The purpose of this study is to determine the recommended dose (RD) for further phase II studies, of the Galectin-1 inhibitor OTX008 given subcutaneously in patients with advanced solid tumors

Start Date01 Feb 2012

Sponsor / Collaborator

Oncoethix GmbH

100 Clinical Results associated with PTX-008

100 Translational Medicine associated with PTX-008

100 Patents (Medical) associated with PTX-008

Literatures (Medical) associated with PTX-008

15 Nov 2024·Cancer Research

Targeting Galectin-1 Overcomes Paclitaxel Resistance in Esophageal Squamous Cell Carcinoma

Article

Author: Liu, Xuejiao ; Liu, Kangdong ; Liu, Wenting ; Wang, Nan ; Luo, Hui ; Ge, Hong ; Wang, Jiutao ; Wang, Penglei ; Zhao, Ran ; Ma, Yijie ; Tian, Jie ; Li, Xiang ; Wang, Keke ; Dong, Zigang ; Zhao, Simin ; Gu, Tingxuan ; Lu, Bingbing ; Zhou, Liting ; Lee, Mee-Hyun ; Chen, Xiaojie ; Nie, Wenna

AbstractResistance to paclitaxel poses a major obstacle in esophageal squamous cell carcinoma (ESCC) treatment. A better understanding of the mechanisms underlying paclitaxel resistance could help identify prognostic biomarkers and improved therapeutic strategies. In this study, we established a patient-derived xenograft model of acquired paclitaxel resistance and used RNA sequencing to identify galectin-1, encoded by LGALS1, as a key mediator of resistance. Integrative analysis of clinical data and physiological studies indicated that serum galectin-1 levels were elevated in resistant patients and correlated with treatment outcomes before and during taxane therapy. Importantly, exposing cells to serum from resistant patients resulted in increased paclitaxel resistance compared to serum from sensitive patients, which was closely associated with galectin-1 concentrations in the serum. The specific clearance of galectin-1 from resistant patient serum significantly restored paclitaxel sensitivity, and inhibiting galectin-1, through knockdown or the pharmacologic inhibitor OTX008, increased sensitivity to paclitaxel. Galectin-1 inhibition reduced the activity of β-catenin, thereby inhibiting stem cell properties induced by the Wnt/β-catenin pathway. Furthermore, galectin-1 regulated MDR1 transcription through increased nuclear accumulation of β-catenin, thus increasing resistance to paclitaxel. 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.Significance: Galectin-1 is a key mediator of paclitaxel resistance in esophageal squamous cell carcinoma that can be targeted to improve taxane efficacy, suggesting broad therapeutic potential for treating various cancer types.

01 Nov 2024·International Immunopharmacology

Gal-1-mediated cytochrome p450 activation promotes fibroblast into myofibroblast differentiation in pulmonary fibrosis

Article

Author: Jin, Haijuan ; Wang, Liang ; Chen, Chan ; Ma, Yuan ; Wang, Zhiyi ; Cheng, Qianhui ; Guan, Jiangan ; Zhang, Ran ; Weng, Jie ; Yang, Jingwen

Pulmonary fibrosis (PF) results from excessive extracellular matrix (ECM) deposition and tissue remodeling after activation of fibroblasts into myofibroblasts. Abnormally deposited fibrotic ECM, in turn, promotes fibroblast activation and accelerates loss of lung structure and function. However, the molecular mediators and exact mechanisms by which fibrotic ECM promotes fibroblast activation are unclear. 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. Using the decellularization technique to prepare decellularized fibrotic ECM and constructing a 3D in vitro co-culture system with fibroblasts, we found that decellularized fibrotic ECM induced a high expression of Gal-1 and promoted the activation of fibroblasts into myofibroblasts. Therefore, Gal-1 has been identified as a pivotal mediator in PF. Further, we found that decellularized fibrotic ECM delivered mechanical signals to cells through the Gal-1-mediated FAK-Src-P130Cas mechanical signalling pathway, while the CYP450 enzymes (mainly involved in CYP1A1, CYP24A1, CYP3A4, and CYP2D6 isoforms) acted as a chemical signalling pathway to receive mechanical signals transmitted from upstream Gal-1, thereby promoting fibroblast activation. 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.

01 Dec 2022·Biomedicine & Pharmacotherapy

Galectin-1, a novel promising target for outcome prediction and treatment in SCLC

Article

Author: Corral, Juan Manuel ; García-Foncillas, Jesús ; Río-Vilariño, Anxo ; Cedeño, Mabel ; Puerto-Nevado, Laura Del ; Mahillo-Fernández, Ignacio ; Cebrián, Arancha ; Baños, Natalia ; Galeano, Carlos ; Dómine, Manuel

INTRODUCTIONsmall-cell lung cancer (SCLC) is one of the most lethal malignancies. Its management is complex due to the lack of biomarkers and limited therapies. Galectin-1 (Gal-1) plays a major role in cancer development and progression. The aim of this study is to assess whether Gal-1 has a predictive role in the disease evolution and its therapeutic potential.MATERIAL AND METHODSThe expression level of Gal-1 was examined by using a public RNA-sequencing (77 SCLC patients) and in-house immunohistochemistry (IHC) performed on biopsies from 81 patients. Survival curves and Cox regression analysis were used to assess the prognostic potential of Gal-1. In addition, a SCLC-PDX model was carried out and treated with either OTX008, an inhibitor of Gal-1, or vehicle to assess the effects of Gal-1 inhibition on this disease in vivo.RESULTSGalectin-1 gene (LGALS1) expression showed a strong negative correlation with outcome in SCLC patients with advanced disease (p = 0.007). IHC unveiled that overall survival (OS) was significantly lower among extensive-stage SCLC (ES-SCLC) patient group with increased level of Gal-1 and platelet-to-lymphocyte ratio (PLR) (HR=3.07, 95% CI: 1.62, 5.79, p < 0.001). The SCLC-PDX model showed a significant reduction in tumor size (tumor growth inhibition [TGI] index 73%) without side effects.DISCUSSIONin 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.

100 Deals associated with PTX-008

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced Malignant Solid Neoplasm	Phase 1	BE	Oncoethix GmbH	01 Feb 2012
Advanced Malignant Solid Neoplasm	Phase 1	FR	Oncoethix GmbH	01 Feb 2012
Neoplasms	Phase 1	US	PepTx, Inc.	09 Apr 2006

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