.
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2021/11/1
Y1 - 2021/11/1
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-20-0446
DO - 10.1158/1078-0432.CCR-20-0446
M3 - Article
C2 - 33097493
AN - SCOPUS:85100907459
SN - 1078-0432
VL - 26
SP - 5709
EP - 5719
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 21
ER -