OTX-008 / Merck (MSD) - LARVOL DELTA

Exploration of the Specific Mechanism of EGR2 Hotspot Mutation Mediating the Upregulation of Galectin-1 Expression in the Progression of CLL Following Treatment with BTK Inhibitor (ASH 2024) - "Results 353 patients with CLL/SLL in the Department of Hematology, the First Affiliated Hospital of Nanjing Medical University were included in this study and 204 of them were treated with BTK inhibitors (ibrutinib, zanubrutinib, orelabrutinib and LOXO-305)...OTX008, a Galectin-1 inhibitor, alone or combined with zanubrutinib or venetoclax, could significantly suppress the proliferation and induce cell apoptosis in EGR2 p.E356K overexpressing MEC-1 cells, partly by downregulating the activation of PI3K-AKT pathway. Conclusions CLL patients harboring the EGR2 p.E356K mutation exhibit enrichment of poor prognostic characteristics. The CLL EGR2 p.E356K mutation facilitated the expression of Galectin-1, promoting the proliferation and anti-apoptosis of CLL cells, and leading to a suppressed T cell immune microenvironment."

Chronic Lymphocytic Leukemia • Hematological Disorders • Richter's Syndrome • ATM • EGR2 • IGH • LGALS1 • PTPRC

Galectin-1 Fuels Monocyte-Driven Hyperinflammation and Represents a Novel Therapeutic Target in Myeloproliferative Neoplasms (ASH 2023) - "Additionally, galectin-1 expression was induced by MPLW515L and JAK2V617F and inhibited by ruxolitinib in Ba/F3 cells...Furthermore, OTX008, a galectin-1 inhibitor, inhibited the transcription and secretion of inflammatory cytokines in MPN patient CD14+ monocytes and monocytic cell lines...We further demonstrate that galectin-1 fuels inflammation potentially via metabolic reprogramming of monocytes and activation of PI3K-AKT-mTOR signaling. Our data also suggest galectin-1 as a putative therapeutic target in MPNs."

Myeloproliferative Neoplasm • Oncology • CD14 • CXCL8 • IL1B • IL6 • ITGAM • LGALS1 • TNFA

Monocyte-Driven Aberrant Inflammation in Myeloproliferative Neoplasms Is Regulated By Galectin-1 (ASH 2024) - "Additionally, Gal-1 expression was induced by MPLW515L and JAK2V617F and inhibited by ruxolitinib, a JAK inhibitor, in Ba/F3 cells...Pharmacologic inhibition of Gal-1 by OTX008 suppressed the expression and secretion of inflammatory cytokines in MPN monocytes and monocytic cell lines...Notably, targeting TLR4 via both neutralizing antibody and pharmacologic inhibition (TAK-242) abrogated the proinflammatory effects of Gal-1 on monocytes...We further evaluated therapeutic effects of targeting global glycosylation in MPN via 2-Deoxy-D-glucose (2-DG), a global glycosylation inhibitor, which decreased splenomegaly and reduced elevated platelets and hematocrit in JAK2V617F knock-in mice...We further demonstrate that Gal-1 fuels monocyte inflammation by interacting with TLR4 and activation of OXPHOS and PI3K-AKT-mTOR signaling pathways. Our results uncover a novel therapeutic avenue for targeting aberrant Gal-1 and global glycosylation in MPNs."

Cardiovascular • Myeloproliferative Neoplasm • Oncology • Thrombosis • CD14 • CXCL8 • IL1B • IL6 • ITGAM • LGALS1 • TLR4

GALECTIN-1 AS A POTENTIAL NOVEL THERAPEUTIC TARGET IN CHRONIC MYELOMONOCYTIC LEUKAEMIA (EHA 2025) - "In addition, OTX008 treatment also resulted in reduced colony formation, suggesting a role for gal-1 in the survival of CMML HSPCs...LGALS1 levels are also correlated with transcriptomic signatures common to venetoclax, cytarabine, (p<0.001) and hypomethylating agent resistance (p<0.05), suggesting the potential use of gal-1 inhibitors to overcome resistance... In conclusion, our data suggest that gal-1 plays a role in the survival of CMML monocytes as well as the self-renewal and myeloid bias of CMML stem cells, suggesting that gal-1, or pathways it is involved in, could act as potential therapeutic targets in CMML."

Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Myeloproliferative Neoplasm • Oncology • FLT3 • ITGAM • LGALS1 • NOTCH1 • NOTCH2

The Immunomodulatory Role of Galectin-1 in the Tumour Microenvironment and Strategies for Therapeutic Applications. (PubMed, Cancers (Basel)) - "Approaches such as OTX008, anti-Gal1 monoclonal antibodies, and Gal1-targeted vaccines have demonstrated the ability to downregulate tumour progression by inhibiting Gal1 activity. These findings highlight the therapeutic promise of Gal1 not only as a novel target for cancer therapy but also as a potential prognostic biomarker, offering opportunities for the development of more effective and less toxic treatment strategies."

Journal • Review • Oncology • FASLG • LGALS1

Galectin-1: An important regulator in myeloid differentiation and acute myeloid leukemia as well as a promising prognostic indicator and therapeutic target. (PubMed, Int Immunopharmacol) - "Treatment with OTX008, an LGALS1 inhibitor, markedly diminished the viability of primary malignant bone marrow cells from AML patients. Notably, LGALS1 expression was significantly reduced exclusively in AML-M5 patients after treatment, which may be due to its higher expression in AML-M5 subtype compared to other FAB subtypes. In summary, our findings indicate that LGALS1 could serve as an independent prognostic risk factor and a promising therapeutic target in AML, providing novel insights into AML pathogenesis and laying the foundation for the development of new therapeutic strategies."

Biomarker • Journal • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • LGALS1

Elucidating the role of LGALS1 in sensitizing HNSCC to immune checkpoint inhibitor (IMMUNOLOGY 2025) - "Using a unique co-culture system, we found that OTX-008 treatment did not affect the percentage of tumor-associated macrophage but altered their phenotypes. Our study identified LGALS1 as a potential target to improve efficacy of combinatorial immunotherapy for HNSCC by targeting both tumor and tumor-infiltrating myeloid cells.Keywords: Animals Rodent; Cells Monocytes/Macrophages"

Checkpoint inhibition • IO biomarker • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • ITGAM • KRAS • LGALS1 • PTPRC • SMAD4

Targeting Galectin-1 Overcomes Paclitaxel Resistance in Esophageal Squamous Cell Carcinoma. (PubMed, Cancer Res) - "Combining OTX008 with clinical taxane formulations effectively reversed paclitaxel resistance in vitro and in vivo. Elevated galectin-1 levels thus serve as an indicator of response to paclitaxel therapy in ESCC, offering a therapeutic intervention strategy to overcome drug resistance."

Journal • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma • ABCB1 • LGALS1

Gal-1-mediated cytochrome p450 activation promotes fibroblast into myofibroblast differentiation in pulmonary fibrosis. (PubMed, Int Immunopharmacol) - "In a bleomycin-induced PF mouse model, we found Galectin-1 (Gal-1) expression was significantly increased in lung tissue, and overexpression of Gal-1 plasmid-transfected fibroblasts were activated into myofibroblasts. The Gal-1 inhibitor OTX008 or the CYP1A1 inhibitor 7-Hydroxyflavone prevented PF in mice and inhibited the role of fibrotic ECM in promoting fibroblast activation into myofibroblasts, preventing PF. These results reveal novel molecular mechanisms of lung fibrosis formation and identify Gal-1 and its downstream CYP1A1 as potential therapeutic targets for PF disease treatmnts."

Journal • Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • CYP1A1 • CYP24A1 • CYP3A4 • LGALS1

Chrysin-loaded calixarene-cyclodextrin ternary drug delivery system inhibits TGF-β and galectin-1 mediated pathways in diabetic liver fibrosis. (PubMed, Biochem Pharmacol) - "The system was designed to enhance the solubility and bioavailability of chrysin (CHR) and calixarene 0118 (OTX008)...Furthermore, it downregulated galectin-1 (Gal-1) gene and protein levels, which correlated with fibrotic markers. In conclusion, the chrysin-loaded calixarene-cyclodextrin ternary DDS presents a promising therapeutic approach for diabetic liver fibrosis, effectively targeting fibrotic pathways and restoring hepatic function and structure."

Journal • Diabetes • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Metabolic Disorders • LGALS1 • SMAD2 • SMAD7 • TGFB1 • TGFBR2

Chrysin Directing an Enhanced Solubility through the Formation of a Supramolecular Cyclodextrin-Calixarene Drug Delivery System: A Potential Strategy in Antifibrotic Diabetes Therapeutics. (PubMed, Pharmaceuticals (Basel)) - "Structural investigations revealed non-covalent interactions essential to complex formation, which showed no cytotoxicity in hyperglycemic in vitro conditions. A new ternary complex has been formulated to deliver promising antifibrotic agents for diabetic complications, featuring OTX008 as a key structural and pharmacological component."

Journal • Diabetes • Fibrosis • Immunology • Infectious Disease • Metabolic Disorders

Chrysin-based supramolecular cyclodextrin-calixarene drug delivery system: a novel approach for attenuating cardiac fibrosis in chronic diabetes. (PubMed, Front Pharmacol) - "Both chrysin (CHR) and calixarene OTX008, a specific inhibitor of galectin 1 (Gal-1), seem able to reduce transforming growth factor beta (TGF-β)/SMAD pro-fibrotic pathways, but their use is limited to their low solubility...Also an improved cardiac tissue remodeling was evident. Therefore, new drug delivery system, which could be considered as a novel putative therapeutic strategy for the treatment of diabetes-induced cardiac fibrosis."

Journal • Diabetes • Fibrosis • Immunology • Metabolic Disorders • LGALS1 • SMAD2 • TGFB1 • TGFBR2

Inhibition of Galectin-1 attenuates lung fibroblast activation and proliferation in lung fibrosis. (PubMed, Cell Mol Biol (Noisy-le-grand)) - "Murine lung fibroblast was pre-treated using Gal-1 inhibitor OTX-008 or overexpression of Gal-1 and then activated using transforming growth factor-beta (TGF-β). Adult male C57BL/6J mice were conducted intratracheal injection of bleomycin (BLM) for lung fibrosis...Moreover, inhibition of Gal-1 in lung fibrosis model attenuates lung fibroblast bioactivity and reduces ECM, leading to improved pulmonary histology and function. Hence, knockdown of Gal-1 in IPF may be a promising target therapy."

Journal • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • LGALS1 • TGFB1

The role of galectin-1 in SCLC: Prognostic significance and therapeutic implications (ESMO 2023) - "The SCLC-PDX model showed a significant reduction in tumor growth in both the OTX008 (T/C 66%) and carboplatin/etoposide (T/C 65%) groups, with the greatest effect attributable to the combination (T/C 46%). Conclusions Our findings suggest that high levels of Gal-1 and PLR are associated with poorer OS in SCLC patients and can be useful as clinical prognostic biomarkers. Moreover, our in vivo model suggests that the inhibition of Gal-1 could be a novel potential therapy with a significant impact in combination with platinum-based therapy."

Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • LGALS1

A Osimertinib And Otx008 Impair Survival Of Glioblastoma Cells By Inhibiting Ras (EANO 2023) - "The constitutive activation of the PI3K/Akt and RAS/MAPK pathways is associated with uncontrolled cell growth and therapeutic resistance. The EGFR-inhibitor Osimertinib and the selective Galectin-1 inhibitor OTX008 showed antiproliferative effect in immortalized glioblastoma cell line U87 and were also able to inhibit activation of Ras. Future experiments should focus on the downstream signalling of the pathways, especially in EGFR mutated glioblastoma stem cells."

Brain Cancer • CNS Tumor • Glioblastoma • Lung Cancer • Oncology • Solid Tumor • LGALS1

Cross-Talk between Hematopoietic Cells and Fibroblast Subsets Drives Inflammation and Remodelling of the Bone Marrow Microenvironment in Myeloproliferative Neoplasms (ASH 2022) - "Inhibition of galectin-1 with OTX008 significantly reduced TGFβ-induced collagen 1 and αSMA expression by human bone marrow stromal cells in 2D cultures as well as in human iPSC-derived bone marrow organoids, and bone marrow biopsies from a cohort of MF and non-fibrotic ET/PV patients showed a striking association of galectin-1 with fibrosis (Fig.1B). We present a roadmap of the cellular and molecular landscape of normal and myelofibrotic bone marrow. We identify two cellular subsets (EBM and iFib) whose role as mediators of the inflammatory microenvironment in MF was previously unappreciated, and propose galectin-1 as a novel biomarker and potential mediator of fibrosis."

Hematological Disorders • Hematological Malignancies • Immunology • Inflammation • Leukemia • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • GLI1 • Glycophorin A • ITGA2B • LEP • LEPR • LGALS1 • LGALS3 • NES • PTPRC • TGFBR2 • TNFA • TNFRSF1A

Galectin-1, a novel promising target for outcome prediction and treatment in SCLC. (PubMed, Biomed Pharmacother) - "in this study, high levels of Gal-1 and PLR were associated with poorer OS in SCLC patients, supporting their utility as clinical prognostic biomarkers. Moreover, the in vivo model suggests the inhibition of Gal-1 as a novel potential therapy for this disease with very poor prognosis."

Journal • Lung Cancer • Neuroendocrine Tumor • Oncology • Small Cell Lung Cancer • Solid Tumor • LGALS1

The LMP1/Lgals1-NF-Kb-IRF1-PDL1 Axis Promotes Immune Escape in Nasopharyngeal Carcinoma (ASTRO 2022) - "Our findings reveal a regulatory axis for programmed death ligand 1 (PD-L1) expression in NPC cells, and targeting one component in this axis, Lgals1, is effective in boosting the immunogenicity of NPCs, providing a therapeutic avenue for treating NPC in clinic."

IO biomarker • Nasopharyngeal Carcinoma • Oncology • Solid Tumor • IRF1 • LGALS1

Effects of the Calix[4]arene Derivative Compound OTX008 on High Glucose-Stimulated ARPE-19 Cells: Focus on Galectin-1/TGF-β/EMT Pathway. (PubMed, Molecules) - "Moreover, epithelial-mesenchymal transition markers were reduced by OTX008 5 μM and 10 μM. The inhibition of galectin-1 by OTX008 in DR may preserve retinal pigment epithelial cell integrity and functionality by reducing their pro-fibrotic phenotype and epithelial-mesenchymal transition phenomenon induced by diabetes."

Journal • Diabetes • Diabetic Retinopathy • Fibrosis • Immunology • Metabolic Disorders • Retinal Disorders • LGALS1 • RELA • TGFB1

Mesenchymal stem cells target microglia via galectin-1 production to rescue aged mice from olfactory dysfunction. (PubMed, Biomed Pharmacother) - "MSCs and their culture supernatant (MSC-CM) could regulate the direction of microglial differentiation by impeding the polarization towards the pro-inflammatory M1 type; notably, a selective Gal1 inhibitor OTX008 could hinder this phenomenon, indicating that Gal1 is involved in immunomodulation exerted by MSCs. Also, acute microglial activation within the OB upon LPS infusion was attenuated by MSC-CM in a Gal1-dependent manner. Our study demonstrates the therapeutic benefit of MSCs on age-related olfactory dysfunction and suggests Gal1 as a key mediator of the anti-inflammatory action of MSCs."

Journal • Preclinical • Immune Modulation • Immunology • Inflammation • CD86 • CTSS • LGALS1

Galectin-1-Dependent Mitochondria Apoptosis Plays an Essential Role in the Potential Protein Targets of DBDCT-Induced Hepatotoxicity as Revealed by Quantitative Proteomic Analyses. (PubMed, Bioinorg Chem Appl) - "In some cases, its activity was close to or even higher than cisplatin, a first-line clinical metallic agent...Correspondingly, NAC (inhibitor of ROS), PDTC (inhibitor of NF-κB), EGF (ERK1/2 activator), and OTX008 (inhibitor of Gal-1) were found to reverse and abolish the DBDCT-associated cytotoxicity partially. In conclusion, Gal-1 might be the potential target for toxicity and biological activity. Moreover, the present study will lay the groundwork for future research about di-n-butyl-di-(4-chlorobenzohydroxamato) tin structure optimization and developing it into a new potential anticancer agent."

IO biomarker • Journal • Hepatology • Oncology • BAX • BCL2 • EGF • FASLG • LGALS1 • RELA • TP53

Single-Cell RNA Sequencing Suggests Novel Drivers of Chronic Lymphocytic Leukemia Patients with Ibrutinib Resistance (ASH 2021) - "In conclusion, our findings demonstrate that ibrutinib-resistant CLL cells exhibit a unique transcriptional pattern. The combination of LGALS1 and LAG3 expression could serve as an indicator of the sensitivity of ibrutinib and prognosis of CLL patients. LGALS1 inhibitor OTX008 helps to overcome ibrutinib-resistance of CLL cells."

Clinical • IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • LAG3 • LGALS1

Effects of galectin-1 inhibitor OTX008 on oral squamous cell carcinoma cells in vitro and the role of AP-1 and the MAPK/ERK pathway. (PubMed, Arch Oral Biol) - "OTX008 decreased the viability of OSCC and NOK cells in a dose-dependent manner. The significant regulation of FOS suggests OTX008 causes early induction of the MAPK pathway via the immediate response gene FOS as a subunit of the AP-1 complex."

Journal • Preclinical • Head and Neck Cancer • Oncology • Oral Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • FOS • LGALS1

RASSF1A independence and early galectin-1 upregulation in PIK3CA-induced hepatocarcinogenesis: new therapeutic venues. (PubMed, Mol Oncol) - "Galectin-1, which was commonly upregulated in preneoplastic lesions and tumors, emerged as a regulator of SCD1. Co-inhibitory treatment with PIK3CA inhibitors and the galectin-1 inhibitor OTX-008 resulted in synergistic cytotoxicity in human HCC cell lines, suggesting novel therapeutic venues."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • FASN • LGALS1 • PIK3CA • RASSF1 • SCD

Transcriptional control of brain tumor stem cells by a carbohydrate binding protein. (PubMed, Cell Rep) - "Importantly, we establish that galectin1 forms a complex with the transcription factor HOXA5 to reprogram the BTSC transcriptional landscape. Our data unravel an oncogenic signaling pathway by which the galectin1/HOXA5 complex maintains BTSCs and promotes glioblastoma."

Journal • Brain Cancer • Gene Therapies • Glioblastoma • Glioma • Oncology • Solid Tumor • STAT3