First described in 1971, the galectin-3 protein has emerged over the last decade as a major focus of research and pharmaceutical development for a wide range of different diseases. A brief survey of the articles searchable on PubMed and the companies involved in the development of galectin-3 inhibitors show the broad potential impact that this research might have on the millions – if not billions – of people affected by cancer, fibrosis, and cardiovascular diseases.
What is Galectin-3?
Galectins are a class of proteins made by many cells in the body but most often concentrated in immune cells. As a group, these proteins are able to bind to sugar molecules that are part of other proteins in and on the cells of our body. Galectin proteins act as a kind of glue, bringing together molecules that have sugars on them.
Secreted galectins have been shown to bind with high affinity to galactose-containing glycoproteins on the cell surface and in the extracellular matrix. While they all bind to glycoproteins with terminal galactose residues, each galectin binds to different sets of glycoproteins in the body thus providing specificity of action. Their ability to dimerize creates the opportunity for galectins to link glycoproteins and form a lattice structure on the cellular surface and to promote cell-cell and cell-matrix interactions (Figure 1).
While galectins are normally expressed in small amounts in many different cell types, they are most highly expressed in macrophages of the immune system and are activated by tissue damage. While this is useful in combating bacterial, viral, or parasitic infection, it can be detrimental in other circumstances. Secreted galectins are markedly increased and have important roles in a wide variety of pathological processes involved in immune regulation, inflammation, fibrogenesis and tumor cell biology. The increase in galectin protein promotes the disease and is detrimental to the patient.
There are 15 galectin protein subtypes. Galectin-1 and galectin-3 are the two most prominent galectins involved in pathological processes. Galectin-3 in particular expresses in many different immune cells and modulates broad biological functions including cell adhesion, cell activation, cell growth, apoptosis, and inflammation.
Galectin-3 is unique among the other galectin protein subtypes as being the sole chimeric protein, being able to link in a five-sided pentamer (Figure 1). At a low concentrations, galectin-3 it is monomeric and acts to inhibit adhesion, but as galectin-3 increases in concentration high it forms large complexes that promote adhesion by bridging between cells and the extracellular matrix.
This ability to bind makes galectin-3 an attractive therapeutic target. For example, there seems to be a tight correlation between galectin-3 expression levels and various types of fibrosis, particularly in cases of liver fibrosis, renal fibrosis, and idiopathic pulmonary fibrosis (IPF). In animal studies with mice deficient in or lacking galectin-3, conditions that might normally cause mice to develop IPF, renal, or liver fibrosis either induced limited fibrosis or failed to induce fibrosis entirely. Companies have developed galectin modulators to block the binding of galectins to carbohydrate structures, offering a potential treatment for fibrosis.
Figure 1. Galectin-3 is the Sole Chimeric Galectin
From Sciacchitano S, Lavra L, Morgante A, et al. Galectin-3: One Molecule for an Alphabet of Diseases, from A to Z. Int J Mol Sci. 2018;19(2):379. Published 2018 Jan 26. doi:10.3390/ijms19020379
Research on Galectin-3 Has Exploded in the Past Decade
According to the PubMed database, over 3,800 research papers have been published on the galectin-3 protein over the past 30 years. This research has exploded over the past decade, with 2,700 papers published since 2008 (Figure 2).
Cancer emerged early on as a particular area of interest for galectin-3 research, as it is found in abundance in tumors and plays an important role in the progression of metastasis. Cancer was the focus of 37% of the papers on galectin-3 in 1998, jumping to 51% in 2008. While remaining a strong area of focus, cancer has dropped to represent on 29% of such papers in 2018, reflecting the growing interest in galectin-3 in other diseases.
Much of the growth in research over the past decade has been on the role of galectin-3 in heart and brain disease. From being mentioned in only 2% of the papers in 2008, galectin-3 in heart disease was the focus of 28% of the papers in 2018, nearly matching cancer at 29%. Brain (particularly stroke, related to heart disease) follows with 10% of the papers in 2018.
While cancer and heart hold nearly 60% share of the research publications on galectin-3, research continues on galectin-3 in liver, lung, kidney, gastrointestinal, and skin disease (Figure 3).
Figure 2. Papers Published on Galectin-3 Since 1989
Data source: PubMed
Figure 3. Research on Galectin-3 in 2018
Data source: PubMed
Overview of the Research on Galectin-3
Drilling into the search results in PubMed shows that research in some diseases and organs is more mature than others. In this case, PubMed’s “Most Relevant” search provided a useful tool for sampling the research being conducted around galectin-3 in a variety of different diseases. While looking only at the “Most Recent” search might skew results because periodical publication cycles might cluster similar articles together in an artificial way, the “Most Relevant” results cut across the past few years to present the most significant papers in each area, ones that have passed the first blush of peer review.
We looked at the first 20 “Most Relevant” papers in each area to determine what specific areas and questions were being explored by researchers.
There have been 185 papers published on galectin-3 in the PubMed database. Looking at the top 20 Most Relevant papers, galectin-3 has an outsized role in non-alcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), and cirrhosis. Over half of the top 20 papers (11 of 20) dealt with one or more of those topics. Research was exploring the role (8 of 20) that galectin-3 plays in liver inflammation, fibrosis, and overall liver injury. Most of the research on its role found it regulates important processes (4 of 8), but it also activates in other circumstances. Galectin-3 was a potential target or biomarker in 4 of the 20 papers. It was also seen as playing a role in liver cancer and Hepatitis-B.
As discussed, the role of galectin-3 in cardiovascular disease is a strong area of research. There have been 622 articles published, and 603 of them have been published since 2008. The top 20 “Most Relevant” papers suggest research in galectin-3 in the heart concentrates on its potential as a biomarker for damage in heart failure, stroke, and other cardiovascular diseases, both acute and long-term (9 of 20). At this time, it is being explored more for its value in predicting patient outcomes than as a potential target for treatment.
Research in kidney disease seems less mature than other areas. There are 211 articles on galectin-3 and kidneys in PubMed. Like with the heart, interest in galectin-3 in the kidneys focuses on its potential as a biomarker in chronic kidney disease (6 of 20), but much more of the research simply seeks to understand the role that galectin-3 plays in kidney disease (8 of 20), especially fibrotic disease and decline in kidney function. Much of the research explores the interrelation between heart health and kidney disease. There are hints that galectin-3 plays a protective role in infectious diseases affecting the kidneys.
There were 109 articles in PubMed for gastrointestinal disease and galectin-3. The biggest interest in this area was cancer (7 out of 20, on gastric and colorectal cancer), with particular attention to galectin-3’s role in metastasis and its suppression of response to chemotherapy. Four of the papers explore galectin-3’s potential as a biomarker for prognosis and response to treatment. There was also a minor focus on ulcerative colitis (3 of 20) and other inflammatory diseases. Much of the research is still focused on animal studies (6 of 20) and the role gal-3 plays in the body, suggesting that our understanding in this area is still at a relatively immature, basic level.
The brain and central nervous system are emerging as major areas of focus. There are 350 articles in PubMed on this topic area, 304 of which were published after 2008. Some of this is no doubt due to the impact that cardiovascular events such as stroke have on the brain. There was strong interest in galectin-3’s potential as a predictive biomarker (9 of 20) for poor outcomes in strokes. Immune response and inflammation are a concern. Five papers dealt with galectin-3’s involvement in traumatic brain injury (TBI). There was a strong connection seen between pulmonary hypertension and heart failure. One intriguing paper explored the serum blood levels of galectin-3 in women suffering delirium postpartum.
Skin is a relatively immature area of research. Only 127 articles appear in PubMed. There are a wide range of areas being explored in the top 20 results, including wound healing, infection, lupus, psoriasis, and cancer. Thirteen of the papers explore the role of galectin-3 in these disease processes. Only two papers were looking at galectin-3 as a potential biomarker.
Over 1500 papers in the PubMed database deal with galectin-3 and cancer. Galectin-3 plays a role in a variety of cancers, with papers being published on its involvement in cervical, breast, endometrial, pancreatic, thyroid, colorectal, and skin cancers. Eight of the top 20 “Most Relevant” papers discuss its potential as a biomarker, while 10 are simply trying to understand its role in the progression and metastasis of tumors. Research has recently explored the role of galectin-3 in the success or failure of immunotherapy in treating cancer.
There are around 200 papers on galectin-3 and the lungs in the PubMed database, 140 of these since 2008. Cancer is a big area of focus in the lung (8 of 20). Fibrosis follows (5 of 20). While galectin-3 is being researched as a potential biomarker in many other organs, research in the lung is still trying to understand the role of galectin-3 in disease (16 out of 20 focused on its role, versus 2 papers on galectin-3 as a potential biomarker or a target).
Pharmaceutical Research and Development
Just as basic medical research on galectin-3 has exploded over the past 30 years, so has research and development in pharmaceutical companies looking to leverage galectin-3 as either a biomarker or a target in a marketable therapy. Given the key role that galectin-3 plays in a broad range of diseases, it makes an attractive therapeutic opportunity, as diseases such as organ fibrosis, cancer, and heart disease affect billions of people across the globe.
Drug development also parallels the published literature in another important way. Many of the companies are still in the very early stages, either in Discover or Pre-clinical phases, trying to understand the role that galectin-3 plays in disease processes and how to target in a way that halts or reverses disease processes. Drug development is promising, but most companies have a long way to go. Galecto Biotech and Galectin Therapeutics are among the few that have progressed into human trials, even to Phase 2 and Phase 3.
Table 1. Companies Developing Galectin3 Inhibitors
|Liver||Galectin Therapeutics||NASH cirrhosis||Phase 3|
|MandalMed, Inc.||Liver fibrosis||Pre-clinical|
|Heart||G3 Pharmaceuticals||Diastolic heart failure, also known as heart failure with preserved ejection fraction or HFpEF||Pre-clinical|
|MandalMed, Inc.||Prevent and treat harmful remodeling after myocardial infarction||Pre-clinical|
|Kidneys||Angion Biomedica||Primary focal segmental glomerulosclerosis (FSGS), a form of chronic kidney disease||Pre-clinical|
|Skin||Galectin Therapeutics||Psoriasis, Atopic dermatitis||Phase 2|
|Cancer||Galectin Therapeutics||Combination immunotherapy therapy with KEYTRUDA in advance melanoma and head and neck cancer||Phase 2|
|iTeos Therapeutics SA||Immunotherapy||Discovery|
|Lung||Galecto Biotech/BMS||IPF (idiopathic pulmonary fibrosis)||Planned Phase 2/3|
The research into the role that galectin-3 plays in many major human diseases is promising. Interest in galectin-3 has exploded over the past 10 years, exploring its role in cancer and heart disease in particular, with brain, kidney, lung and liver also getting attention. Drug development has progressed the farthest with fibrosis in both the liver and the lungs, though cancer immunotherapy and heart disease are also being targets for drug development.
Galectin-3 is likely to remain an important area of focus for medical research, as we come to understand its role in disease process and how we can use its presence as a biomarker for disease progression or a target for effective therapies.
About Harold Shlevin
Harold H. Shlevin, Ph.D., is the president and chief executive officer of Galectin Therapeutics, a leading developer of therapeutics that target galectin proteins. Galectin Therapeutics is launching a Phase 3 clinical trial of its belapectin galectin-3 inhibitor in the treatment of nonalcoholic steatohepatitis (NASH) with cirrhosis. Belapectin is the first drug candidate to show evidence of therapeutic effect in NASH cirrhosis in a Phase 2 clinical trial.
Reference from source: www.pharma-iq.com