You would think the worst thing you could do to a cancer patient is to “feed” their tumour. Yet drugs that improve the blood supply to tumours can help hasten their destruction, new research has shown.
The hope is that by giving the drugs to sufferers as a pre-treatment, it will make their cancers more vulnerable to subsequent chemotherapy or radiotherapy.
The strategy has already had some success in patients with pancreatic cancer, and a larger trial is planned now that the mechanism by which it works has been demonstrated in mice.
Oxygen attack
The drugs work by repairing and improving the quality of blood vessels supplying tumours with blood.
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Most tumours have blood supplies that leave parts of the tumour starved of oxygen, or “hypoxic”. The vessels are also leaky, stopping chemotherapy drugs penetrating deeply enough to kill the growth. The hypoxic regions also promote the genesis of the most malignant types of cancer cells, as they have to be hardier to survive the suffocating conditions.
This means that tumours well supplied with oxygen are actually more vulnerable to chemo- or radiotherapy, and researchers have for years sought ways to make use of this fact, including putting patients in oxygen chambers.
Now four drugs have been found that have the potential to weaken tumours in as little as three days by improving their oxygen supply.
Twin approach
The finding is counterintuitive because many new cancer drugs aim to do the exact opposite and cut off tumours’ supply of blood. However, the researchers involved say the two strategies are complementary.
“You could use drugs that improve blood supply to get a bigger bang for your buck from chemotherapy, then when the tumour has shrunk to almost nothing, finish it off with a drug that cuts off its blood supply,” says team leader Gillies McKenna of the Gray Institute for Radiation Oncology and Biology at the University of Oxford.
McKenna and his colleagues had already identified a four-stage gene pathway by which cancer cells became oxygen-starved. So they gave mice cancers and treated the tumours with any of four different drugs they knew would block different stages in the pathway.
They found that the whole pathway, involving a gene often linked with cancer, Ras, could be aborted if any of the four stages was disrupted with the various drugs, called Iressa, Nelfinavir, PI-103 and L778123.
“We discovered that it doesn’t matter where you pick on it, as hitting any of those four stages will get rid of the pathway and get rid of the hypoxia,” says McKenna.
Vanishing glow
The team could tell when mice were no longer hypoxic because they marked a gene linked with oxygen starvation – called hypoxia inducing factor, or HIF – with a protein that would glow green if the gene was active. Sure enough, as the tumours became nourished with oxygen, the glow disappeared.
McKenna says that one of the drugs, Nelfinavir, had already shown benefit in 10 patients with advanced pancreatic cancer about to undergo chemo- and radiotherapy. Normally, he says, tumours would be expected to shrink to a size where they could be surgically cut out in only one of 10 patients, but in the trial, six of 10 were surgically removable after drug treatment. Also, scans showed that tumours in half the patients had lost their hypoxia.
Now, McKenna and his colleagues have begun a second, larger trial in Oxford, UK, which will treat about 50 patients, again with pancreatic cancer.
Journal reference: Cancer Research (DOI: 10.1158/0008-5472.CAN-09-0657)
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