Replumbing cancer – how to teach a new drug even newer tricks

Tumours often have dodgy plumbing

Rakesh Jain, Professor of Tumour Biology at Harvard Medical School, has a somewhat controversial viewpoint, which he spoke about at this year’s NCRI Conference.

He thinks scientists may have got the wrong end of the stick about angiogenesis inhibitors – relatively new cancer drugs that are designed to block the growth of blood vessels in tumours. If he’s right, it could mean that the drugs’ success to date has been no more than a happy accident, and their full potential for treating cancer is yet to be unlocked.

Moreover, they could also be used to treat a range of other blood-related diseases, from heart disease to some forms of blindness.

Cancer – a ‘rogue organ’

It is a mistake – and an over-simplification – to think of a tumour as just a lump of rapidly growing cancer cells, stemming from a single faulty ‘parent’ cell. In reality, a tumour is more like a small, dysfunctional organ, composed of an unruly mish-mash of normal body cells, cancer cells, immune cells, lymph vessels and – fuelling it all – a chaotic, disordered network of blood vessels.

Over the last few decades, scientists have come to understand in great detail just how messed up a tumour’s blood supply is. Molecular studies have revealed that tumour blood vessels are fundamentally different from the ‘normal’ capillaries that feed our healthy tissues.

And new imaging techniques have shown that, rather than an ordered array of pipes, a tumour’s plumbing looks like it was done by the worst sort of cowboy builder.

Dodgy plumbing

As a result, this means that the blood flow round a tumour is patchy – some areas have incredibly high blood pressure, blocking the diffusion of cancer drugs out of the blood and into cells. Other bits have virtually no supply at all, and become ‘hypoxic‘ – again, meaning they’re difficult to attack with most cancer treatments.

So researchers have tried  to use this knowledge to their advantage. If this plumbing is so radically different, they reasoned, it should be unique enough to target with drugs, cutting off a tumour’s blood supply and starving it of nutrients.

Decades of research in this field duly yielded a plethora of new agents designed to target tumours’ supply lines, and some of these, like Avastin, were shown to work in clinical trials and are now used to treat some patients routinely.

Except, according to Professor Jain, they don’t cut off a tumour’s blood supply at all.  He suspects that these drugs work in completely the opposite way – actually repairing the dodgy plumbing, rather than ripping it out.

This, he says, should allow cancer drugs to penetrate deep inside the tumour. It also explains the fact that angiogenesis inhibitors don’t seem to be that effective on their own – they work best when given with chemotherapy.

And he’s got evidence. Using cutting edge molecular imaging techniques, his lab has shown that the blood vessels inside tumours treated with drugs like Avastin actually start to look more ‘normal’, rather than being destroyed.

What does it mean?

There are two important conclusions from this view.

Firstly, it suggests that there’s a ‘window of opportunity’ that arises inside a tumour after a patient is given an angiogenesis inhibitor, when the blood vessels have become the most ‘normal’ and standard chemotherapy will be most effective. Professor Jain is carrying out studies to work out long this window is open for.

Secondly, it means that these drugs might not need to be given constantly – they might just be worth giving intermittently. This, in turn, means two things. Angiogenesis inhibitors can have unpleasant side-effects, and people sometimes have to stop taking them. If they only had to take infrequent doses, the side-effects could be much less uncomfortable.

It also means using less of the drug. And given that these new generation of cancer therapies are extremely expensive, finding out how them sparingly yet effectively, so that health service budgets aren’t hit so hard, is hugely important.

Professor Jain’s ideas aren’t yet widely accepted, but if he’s proven right by further research, we may have developed a more potent weapon against cancer than we thought.

Henry