Circulating galectin-1 delineates response to bevacizumab in melanoma patients and reprograms endothelial cell biology

Proc Natl Acad Sci U S A. 2023 Jan 17;120(3):e2214350120. doi: 10.1073/pnas.2214350120. Epub 2023 Jan 12.


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.

Keywords: angiogenesis; cancer therapy; galectin-1; inflammation; survival.

Publication types

  • Randomized Controlled Trial
  • Multicenter Study
  • Clinical Trial, Phase III
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / pharmacology
  • Animals
  • Antibodies, Monoclonal, Humanized / pharmacology
  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Bevacizumab / pharmacology
  • Bevacizumab / therapeutic use
  • Biology
  • Endothelial Cells / pathology
  • Galectin 1
  • Humans
  • Melanoma* / drug therapy
  • Melanoma* / pathology
  • Mice
  • Vascular Endothelial Growth Factor A*
  • Vascular Endothelial Growth Factors


  • Bevacizumab
  • Vascular Endothelial Growth Factor A
  • Galectin 1
  • Antibodies, Monoclonal, Humanized
  • Vascular Endothelial Growth Factors
  • Angiogenesis Inhibitors