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Published on: February 20, 2018
Pharmacological Characterization of GB1908, a Selective Galectin-1 Carbohydrate Binding Domain Inhibitor for the
Kimberly D Herman1, Ian Holyer1, Duncan C Humphries1
1Galecto Biotech AB, Copenhagen, Denmark.
Introduction:
Galectin-1 (Gal-1) is a lectin that has been shown to be involved in a number of pro-tumorigenic mechanisms and has also been shown to be immune-suppressive. Therefore, pharmacological blockade of Gal-1 has the potential to be therapeutically beneficial in cancers that overexpress this lectin where it is hypothesized to be driving cancer progression.
Methods:
GB1908 is a novel, selective and high affinity inhibitor of the Gal-1 carbohydrate recognition domain and in this study, we have pharmacologically characterized this small molecule in a range of in vitro and in vivo systems in the context of cancer therapy. In addition, we used a data-driven approach to identify the cancer types which may benefit from Gal-1 inhibitor therapy.
Results:
The selectivity of GB1908 for Gal-1 compared with galectin-3 (Gal-3) was confirmed in biophysical and cellular assays. GB1908 attenuated Gal-1-induced T cell (Jurkat) apoptosis and reduced the production of immunosuppressive cytokines in a stromal non-small cell lung cancer tumor microenvironment model. Breast carcinoma and metastatic skin cutaneous melanoma were identified as cancers in which high Gal-1 expression correlated with poorer survival outcomes in patients. Treatment with GB1908 slowed tumor growth in syngeneic mouse models of these cancers.
Conclusion:
The inhibition of both tumor growth and immune-suppressive cytokines, in cancers in which high Gal-1 is associated with poorer survival outcomes, suggests a potential therapeutic benefit for Gal-1 inhibitors such as GB1908.
Insights
Galectin-1 (Gal-1) blockade with GB1908 shows therapeutic potential in cancers. This Gal-1 inhibitor reduced tumor growth and immunosuppression, suggesting a new cancer treatment strategy.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Galectin-1 (Gal-1) is implicated in pro-tumorigenic and immunosuppressive mechanisms.
- Targeting Gal-1 offers potential therapeutic benefits for cancers overexpressing this lectin.
Purpose of the Study:
- To pharmacologically characterize GB1908, a selective Gal-1 inhibitor, for cancer therapy.
- To identify cancer types that may benefit from Gal-1 inhibitor therapy using a data-driven approach.
Main Methods:
- GB1908 selectivity for Gal-1 over Gal-3 was confirmed via biophysical and cellular assays.
- In vitro and in vivo cancer models were used to evaluate GB1908's efficacy.
- Patient data analysis identified cancer types with high Gal-1 expression and poor survival.
Main Results:
- GB1908 inhibited Gal-1-induced T cell apoptosis and reduced immunosuppressive cytokines in a lung cancer model.
- High Gal-1 expression correlated with poorer survival in breast carcinoma and melanoma patients.
- GB1908 treatment slowed tumor growth in syngeneic mouse models of these cancers.
Conclusions:
- GB1908 demonstrates potential as a therapeutic agent by inhibiting tumor growth and immune suppression.
- Gal-1 inhibitors like GB1908 may offer clinical benefits for specific cancer types associated with high Gal-1 expression.
