Pharmacokinetics and antineoplastic activity of galectin-1-targeting OTX008 in combination with sunitinib

Zucchetti, Massimo; Bonezzi, Katiuscia; Frapolli, Roberta; Sala, Federica; Borsotti, Patrizia; Zangarini, Monique; Cvitkovic, Esteban; Noel, Kay; Ubezio, Paolo; Giavazzi, Raffaella; D’Incalci, Maurizio; Taraboletti, Giulia

doi:10.1007/s00280-013-2270-2

Cited by 36 publications

(29 citation statements)

References 24 publications

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“…Our continued investigation focuses on the molecular pathways involved in Gal-1 modulation of the tumor microenvironment, including its effect on angiogenesis, to improve the anti-tumor immune response with RT. Gal-1 blockade is currently achieved with neutralizing antibodies as well as peptide and synthetic small module inhibitors (35-38). Altogether, our future work will focus on the best way to inhibit Gal-1 function in combination with radiotherapy in order to improve curability in NSCLC.…”

Section: Discussionmentioning

confidence: 99%

Galectin-1 Mediates Radiation-Related Lymphopenia and Attenuates NSCLC Radiation Response

Kuo

Bratman

Shultz

et al. 2014

Clinical Cancer Research

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Purpose Radiotherapy (RT) can result in lymphopenia, which has been linked to poorer survival. Here, we test the hypothesis that RT-induced lymphopenia is mediated by a tumor-secreted factor, Galectin-1 (Gal-1), which possesses T-cell pro-apoptotic activities. Experimental Design Matched Gal-1 wildtype or null mice were implanted with Lewis Lung carcinoma (LLC-1) that either expressed Gal-1 or had Gal-1 stably down-regulated. Tumors were irradiated locally and circulating Gal-1 and T-cells were measured. Tumor growth, lung metastasis, intratumoral T-cell apoptosis, and microvessel density count were quantified. Thiodigalatoside (TDG), a Gal-1 inhibitor, was used to inhibit Gal-1 function in another group of mice to validate the observations noted with Gal-1 down-regulation. Lymphocyte counts, survival and plasma Gal-1 were analyzed in cohorts of RT-treated lung (NSCLC) and head and neck cancer patients. Results LLC irradiation increased Gal-1 secretion and decreased circulating T-cells in mice, regardless of host Gal-1 expression. Inhibition of tumor Gal-1 with either shRNA or TDG ablated RT-induced lymphopenia. Irradiated shGal-1 tumors showed significantly less intratumoral CD8+ T-cell apoptosis and microvessel density, which led to marked tumor growth delay and reduced lung metastasis compared to controls. Similar observations were made after TDG treatment. RT-induced lymphopenia was associated with poorer overall survival in NSCLC patients treated with hypofractionated RT. Plasma Gal-1 increased while T-cell decreased after radiation in another group of patients. Conclusions RT-related systemic lymphopenia appeared to be mediated by RT-induced tumor Gal-1 secretion that could lead to tumor progression through intratumoral immune suppression and enhanced angiogenesis.

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Section: Discussionmentioning

confidence: 99%

Galectin-1 Mediates Radiation-Related Lymphopenia and Attenuates NSCLC Radiation Response

Kuo

Bratman

Shultz

et al. 2014

Clinical Cancer Research

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“…HRAS-tR). To address this, we utilized OTX008, a small-molecule inhibitor of GAL1 which has been demonstrated to be an anticancer agent (18,19). We assessed membrane microdomain distribution of HRAS in allograft tumors resected from mice following treatment with either OTX008 or vehicle, and found that OTX008 treatment resulted in enrichment of HRAS in L o domains, similar to HRAS-tR, as indicated by co-sedimentation with L o marker CAV1 (Figure 3a).…”

Section: Resultsmentioning

confidence: 99%

Inhibition of Galectin-1 Sensitizes HRAS-driven Tumor Growth to Rapamycin Treatment

Michael

Wurtzel

Goldfinger

2016

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“…Interestingly, this inhibitor is also capable of directly and indirectly affecting cell cycle and survival and angiogenesis (6). Moreover, its in vitro and in vivo efficacy has been proven in several studies either as monotherapy or in combination with other regimens (45)(46)(47).…”

Section: α Epithelialmentioning

confidence: 99%

Galectin 1 in dermatology: current knowledge and perspectives

Pasmatzi

Papadionysiou

Monastirli

et al. 2019

Acta Dermatovenerologica Alpina Pannonica Et Adriatica

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Gal 1, the first identified and best-studied prototypical member of the galectin family, is encoded in humans by the LGALS1 gene, which is located on chromosome 22 (q12) (10). It is a noncovalent homodimeric protein with a 14 kDa monomer that contains one CRD and preferentially recognizes galactose-β1-4-N-acetyl-glucosamine sequences on N-or O-linked glycans (11). AbstractGalectins are a family of soluble proteins that are widely distributed in nature and bind to a variety of glycoproteins and glycolipids bearing β-galactoside residues. They are involved in highly important processes at the molecular and cellular level in human cutaneous and extracutaneous tissues, and they exert biological effects of paramount importance through their interaction with cytoplasmic and nuclear proteins and the components of the cell surface and extracellular matrix. Galectin 1 (Gal 1), the first galectin isolated, is a noncovalent homodimeric protein with a 14 kDa monomer that contains one carbohydrate-recognition domain (CRD) and preferentially recognizes galactose-β1-4-N-acetyl-glucosamine sequences on N-or O-linked glycans. Gal 1 occurs intracellularly, extracellularly, and on the cell surface. In the last few years Gal 1 has emerged as a multifaceted protein that exerts a wide spectrum of regulatory effects in diverse normal and abnormal tissues and conditions, indicating a tremendous therapeutic potential. This review summarizes current knowledge on the expression of Gal 1 in normal and diseased human skin, its implications in the pathogenesis, diagnosis, and prognosis of cutaneous disorders, and the novel approach to the treatment of these disorders offered by the use of Gal 1 or its inhibitors/antagonists.

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Pharmacokinetics and antineoplastic activity of galectin-1-targeting OTX008 in combination with sunitinib

Abstract: OTX008-alone or in combination with sunitinib-has a favorable PK and antineoplastic activity on selected tumor models through the effects on both endothelial and tumor cells.

Cited by 36 publications

References 24 publications

Galectin-1 Mediates Radiation-Related Lymphopenia and Attenuates NSCLC Radiation Response

Galectin-1 Mediates Radiation-Related Lymphopenia and Attenuates NSCLC Radiation Response

Inhibition of Galectin-1 Sensitizes HRAS-driven Tumor Growth to Rapamycin Treatment

Galectin 1 in dermatology: current knowledge and perspectives

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