Robert Gilbert: Targeting cancer mechanisms

Q: What can structural biology tell us about cancer?

RG: Cells in our bodies are kept in control both by external contact and also by switching mechanisms which are internal to them. Structural biology allows us to look in atomic detail at the molecules - mostly proteins - which are responsible for those external contacts and switching mechanisms inside.

If we can understand those atomic structures, we can come up with ways of understanding the mechanisms that those proteins use, and then we can come up with inhibitors or other molecules that can moderate how they act, and which therefore give us new therapeutic lines to follow.

Q: What is the specific problem you are working on?

RG: The set of signals we are working on are internal signals to the cells. They are actually made of RNA, a copy of parts of the DNA inside our nuclei. These RNA signals control the switching of a whole set of proteins associated with cancers.

We are looking at the enzymes which regulate how those signals are matured and how long they persist. If we can come up with a way of inhibiting proteins which stop them continuing to have their effect, we can come up with a new way of approaching cancer therapy that hasn't been tried before. This is undercutting some of the other therapies we already have by switching off protein production at a very basic level, rather than trying to inhibit the proteins that we already know are involved in cancer, such as a variety of receptors and enzymes.

Q: How might your research change the treatments?

RG: Our research might change the treatments because currently, for example, a well-known drug is Herceptin that targets a protein called HER2. There are other drugs which target proteins, for example one called Bcl-2 which is involved in blood cancers; another one which we have inhibitors for is called cyclin D.

Those are downstream, as it were, of the process that we are targeting. We are targeting a process which would stop Bcl-2, HER2 and cyclin D being made, and a host of other proteins which are involved. The result could be a game changing approach to cancer therapy because rather than targeting what we call the phenotype (the expression of a particular kind of characteristic in a cell), it is targeting a very fundamental aspect of cell biology.

Q: What are the most important lines of research that have emerged in the last 5-10 years?

RG: In my particular area, I would say the most important new development is the fact that we have come to the understanding of these RNA signals controlling what we call stem cell biology.

Many people have heard of stem cells; cancer stem cells are a particular subtype of stem cells that are important both in cancer spread and its development. The more serious a cancer is the more likely it is to have cancer stem cells involved. We work on the mechanisms underlying the occurrence of cancer stem cells in the first place. For the particular area that we are addressing, we now understand the way in which particular subsets of these RNA signals, which are called let-7 microRNAs, target the production of proteins generating stem cell-like characteristics.

As you can see it is an undercutting of the basic biology of the cancer: rather than allowing the cancer to spread and develop as it wants to, we are cutting off its capacity to adapt to the environment in which it finds itself and to cause disease in distant parts of the body. That is of course the most serious thing with cancers: most people die of cancer spread, of metastasised cancer, rather than the primary tumour which we first identify.

Q: Why does your research matter and why should we fund it?

RG: I think my research matters because it has the capacity to provide an atomic resolution understanding of how mechanisms controlling cancer act, but it also has the capacity to deliver novel approaches to therapy and novel inhibitors which would give us a new way of targeting not just one cancer but several different cancers with the same kind of treatment. In fact the therapies that we are pursuing are important for a number of what we call counters of unmet needs. One we are particularly focusing on is non-small cell lung carcinoma, but it's also relevant to cancers such as pancreatic cancer and forms of brain tumour which are very hard to treat, as well as a host of other cancers including breast cancer and intestinal cancer. It is appropriate to a lot of different cancers and that is what is interesting and what I think gives us a funding priority, if you like. It gives us a basis for justifying the funding that we receive because we are taking this new kind of approach. It could have a much wider spread than the kind of therapies that are developed to target just one kind of cancer or another.

Q: How does your research fit into translational medicine within the department?

RG: Our translational contacts within the department, and indeed within Oxford in general, have been extremely important. We have had an excellent partnership with the Target Discovery Institute: in partnership with them we have been able to develop new lines of research for them as part of our collaboration, and it has been of great help for us to be able to access their expertise. At the same time we have also been working with colleagues in Oncology who have particular expertise in lung cancer, and can help us in cell testing of inhibitors that we identify. We feel that with our Cancer Research UK funding, relating to the Target Discovery Institute, also in partnership with Cancer Research Technology - the CRUK drug discovery company - we are well placed to translate our work towards the clinic in an effective way.