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

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 sur-vival 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 compen-satory 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 devel-oped 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. Significance Translating preclinical success of VEGF-targeted therapies into clinical practice has been challenging due to development of resistance mechanisms and lack of reliable biomarkers of treatment response. Here, we show that galectin-1 (Gal1), a beta-galactoside-binding lectin with proangiogenic and immunoregulatory activities, is elevated in plasma from bevacizumab-treated melanoma patients participating in AVAST-M, a phase 3 clinical trial of adjuvant bevacizumab versus standard surveillance. Notably, increasing Gal1 levels over time enhance the risk of recurrence and death only in patients in the bevacizumab arm. Using a newly developed fully human anti-Gal1 antibody, we demonstrated that circulating Gal1 was functionally active as it was able to reprogram endothelial cell biology. Thus, changes in plasma Gal1 levels may delineate resistance to VEGF-targeted therapies.