The interface between signal transduction and transcription regulation coordinates gene expression. Deregulation of transcription is a key factor in cancer. Professor Colin Goding studies how a precise programme of transcription regulation is achieved, particularly in the transition between normal and cancer stem cells, and the parallels with normal stem cell populations.
Melanoma or skin cancer is one of the fastest rising cancer types. When identified early, melanoma is relatively easy to cure, but once it starts to metastasise, it becomes very difficult to treat. Treatments rapidely induce drug resistance. However, recent research has shown that within a tumour, it is possible to change drug resistant cells to drug sensitive cells, opening possibilities for new therapies.
Ultimately, medical research must translate into improved treatments for patients. At the Nuffield Department of Medicine, our researchers collaborate to develop better health care, improved quality of life, and enhanced preventative measures for all patients. Our findings in the laboratory are translated into changes in clinical practice, from bench to bedside.
Q: How common is melanoma?
Colin Goding: There are about 13,000 new cases per year in the UK and about 100,000 throughout Europe. Over the last 40 years, the instance of melanoma has doubled every 10 years: it has one of the fastest rising incidence. The good news is that if you detect it early enough, you can just cut it out and that is an effective cure. The bad news is that if it spreads to other parts of the body, i.e., it metastasises, it becomes very difficult to treat.
Q: How does melanoma develop?
CG: It is pretty clear that the major trigger for melanoma is damage to DNA in the skin from ultraviolet light, from the sun. It correlates best with sunburn, especially sunburn that you might get in childhood.
But not all melanomas are derived from sun-induced DNA damage. There are some melanomas that you may get on non sun-exposed sites: for these, we do not really understand the cause. The vast majority are preventable and are caused by damage to DNA in the skin caused by the ultraviolet light from the sun.
Everybody who has been sunburnt knows exactly what that means: you get initial redness which may go away after a few days. The peeling afterwards represents the cells in the skin that have undergone so much DNA damage they have kind of committed suicide: this is one of the major protective mechanisms against getting cancer. Unfortunately some cells, melanocytes, may get enough DNA damage and instead of dying may get just the right kinds of mutations to trigger the onset of the disease, melanoma.
Q: What are the most important lines of research that have developed over the last 5-10 years?
CG: I think the most important is understanding the full repertoire of genes that are implicated in melanoma. As you get damage from ultraviolet light, certain genes have to be mutated for that disease to occur. The analogy would be a car: for it to go forward, you need to get off the brake and push on the accelerator. That is exactly what damage to DNA in the pigment cells does: it inactivates the brake and activates the accelerator which makes the cell divide. This has to happen in a particular order. If you just inactivate the brake nothing much happens on its own. And they have to be done in combination.
Over the past 12-15 years we have identified, in research across the world, the full repertoire of all those mechanisms that cause this disease, all the genes that we think are really important. That gives you great opportunities for targeting those damaged genes to develop new therapies to combat the disease.
Q: Do different melanoma types respond differently to treatment?
CG: That is one of the lessons that have come out of this research. By understanding the full repertoire, we know that certain melanomas, for example those in the eye, do not have the same mutated genes as some of those in the skin. We also know that some melanomas from the skin that are found in patients who worked outside and were chronically sun-exposed are different from those that got childhood sunburn. You would want to treat people differently based on different genetics. We have identified an 'accelerated pedal' gene called BRAF in 2002. If you target this gene, you get a very effective therapy, but it is no good using that drug for patients who do not have that mutation. So we have to choose which subsets of melanoma you want to deal with, with which drug combinations.
Q: What does your line of research matter and why should we fund it?
CG: What we are really interested in are the mechanisms of resistance to drugs. Unlike previous chemotherapies that came with a lot of side effects (everybody knows that people who get chemotherapy tend to have their hair fall out, they feel unwell and so on), BRAF therapy is much more targeted. That’s what all of us in cancer biology/cancer therapy are really interested in: how do we get drugs that target in a very specific way with as few side effects as possible?
However, even with these targeted therapies that are extremely effective in the short term, within some months you get resistance. So the question is: what are the mechanisms of resistance and what can we do about it? Are there 'accelerator pedal' genes getting mutated and bypassing the blockade of the first drug?
What we are more interested in is a different kind of mechanism where some cells have different characteristics within the tumour because they are exposed to different levels of hypoxia (oxygen levels) or different levels of nutrients. It is as if they adopt different personalities depending on their environment and some of those are drug resistant. We have worked out that this is very dynamic and reversible, and we can therefore identify drugs to switch cells which are drug resistant to cells which are drug sensitive.
Q: How does your research fit into translational medicine within the department?
CG: What is important there is to try and take our observations that we have built upon as scientists over the last 30 years to the clinic. We are very aware that the ultimate aim of any scientist is to do their work for patient benefit. What we have been able to do in recent years is based on the understanding that cells can switch their characteristics from drug sensitive to drug resistant and back again. Can we direct these drug resistant cells to drug sensitive cells?
What we have done in collaboration with groups in Spain and more recently with the National Institute of Health in the United States is identify ways in which we think we can do that in some model systems. It looks like it is going to work and at the moment we are trying to work out the best way to deliver these news drugs to patients: what is the best way to take the drugs? Is it a pill? Is it an injection? What are the side effects? Are there problems with toxicity? Once we have all of that done, I think we will be in a much better position to know whether we can get this drug into the clinic to treat patients with what are currently drug resistant melanomas.