Our work focusses on the effect of hypoxia on cancer progression and the adaptive responses to hypoxia that are mediated by a transcription factor that we discovered called hypoxia inducible factor 1 or HIF1. So as the tumour grows the increased numbers of cells result in increased oxygen consumption and oxygen becomes limiting within the tumour. This induces the activity of HIF1 and then HIF1 activates the expression of genes that allow the cancer cells to adapt to the reduced oxygen availability. For example, the production of angiogenic factors that allow the tumour to develop blood vessels to increase oxygen delivery but also the expression of genes that promote cancer invasion and metastasis, the processes that ultimately kill the patient.
Does this affect the spread or growth of tumours?
Actually both, so by focussing on HIF1 we’re exploring both the processes that are required for the growth of the primary tumour and then also for the spread of the tumour throughout the body. As a result we think that targeting HIF1 for therapy may be a useful strategy and we’ve identified a number of drugs that inhibit HIF1 and that also block both primary tumour growth and metastasis in animal models. So one of the agents that we identified was a drug called digoxin that has been used for decades to treat heart disease. We found that it interferes with the accumulation of HIF1-alpha subunit within cancer cells. Again in animal models it’s very effective at limiting the primary growth of breast tumours and also the metastasis of breast cancer cells to the lungs and the lymph nodes. We’re just starting a clinical trial to study whether at the doses that digoxin can be given safely to patients whether it can effectively inhibit HIF activity in breast cancer.
Does more work need to be done investigating agents used to treat other conditions?
A number of people have put together libraries of all the existing drugs and this is several thousand. Screening these libraries has been very useful because any hits that come out are drugs that have already shown to be safe for use in patients whereas when people screen compound libraries, chemical compounds, they may find compounds that have the desired activity in cells but it turns out that those compounds cannot be transformed into drugs, that’s a major obstacle for development. So the advantage of screening existing drugs is that if there is a hit it can go right into clinical trials.
Will this also affect the approach to personalised medicine?
For example it has been possible to take tumour biopsies and look at the levels of HIF1 in the tumour biopsies and it’s been found that the people whose cancers have very high levels of HIF1 are at greatly increased risk of metastasis and mortality, even if they have a cancer that would otherwise be considered low risk. So this might identify a subset of patients with, for example, breast cancer who are at greater risk of developing metastatic disease and for whom more aggressive therapy would be indicated compared to the overall population.
