Targeting galectin-driven regulatory circuits in cancer and fibrosis

nature reviews drug discovery https://doi.org/10.1038/s41573-023-00636-2 Review article Check for updates Targeting galectin-driven regulatory circuits in cancer and fibrosis Karina V. Mariño , Alejandro J. Cagnoni1,2, Diego O. Croci3 & Gabriel A. Rabinovich 1 2,4 Abstract Sections Galectins are a family of endogenous glycan-binding proteins that have crucial roles in a broad range of physiological and pathological processes. As a group, these proteins use both extracellular and intracellular mechanisms as well as glycan-dependent and independent pathways to reprogramme the fate and function of numerous cell types. Given their multifunctional roles in both tissue fibrosis and cancer, galectins have been identified as potential therapeutic targets for these disorders. Here, we focus on the therapeutic relevance of galectins, particularly galectin 1 (GAL1), GAL3 and GAL9 to tumour progression and fibrotic diseases. We consider an array of galectin-targeted strategies, including small-molecule carbohydrate inhibitors, natural polysaccharides and their derivatives, peptides, peptidomimetics and biological agents (notably, neutralizing monoclonal antibodies and truncated galectins) and discuss their mechanisms of action, selectivity and therapeutic potential in preclinical models of fibrosis and cancer. We also review the results of clinical trials that aim to evaluate the efficacy of galectin inhibitors in patients with idiopathic pulmonary fibrosis, nonalcoholic steatohepatitis and cancer. The rapid pace of glycobiology research, combined with the acute need for drugs to alleviate fibrotic inflammation and overcome resistance to anticancer therapies, will accelerate the translation of anti-galectin therapeutics into clinical practice. Introduction Laboratorio de Glicómica Funcional y Molecular, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina. 2Laboratorio de Glicomedicina, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina. 3Laboratorio de Glicobiología y Biología Vascular, Instituto de Histología y Embriología de Mendoza (IHEM), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET); Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Cuyo, Mendoza, Argentina. 4Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina. e-mail: 1 Nature Reviews Drug Discovery Cellular roles of galectins Galectins in cancer Galectins in fibrosis Galectin-targeted strategies Future potential of galectin inhibitors Review article Introduction The complex repertoire of glycan structures present in cells and tissues (that is, the glycome) stores crucial biological information that contributes to the reprogramming of cellular fate and function and thus has a profound influence on the delicate balance between health and disease1–4. The diversity and spatiotemporal regulation of glycans within glycoconjugates rely on the synchronized action of glycan-modifying enzymes, including glycosyltransferases and glyco sylhydrolases. Glycan remodelling is regulated by intracellular and environmental signals, such as metabolic stress, oxygen and nutrient availability, growth factors and cytokines2,5. Dysregulation of many cellular processes, including cellular communication, proliferation, differentiation and survival has been linked to aberrant glycosylation. This finding implicates the glycome in the pathophysiology of nearly every major disease, with notable impact on cancer, inflammation and fibrosis5,6. Changes in the glycosylation signature of tumour, immune and endothelial cells (ECs) are among the common hallmarks of the tumorigenic process, as these signatures can influence cell adhesion, epithelial-to-mesenchymal transition (EMT), angiogenesis, immuno editing and metastasis1,5,7–12. Moreover, selective glycan profiles may also help to control the initiation, persistence and resolution of inflammatory and fibrotic processes1,13. Thus, an aberrant glycome might alter cellular functions by regulating the exposure or masking of specific glycoepitopes. These aberrations can ultimately lead to the development of pathological responses. Converting glycan-encoded information into biological programmes relies, at least in part, on the contributions of endogenous glycan-binding proteins or lectins6. The three major lectin families that have decisive roles in shaping both inflammatory and tumour microenvironments are sialic acid-binding immunoglobulin-like lectins (Siglecs), C-type lectin receptors (including selectins14) and galectins. Galectins are a family of soluble lectins that share affinity for β-galactoside-containing saccharides15. Examples of some natural ligands for mammalian galectins are summarized in Box 1. Galectins might be involved in the transition from healthy to neoplastic or inflamed tissues and contribute to the persistence of these pathological conditions via both intracellular and extracellular mechanisms16,17. Galectins also influence most hallmarks of tumour progression17 and modulate resistance to numerous anticancer treatments, including immunotherapy, chemotherapy, radiotherapy, targeted therapies and anti-angiogenic therapy18. Furthermore, galectins might contribute to regulatory circuits that amplify, sustain or alleviate tissue fibrosis and inflammation by selectively targeting different cell types and their microenvironments16,19–21. Accordingly, these glycan-binding proteins have been proposed as therapeutic targets in a broad range of pathological conditions and are currently under clinical evaluation. In this Review, we consider the pathophysiological relevance of specific galectin–glycan interactions from a translational perspective and discuss the design, mechanisms of action, selectivity and therapeutic relevance of galectin-targeted agents. We focus on the results of preclinical studies and clinical trials and highlight lessons learned from targeting galectins in a diverse group of disease states, including nonalcoholic steatohepatitis (NASH)19, idiopathic pulmonary fibrosis (IPF)22–24, as well as various malignancies11,17. These examples underscore the numerous potential opportunities to capitalize on galectin–glycan interactions for therapeutic purposes. We focus in particular on agents designed to target galectin– glycan interactions, including small-molecule inhibitors, natural polysaccharides and their synthetic derivatives, as well as peptides Nature Reviews Drug Discovery and peptidomimetics. We also discuss the relevance of biological agents such as neutralizing monoclonal antibodies (mAbs), aptamers and truncated galectins, which have emerged as potential therapeutic modalities to target galectin-regulated circuits. Finally, we discuss various galectin-targeted strategies, highligh (...truncated)