Through the eye of a needle: Molecular immunology and anti-cancer drugs
Finding drugs that can target cancer cells but leave healthy cells unharmed is an ongoing problem in cancer research. At the University of Oxford, Professor Terry Rabbitts is exploring ways to create targeted drugs that work by blocking blood cancer proteins from interacting with healthy proteins – and the technique he’s developed for making these drugs could also have an impact on many other diseases. Read on to find out more…
Inside every cancer cell, one or more proteins are no longer working properly thanks to errors in the genes that provide the instructions to make them. These cancer proteins can then interact with proteins made by other, healthy genes, and prevent them doing their jobs, like the proverbial bad apple ruining the whole barrel.
“Many cancer proteins work inside cancer cells by binding to other proteins. By stopping this from happening, we can stop cancer cells growing, or even kill them off,” says Terry Rabbitts, Professor of Molecular Biology in the MRC Weatherall Institute of Molecular Medicine at the University of Oxford.
Blocking the cancer proteins from interacting with healthy proteins is therefore a promising prospect for treating cancers – but this is a difficult problem because it can be very tricky to get a drug that is capable of blocking interactions between proteins a cancer cell. One way to block these interactions is by using antibodies, parts of the body’s immune system that are good at recognising disease and can ‘tag’ cells or bacteria for destruction. Unfortunately, antibodies are fairly large molecules, so because of their size it is a struggle to get them into a cell.
Just like a thread will only go through the eye of a needle if it’s small enough, a molecule can only enter a cell if it’s small enough
Professor Rabbitts’ goal, therefore, is to make a smaller molecule that does the same job as an antibody. In his most recent research, carried out in collaboration with colleagues around the world and published in Nature Communications, he has been developing a way to make drugs small enough to enter cells and prevent cancer proteins interacting with healthy proteins.
Breaking down antibodies
Antibodies are Y-shaped molecules made up of several sections, as shown in the diagram below. The small yellow parts are called ‘antigen binding regions’, which are capable of recognising and attaching to molecules belonging to invading diseases, or to unhealthy cells that need to be killed. The larger green part of the molecule determines exactly what response the immune system will make once the antigen binding regions have attached to the cell. Getting the whole antibody into a cell is, as we already know, very difficult – but the antigen binding regions are much smaller.
The Y shape of an antibody, with antigen binding regions (the parts that recognise and bind to diseases) in yellow.
Unfortunately, these smaller molecules which make up just the antigen binding regions also cannot readily get inside the cell, but they are useful in identifying even smaller molecules that could get inside the cell to block cancer proteins.
Antigen binding region versus drug
Professor Rabbitts and his collaborators focused on blocking the action of a group of cancer proteins called ‘RAS’, which are affected in many different human cancers including acute lymphoblastic leukaemia and acute myeloid leukaemia, as well as cancers of the lung, pancreas and colon.
In earlier research, they had already identified an antigen binding region (i.e. the yellow part of the antibody in the picture) that was known to block proteins in the RAS family. This time, they used that antigen binding region to find other small molecules that could also block the proteins, in a technique called a competition assay. In the competition assay, a small molecule that is being tested as a potential drug is released into a liquid containing the RAS protein, along with the antigen binding region that is known to bind to the RAS protein. The new small molecule and the antigen binding region compete with each other to bind to the RAS protein. The antigen binding region can bind very tightly to the RAS protein, so small molecules which bind to the same region lose out in this competition – these ‘losing’ molecules are likely to make the best drugs because they are extremely well targeted to the specific protein and therefore have few side effects.
The competition assay technique allowed the researchers to find the most highly targeted drugs for a particular protein
Using this technique, the team have identified a group of molecules that can bind to RAS, which could be developed into drugs. The research is still in its early stages, however. “Next, we need to perfect these potential drugs so that they are more potent and less toxic,” says Professor Rabbitts. “We want to make sure that low doses can be used to produce a highly effective therapy with very low side effects. Eventually, we hope that the drugs will benefit people with RAS mutations in their cancer.”
Excitingly, as well as providing a potential new treatment for the multiple different cancers that involve the RAS protein family, the team’s technique can be used to find molecules that can specifically target other proteins involved in cancer, or proteins that are key to infection or inflammatory diseases.
“Drug development can be a difficult process because one doesn’t know where to start on the disease target,” Says Professor Rabbitts. “Using the binding sites of antibody fragments, we can pin-point the starting point to kick-start small molecule drug development.”
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