New cellular imaging paves way for cancer treatment
A new technique using fluorescent imaging to track the actions of enzymes might aid drug design for new anti-cancer, inflammation and kidney disease treatments. Researchers at the University of York and Leiden University have published these findings in Nature Chemical Biology.
The imaging technique will also provide diagnostic tools for disease identification and allow medical professionals to measure the effectiveness of drug treatment regimes in an easy laboratory manner, the scientists hope.
New fluorescent imaging agents
The scientists studied heparanase – a key enzyme in the development and metastasis of human cancers. They unveiled new fluorescent imaging agents that detect heparanase activity in healthy and diseased tissues. The research builds upon previous work revealing heparanase’s three-dimensional structure. The new imaging agents are based on a probe that fits tightly in the heparanase active site, thus providing information about this enzyme.
Major drug target
Heparanase is a long-studied protein in human tissues involved in breaking down the complex sugars of the extracellular matrix – the material surrounding cells that provides structure and stability. It’s dysfunction is linked to the spread of cancers both through the breakdown of this matrix and via the subsequent release of growth factors – chemicals that promote tumour development. Gideon Davies, Professor of Structural Enzymology and Carbohydrate Chemistry at the University of York, said: ‘Heparanase is a key human enzyme. Its dysregulation is involved in inherited genetic disorders, and it is also a major anti-cancer target and increasingly implicated in kidney disease.’ For this reason, heparanase is a major drug target.
‘Our work allows us to probe the activity of heparanase in human samples – allowing early disease identification and a direct measure of the success of drugs in humans,’ says Gideon. ‘This work is a great example of the power of EU collaboration and science funding from the European Research Council.’
Powerful screening tool
Hermen Overkleeft, Professor of Bio-Organic Synthesis at Leiden University, added: ‘This work reveals the power of activity-based protein profiling. First, the probe described here enables screening for heparanase inhibitors from large compound collections, thereby helping the drug discovery process. In addition, the probe molecule is a lead compound for drug development in its own right. While the road to heparanase-targeting clinical drugs is long and fraught with risks, with this work we believe to have taken a major step in realising the therapeutic potential of this promising clinical target.’
Putting the probe to work
Overkleeft is already planning on using the new imaging agents in a joint study with LUMC-researchers Ton Rabelink and Bernard van den Berg. Rabelink: ‘We are interested in conditions in which heparanase is proven to be an important factor in inflammations and metastasis of cancers. For example, our attention goes out to the inflammation of the filtering units of the kidney, that can be found in numerous diseases such as diabetes.
We currently lack a good medicine to inhibit heparanase and thus intervene in these important disease processes. With the aid of the probe, we aim to develop new medicines. In our collaboration we will also deploy our models to test these medicines to eventually hopefully enter them into clinical trials.’
The probe might also be useful to identify patients with increased levels of heparanase activity, Rabelink adds, for example in a urine test. ‘This would be helpful in selecting patients who might actually benefit from heparanase inhibition.’
Activity-based probes for functional interrogation of retaining β-glucuronidases is published in Nature Chemical Biology and is supported by the European Research Council.