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Circulating galectin-1 delineates response to bevacizumab in melanoma patients and reprograms endothelial cell biology
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Bannoud, Nadia, Stupirski, Juan C., Cagnoni, Alejandro J., Hockl, Pablo F., Pérez Sáez, Juan M., García, P. Alfredo, Mahmoud, Yamil D., Gambarte Tudela, Julián, Scheidegger, Marco A., Marshall, Andrea, Corrie, Pippa G., Middleton, Mark R., Mariño, Karina V., Girotti, M. Romina, Croci, Diego O. and Rabinovich, Gabriel A. (2023) Circulating galectin-1 delineates response to bevacizumab in melanoma patients and reprograms endothelial cell biology. Proceedings of the National Academy of Sciences of the United States of America, 120 (3). e2214350120. doi:10.1073/pnas.2214350120 ISSN 0027-8424.
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WRAP-Circulating-galectin-1-delineates-response-to-bevacizumab-in-melanoma-patients-and-reprograms-endothelial-cell-biology-Marshall-2023.pdf - Published Version - Requires a PDF viewer. Available under License Creative Commons Attribution Non-commercial No Derivatives 4.0. Download (2313Kb) | Preview |
Official URL: http://dx.doi.org/10.1073/pnas.2214350120
Abstract
Blockade of vascular endothelial growth factor (VEGF) signaling with bevacizumab, a humanized anti-VEGF monoclonal antibody (mAb), or with receptor tyrosine kinase inhibitors, has improved progression-free survival and, in some indications, overall survival across several types of cancers by interrupting tumor angiogenesis. However, the clinical benefit conferred by these therapies is variable, and tumors from treated patients eventually reinitiate growth. Previously we demonstrated, in mouse tumor models, that galectin-1 (Gal1), an endogenous glycan-binding protein, preserves angiogenesis in anti-VEGF–resistant tumors by co-opting the VEGF receptor (VEGFR)2 signaling pathway in the absence of VEGF. However, the relevance of these findings in clinical settings is uncertain. Here, we explored, in a cohort of melanoma patients from AVAST-M, a multicenter, open-label, randomized controlled phase 3 trial of adjuvant bevacizumab versus standard surveillance, the role of circulating plasma Gal1 as part of a compensatory mechanism that orchestrates endothelial cell programs in bevacizumab-treated melanoma patients. We found that increasing Gal1 levels over time in patients in the bevacizumab arm, but not in the observation arm, significantly increased their risks of recurrence and death. Remarkably, plasma Gal1 was functionally active as it was able to reprogram endothelial cell biology, promoting migration, tubulogenesis, and VEGFR2 phosphorylation. These effects were prevented by blockade of Gal1 using a newly developed fully human anti-Gal1 neutralizing mAb. Thus, using samples from a large-scale clinical trial from stage II and III melanoma patients, we validated the clinical relevance of Gal1 as a potential mechanism of resistance to bevacizumab treatment.
| Item Type: | Journal Article | |||||||||||||||||||||||||||||||||||||||
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| Subjects: | Q Science > QD Chemistry Q Science > QP Physiology R Medicine > RB Pathology R Medicine > RC Internal medicine |
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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 |
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| Library of Congress Subject Headings (LCSH): | Lectins, Galactose, Blood-vessels -- Growth , Inflammation , Cancer -- Treatment | |||||||||||||||||||||||||||||||||||||||
| Journal or Publication Title: | Proceedings of the National Academy of Sciences of the United States of America | |||||||||||||||||||||||||||||||||||||||
| Publisher: | National Academy of Sciences | |||||||||||||||||||||||||||||||||||||||
| ISSN: | 0027-8424 | |||||||||||||||||||||||||||||||||||||||
| Official Date: | 12 January 2023 | |||||||||||||||||||||||||||||||||||||||
| Dates: |
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| Volume: | 120 | |||||||||||||||||||||||||||||||||||||||
| Number: | 3 | |||||||||||||||||||||||||||||||||||||||
| Number of Pages: | 11 | |||||||||||||||||||||||||||||||||||||||
| Article Number: | e2214350120 | |||||||||||||||||||||||||||||||||||||||
| DOI: | 10.1073/pnas.2214350120 | |||||||||||||||||||||||||||||||||||||||
| Status: | Peer Reviewed | |||||||||||||||||||||||||||||||||||||||
| Publication Status: | Published | |||||||||||||||||||||||||||||||||||||||
| Access rights to Published version: | Open Access (Creative Commons) | |||||||||||||||||||||||||||||||||||||||
| Date of first compliant deposit: | 17 January 2023 | |||||||||||||||||||||||||||||||||||||||
| Date of first compliant Open Access: | 18 January 2023 | |||||||||||||||||||||||||||||||||||||||
| RIOXX Funder/Project Grant: |
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