Re-engineering viruses may improve cancer treatmentsZidbits dotcom

Bioengineers are taking inspiration from viruses to synthesise super-specific targeted vessels for chemotherapy drugs.

James Swartz and his team at Stanford have been re-engineering viruses to bring us closer to using virus-like particles in modern cancer therapy. They have added structures that enable a virus to bind to specific cancer cell markers, and have modified the existing structure to make it less likely to activate the body’s normal immune system. Four years ago, funding agencies said it couldn’t be done.

These findings highlight the potential for viruses to guide us towards the next big steps in drug therapies, in particular for cancer. As is widely known, current treatments such as chemotherapy and radiotherapy have many different side effects because they harm healthy cells in the process of destroying tumour cells. If treatments become even more specific, not only could they increase effectiveness, but they could also reduce the impact of side effects.

Most current cancer therapies rely on molecules which target a particular characteristic of tumour cells. Such characteristics include rapid growth, division and replication (sometimes leading to a lump appearing where it shouldn’t be), resistance to ‘self-destruct’ signals from other parts of the body, and the secretion of chemicals which change the cells nearby so that the tumour can invade or increase blood supply. Some side effects arise because other cells – such as hair follicles – also show rapid growth and replication. Hence why hairloss is a side-effect of cancer treatment.

These ‘hallmarks of cancer’ go hand-in-hand with chemical changes within tumour cells, and most importantly, changes in the cell membrane. For example, in stomach cancer, cells demonstrate marker-molecules on the surface called MS57A and MS57B that would not usually be present.

So modern cancer therapies target these markers. Antibodies are the cells that make you immune to a disease by being able to recognise foreign markers, and drug manufacturers can modify these highly specific cells to recognise cancer cells. The limitation? Antibodies lock onto the surface of the cells, but do not enter; rather, they may kick-start an immune response that ideally destroys the cell – but may also make you feel like you’re fighting off the ‘flu. This is sufficient for some cancers. Some types of lung cancer can be treated like this, for example.

A real breakthrough in targeted cancer therapy would be a treatment that can enter cancer cells – and only cancer cells. Cell membranes, however, are very good at allowing through only the things that should be going in and out. Only a small, uncharged molecule could possibly slip through the membrane without a channel. Again, this works for some cancers, such as chronic myeloid leukaemia. But viruses are up to a hundred times bigger than a small molecule. Nevertheless, they consistently succeed in invading cells and releasing viral genetic material inside.

What properties do viruses have that make them so useful for cancer research? In short, their self-assembling structure, the fact that they can be directed to the appropriate cells, and their ability to contain more protein – which is usually their genetic material, either DNA or RNA.

Self-assembly is highly useful. The protective protein coat that contains the genetic material is called a capsid, and consists of many proteins which interact with each other, attracting or repelling, to form a stable closed container. In the lab, it is possible to put individual capsid proteins alongside each other and wait for them to assemble into the recognisable virus structure. Bioengineers like Swartz and his team can therefore modify the capsid proteins, and then see how they actually function when assembled as one. When synthesised this way, they are called virus-like particles.

Natural viruses are not like antibodies, which target specific foreign bodies only. Rather, because they have to integrate into cell metabolism to replicate, they are usually specific to a species. In the lab, bioengineers can add tags to the structure – like address labels, determining which cell type can be entered, and thus where the virus-like particle will deliver its contents. Swartz and his team found that replacing the charged regions (that make viruses soluble) with ‘spikes’ not only reduced the chances of an immune response kicking in, but also provided a convenient point to tag with address labels.

Finally, the feature which makes all this bioengineering worth the effort: where viruses contain DNA or RNA, virus-like particles could contain chemotherapy drugs. The significance of such a highly specific delivery system could be huge for cancer research.

We’re not close to that yet; a lot more investigation needs to be done. The work in Stanford shows that virus-like particles can be engineered to be safe and useful vessels. The next step towards a viable cancer therapy will require further modifications so that the self-assembling capsid forms around a medicinal ‘package’. But the first step – showing that virus-like particles could be a feasible cancer therapy – has just been made.