Understanding the viruses that kill cancer cells

Taking inspiration from virology to find better treatments for cancer

There are some viruses, called oncolytic viruses, that can be trained to target and kill cancer cells. Scientists in the field of oncolytics want to engineer these viruses to make them safer and more effective so they can be used to treat more people and different types of cancers. To achieve this, they first have to fully understand at the molecular level all the different ways that the virus has evolved to infect healthy cells and cause disease. A research team from Cardiff University set out to better understand how a protein on the surface of a virus often used to kill cancer, called an adenovirus, binds to human cells to cause an infection. Using X-ray crystallography, the team was able to determine the structure of one the key adenovirus proteins. Using this information and after extensive computational analysis, the research team realised the virus was not binding the receptor on the cells that was originally thought. This has important implications for the development of new virotherapies and engineering of viruses to treat cancer. The more thoroughly the researchers can understand how the adenoviruses interact with cancer cells at the molecular level, the more safe and effective treatments can be brought to clinical trial in the future. 

     

Studying viruses that kill cancer cells

Oncolytic virology is the study of viruses that target and kill cancer cells. There are a few naturally occurring viruses that do this, but since the 1960s many have been engineered in labs to target a variety of different cancers. There is a huge benefit to using viruses to fight cancer as they can unpick all of the surreptitious ways cancer cells evade other treatments. Firstly, viruses can be engineered to target cancer cells very specifically which minimises adverse effects around the body. Once they seek out cancer cells, they infect and replicate within them, killing the cell and releasing thousands more viruses to kill the rest of the tumour. The virus is therefore able to spread within the tumour to neighbouring cancer cells which is often difficult for cancer drugs. In effect, the viruses act as a cancer treatment that can self-amplify at the site of the tumour.

One virus family that is often used in oncolytics is the adenovirus family. Alex Baker, a PhD student from Cardiff University who recently carried out experiments at I04, is studying understudied types of Adenovirus. He explained that:

They are rarely occurring which means people don’t often have pre-existing immunity to them.

This is important in oncolytics where previous exposure to the virus can often result in the immune system rapidly recognising the virus as foreign and eliminating it, rendering the treatment useless.

Using crystallography to establish how viruses infect cells

Rare viruses don’t represent a significant healthcare burden and so haven’t been a research priority until now, however they can make good candidates for Oncolytics which has renewed scientific interest in these rarely isolated viruses. Before using a virus as a treatment, it is important to know how it is going to behave, and many potentially useful viruses are poorly understood on account of being rare. So, it us up to researchers like Alex and the team of researchers led by Alan Parker at Cardiff university to better understand these viruses.

The entire article published in Nature Communications started as a side project for Alex. He began making some protein crystals of adenovirus proteins which were worked on previously in the lab. The idea was to use the structural outputs to help understand which receptors they were binding to on host cells. The purified proteins from the viruses were prepared as protein crystals and put to one side leading up to a trip to Diamond and the I04 beamline. The main purpose of the trip was to examine proteins from a different experiment, and everything was ready for a productive shift, but unfortunately, nine hours in, hardly any of their samples generated results. After a lot of frustration, the team turned to Alex’s side project and put it into the X-ray beam. To their delight, they generated some of the best diffraction data the team had ever seen. The mood improved a lot and the team went on to collect more diffraction data.
 

Changing the status quo in the field of viral vaccines

After returning to Cardiff, the data analysis really started. The first thoughts were that the structure would be published on its own in a small paper, but Alex had other ideas. He wanted to use the structural data to try and work out how these rare viruses were infecting cells. Alan Parker suggested that he investigated the protein CD46. Alex modeled interactions between their new adenovirus fiber-knob protein and CD46 in order to investigate whether or not CD46 could be used as a receptor. A vaccine based on this rare adenovirus is under late phase clinical trials  and was assumed to bind the CD46 receptor to enter cells and produce proteins to generate an immune response. After painstakingly crunching the numbers, the team were surprised to discover that there could be no interaction with CD46 at all. The computational results were backed up by binding studies using Surface Plasmon Resonance which is a gold standard technique for measuring the binding of two molecules.
 
The findings in this paper have broad clinical significance as well as being important for the research field. Using X-ray crystallography, computational modelling and surface plasmon resonance, the experimental results showed that there was no binding to the receptor that was previously thought essential for infection. While specific molecular interactions are not known for many oncolytic viruses, elucidating them correctly can help to optimise treatment using those reagents and improve the prognosis for patients.
 
This work also opens the door for future engineering approaches when it comes to oncolytics. Alex Baker explained:

If we know how the viruses work, we can either make them do it better, or stop them doing it altogether.

The idea is that by understanding the molecular detail of all components that make up an oncolytic therapy, then we can engineer them to be more effective and safer.

To learn more about the I04 beamline, or to discuss potential applications, please contact Principal Beamline Scientist Ralf Flaig: ralf.flaig@diamond.ac.uk

Related Publication:

Baker, A.T., Greenshields-Watson, A., Coughlan, L., Davies, J.A., Uusi-Kerttula, H., Cole, D.K., Rizkallah, P.J.,Parker, A.L.. Diversity within the adenovirus fiber knob hypervariable loops influences primary receptor interactions. Nature Communications. 10.Article number: 741. https://doi.org/10.1038/s41467-019-08599-y (2019)