The development of angiogenesis inhibitors as potential treatments for cancer - i.e. inhibiting growth of a tumour by disrupting the blood vessels that supply it - has been ongoing for more than a decade, but it is only recently that candidate drugs have made it through to late-stage clinical trials.
The discovery that blood vessel lumens (the space within the blood vessels) of the tumour can contract in response to increases in pressure has lead to the theory that is ripe for exploitation by existing and new cancer drug treatments. Equivalent sized blood vessels in healthy tissue are unable to do this.
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 findings from the University of Louvain Medical School was revealed at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Switzerland.
Dr. Olivier Feron, lead researcher in the study said: "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."
"The effect of ET-1 in tumours has been underestimated up to now. ET-1 has been known for years in cardiology as a very potent blood vessel constrictor, Dr. Feron said."
"We found that the myogenic tone (mechanical force) with which the tumour blood vessels contract and expand is exquisitely dependent on the endothelin pathway."
The team's strategy of research used an endolthelin antagonistin, a cyclic peptide called BQ123, to target selectively one of the ET receptors, ET-A, that was 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.
They were able to demonstrate increased blood flow to the tumour but that healthy tissue was not affected. Furthermore they were able to demonstrate that administering BQ123 could significantly increase the delivery of the anti-cancer drug cyclophosphamide to the tumour.
Tumour response to fractionated radiotherapy was also improved significantly because the increased blood flow carried more oxygen to the tumour.
Feron said the team were 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 added.
While the research in mice was early days and potentially promising the concept 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.
This latest discovery could herald the latest generation of cancer treatments signifying its overall importance. The original concept of treating cancer by blocking angiogenesis was first put forward in the 1970s by Judah Folkman, then a professor of surgery at the Boston Children's Hospital in the US,
Since then, dozens of compounds designed to treat cancer by blocking angiogenesis have entered into development and failed, including endostatin and angiostatin which were originally discovered by Folkman and abandoned by licensee company EntreMed in 2002.