Novel Therapeutic Leads from Non-anticoagulant Heparin Derivatives That Block Galectin-3-mediated Cancer Metastasis
Lead Research Organisation:
University of Liverpool
Department Name: Biomedical Sciences
Abstract
Cancer cell metastatic spread to secondary tumour sites is the main reason for cancer-associated mortality. Our recent studies have shown that a small protein called galectin-3 whose concentration is highly increased in the blood circulation of cancer patients plays a very important role in promoting cancer cell spreading. Galectin-3 binds to cancer cells and increases the likelihood that any cancer cells released into the circulation will seed at distant organs and develop into secondary tumours. Therapeutic agents that can inhibit this action of galectin-3 therefore have considerable potential to prevent cancer spread and improve chances of survival. We have evidence showing that chemical modification of certain naturally-accurring glycan compounds can inhibit this effects of galectin-3 on cancer cell spread in the laboratory. The unmodified forms of those compounds are widely used in clinic as blood thinning agents to prevent clotting but our modificcations block these anti-clotting effects thus considerably increasing the likely safety of these compounds if used long term. This study aims to identify small fractions of these specific glycan compounds that have particular efficancy against galectin-3-mediated cancer cell spread. This will lay the foundation for identification of 1 or 2 lead compounds for subsequent clinical trials in cancer patients. The galectin-3 inhibitors developed from such a strategy could be useful for the treatment of most cancer types during several cancer stages.
Technical Summary
Blood-borne metastasis is the main reason for cancer mortality. We have identified a new therapeutic target based on the metastasis-promoting interaction between the circulating galactoside-binding protein, galectin-3, and cancer cells. Galectin-3 binds the oncofetal Gala1,3GalNAc- (TF) carbohydrate antigen that is commonly over-expressed on cancer cell surface molecules, including the large transmembrane mucin MUC1. Galectin-3 promotes metastasis by enhancing disseminating cancer cell adhesion to vascular endothelium and by inducing homotypic aggregation of cancer cells to form microemboli. Galectin-3 induces clustering of cell surface MUC1 with consequent exposure of underlying adhesion molecules but also causes substantial MUC1-independent stimulation of adhesion and enhances invasion. Agents that can inhibit these interactions therefore have potential as novel metastasis inhibitors to improve patient survival. We have preliminary data showing that certain non-anticoagulant chemically-modified heparin derivatives can potently inhibit the galectin-3-ligand interaction and block galectin-3-mediated cancer-endothelial adhesion. The proposed studies will identify optimised fractions of these specific heparin derivatives that have particular efficacy, using a focussed screening program testing in vitro and in vivo activity against galectin-3-mediated cancer cell invasion and metastasis, and thus identify lead compounds for taking forward to clinical trials.
Publications


Chen C
(2013)
Increased circulation of galectin-3 in cancer induces secretion of metastasis-promoting cytokines from blood vascular endothelium.
in Clinical cancer research : an official journal of the American Association for Cancer Research

Duckworth C
(2012)
Galectins and Disease Implications for Targeted Therapeutics


Sindrewicz P
(2020)
Interaction with the heparin-derived binding inhibitors destabilizes galectin-3 protein structure.
in Biochemical and biophysical research communications

Sindrewicz P
(2019)
Intrinsic tryptophan fluorescence spectroscopy reliably determines galectin-ligand interactions.
in Scientific reports
Description | The interaction of the SARS CoV-2 spike protein receptor binding domain with heparin and its derivatives. |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Influenced training of practitioners or researchers |
Impact | Our study of the interaction of the SARS CoV-2 spike protein receptor binding domain with heparin and its derivatives, both as models of the cell surface ligand, heparan sulfate, and as potential therapeutics, underpinned the international CHARTER (Can nebulised heparin reduce time to extubation in SARS-CoV-2?) clinical trial. Our work was published originally in March 2020 on the BioRiv server [1], then in the peer-reviewed journal, Thrombosis and Haemostasis [2], and underpins both the present Wellcome Trust application as well as a recent application to NIHR. The protocol [3], which was adopted for CHARTER, also involved several of the applicants as well as an international group of collaborating clinicians. Now, the findings of the CHARLI (Can heparin administration reduce lung injury?) clinical trial, conducted by the same international group of collaborators, have been published in Lancet Respiratory Medicine ('Nebulised heparin for patients with or at risk of acute respiratory distress syndrome; a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.' by B Dixon et al., [4]. The results from CHARLI confirm the safety of nebulised heparin for the treatment of non-viral ARDS, indicating a reduction in the extent of lung damage, while enabling an earlier return home than patient control groups. Since the publication by Dixon et al., there has been enthusiasm among the scientific community to test nebulised heparin in a more homogenous population than was used in the initial study, since ARDS can take many forms; a view echoed in a recent publication in The Lancet Respiratory Medicine [5]. Very recently, a study in the BMJ [6] has shown that early prophylaxis with heparin decreases the 30-day mortality in a cohort of COVID-19 patients who had no increased risk of serious bleeding events, a risk factor for the use of conventional heparin. These findings provide further confidence in the possible application of better-optimised compounds derived from crude heparin, a source of greater structural and bioactivity diversity than the conventional pharmaceutical heparin employed in the CHARLI clinical trial, and ones from which bleeding complications can be essentially eliminated. [1] https://doi.org/10.1101/2020.02.29.971093 [2] Thromb Haemost 2020; 120(12): 1700-1715 DOI: 10.1055/s-0040-1721319 [3] https://doi.org/10.1101/2020.04.28.20082552 [4] DOI: 10.1016/S2213-2600(20)30470-7 [5] https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30513-0/fulltext [6] https://www.bmj.com/content/372/bmj.n311 |
Title | PREVENTION AND/OR TREATMENT OF CANCER AND/OR CANCER METASTASIS |
Description | The present invention relates to the use of heparin derivatives for the prevention and/or treatment of cancer and/or cancer metastasis. The heparin derivatives are substantially 2-O and/or 6-O desulphated heparins which function as inhibitors of galectin-3 activity. |
IP Reference | WO2013045955 |
Protection | Patent application published |
Year Protection Granted | 2013 |
Licensed | No |
Impact | Under further development |
Title | PREVENTION AND/OR TREATMENT OF CANCER AND/OR CANCER METASTASIS |
Description | The present invention resides in the discovery that certain heparin derivatives act as inhibitors of galectin-3 activity. Accordingly, the heparin derivatives of the present invention are potentially useful agents for the prevention and/or treatment of cancer and/or cancer metastasis. |
IP Reference | EP2760458 |
Protection | Patent application published |
Year Protection Granted | 2014 |
Licensed | No |
Impact | Galectin-3 is promoter of cancer progression and metastasis via multiple mechanisms. The present invention resides in the discovery that certain chemically modified heparin derivatives act as inhibitors of galectin-3 activity. Accordingly, such modified heparin derivatives of the present invention are potentially useful agents for the prevention and/or treatment of cancer and/or cancer metastasis. |
Title | Use of modified heparin derivatives for cancer treatment |
Description | The present invention resides in the discovery that certain chemically modified heparin derivatives act as inhibitors of galectin-3 activity. Accordingly, the heparin derivatives of the present invention are potentially useful agents for the prevention and/or treatment of cancer and/or cancer metastasis. |
IP Reference | 20180228834 |
Protection | Patent application published |
Year Protection Granted | 2018 |
Licensed | No |
Impact | Galectin-3 is promoter of cancer progression and metastasis via multiple mechanisms. The present invention resides in the discovery that certain chemically modified heparin derivatives act as inhibitors of galectin-3 . Accordingly, the heparin derivatives of the present invention are potentially useful agents for the prevention and/or treatment of cancer and/or cancer metastasis. |