A revolutionary approach to angiogenesis by a team of Belgian researchers could make cancer treatment more effective at killing tumours.
Dr. Olivier Feron and his team from the University of Louvain Medical School in Brussels have turned the whole concept of targeting tumour blood vessels on its head. Instead of the conventional approach of trying to starve tumour cells of the blood supply they need to grow, they are doing the opposite – opening up the tumour blood supply to allow better access for cancer drugs and more effective radiotherapy.
The potential for exploiting tumour blood vessels has been made possible by their discovery in a study in mice that the arterioles (blood vessels less than 0.5mm in diameter) that feed tumours have the ability to contract in response to increases in pressure within their lumen (the space within the blood vessels). Equivalent sized blood vessels in healthy tissue can’t do this.
"What this means is that we may have the potential to use drugs to selectively exploit these blood vessels against the tumour instead of, or before, killing them. Exploiting tumour blood vessels instead of destroying them by anti-angiogenic drugs constitutes a paradigm shift in approach to angiogenesis," Dr. Feron told a news briefing today (Thursday 30 September) at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics.
The key to the ability of tumour arterioles to contract lies with endothelin-1 (ET-1) a peptide released in large amounts by many tumour cells, which stimulates their proliferation.
"The effect of ET-1 in tumours has been underestimated up to now," Dr. Feron said. "ET-1 has been known for years in cardiology as a very potent blood vessel constrictor. Here, we found that the myogenic tone (mechanical force) with which the tumour blood vessels contract and expand is exquisitely dependent on the endothelin pathway.
"What we did was to use a an endolthelin antagonist – in this case a cyclic peptide called BQ123 – to target selectively one of the ET receptors, ET-A, that we found was particularly dense in the tumour arterioles. This peptide completely wiped out the ability of the arterioles to contract and kept them wide open. We were able to demonstrate, using laser doppler probes and imaging that this increased blood flow to the tumour but that healthy tissue was not affected. We were then also able demonstrate that administering BQ123 could significantly increase the delivery of the anti-cancer drug cyclophosphamide to the tumour. Furthermore, tumour response to fractionated radiotherapy was also improved significantly because the increased blood flow carried more oxygen to the tumour."
Dr. Feron, who is an assistant professor and research associate in the Department of Internal Medicine at the University of Louvain, said that the team was now planning to start Phase I clinical trials in patients. "The chances for this anti-tumour adjuvant therapy to be well tolerated are high as ET-1 antagonists would be used acutely to produce an immediate effect on the tumour blood vessels – i.e. given at the same time that the chemotherapy or radiotherapy is administered."
He said that although the research was in mice and that it was early days as the concept still had to be proved in patients, the principle of keeping tumour arterioles open to boost responses to treatment should work in the many tumour types where ET-1 was expressed.