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Translational Cancer Mechanisms and Therapy

sFRP2 Supersedes VEGF as an Age-related Driver of Angiogenesis in Melanoma, Affecting Response to Anti-VEGF Therapy in Older Patients

Mitchell E. Fane, Brett L. Ecker, Amanpreet Kaur, Gloria E. Marino, Gretchen M. Alicea, Stephen M. Douglass, Yash Chhabra, Marie R. Webster, Andrea Marshall, Richard Colling, Olivia Espinosa, Nicholas Coupe, Neera Maroo, Leticia Campo, Mark R. Middleton, Pippa Corrie, Xiaowei Xu, Giorgos C. Karakousis and Ashani T. Weeraratna
Mitchell E. Fane
1Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
2Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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Brett L. Ecker
3Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania.
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Amanpreet Kaur
4Department of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, Pennsylvania.
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Gloria E. Marino
1Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
2Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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  • ORCID record for Gloria E. Marino
Gretchen M. Alicea
1Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
2Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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Stephen M. Douglass
1Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
2Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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Yash Chhabra
1Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
2Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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Marie R. Webster
5The Lankenau Institute for Medical Research, Wynnewood, Pennsylvania.
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Andrea Marshall
6Warwick Clinical Trials Unit, University of Warwick, Coventry, United Kingdom.
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Richard Colling
7Department of Cellular Pathology, Oxford University Hospitals, University of Oxford, Oxford, United Kingdom.
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Olivia Espinosa
7Department of Cellular Pathology, Oxford University Hospitals, University of Oxford, Oxford, United Kingdom.
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Nicholas Coupe
8Department of Oncology, University of Oxford, Oxford, United Kingdom.
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Neera Maroo
8Department of Oncology, University of Oxford, Oxford, United Kingdom.
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Leticia Campo
8Department of Oncology, University of Oxford, Oxford, United Kingdom.
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Mark R. Middleton
8Department of Oncology, University of Oxford, Oxford, United Kingdom.
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Pippa Corrie
8Department of Oncology, University of Oxford, Oxford, United Kingdom.
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Xiaowei Xu
9Department of Pathology, University of Pennsylvania, Philadelphia, Pennsylvania.
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Giorgos C. Karakousis
3Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania.
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Ashani T. Weeraratna
1Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
2Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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  • For correspondence: aweerarl@jhu.edu
DOI: 10.1158/1078-0432.CCR-20-0446 Published November 2020
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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.

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Clin Cancer Res 2020;26:5709–19

  • Received February 6, 2020.
  • Revision received June 30, 2020.
  • Accepted August 27, 2020.
  • Published first October 23, 2020.
  • ©2020 American Association for Cancer Research.
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Clinical Cancer Research: 26 (21)
November 2020
Volume 26, Issue 21
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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
Mitchell E. Fane, Brett L. Ecker, Amanpreet Kaur, Gloria E. Marino, Gretchen M. Alicea, Stephen M. Douglass, Yash Chhabra, Marie R. Webster, Andrea Marshall, Richard Colling, Olivia Espinosa, Nicholas Coupe, Neera Maroo, Leticia Campo, Mark R. Middleton, Pippa Corrie, Xiaowei Xu, Giorgos C. Karakousis and Ashani T. Weeraratna
Clin Cancer Res November 1 2020 (26) (21) 5709-5719; DOI: 10.1158/1078-0432.CCR-20-0446

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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
Mitchell E. Fane, Brett L. Ecker, Amanpreet Kaur, Gloria E. Marino, Gretchen M. Alicea, Stephen M. Douglass, Yash Chhabra, Marie R. Webster, Andrea Marshall, Richard Colling, Olivia Espinosa, Nicholas Coupe, Neera Maroo, Leticia Campo, Mark R. Middleton, Pippa Corrie, Xiaowei Xu, Giorgos C. Karakousis and Ashani T. Weeraratna
Clin Cancer Res November 1 2020 (26) (21) 5709-5719; DOI: 10.1158/1078-0432.CCR-20-0446
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