Anti-angiogenesis drugs: why low doses could do more harm than good

Angiogenesis – the growth of new blood vessels– is a hot topic in cancer research.  Many scientists (including those funded by Cancer Research UK) are researching the process by which tumours ‘hijack’ blood vessels to feed themselves, and developing new treatments that can block it.

Some drugs, such as Avastin or Sutent are already being used to treat cancer patients, while many others are currently being tested in clinical trials. The results for some patients taking Avastin and Sutent have been good, but they don’t work for everyone.

And some of the even newer treatments being tested in clinical trials have shown surprisingly poor results, sometimes even encouraging the growth and spread of cancer (for example, papers published here and here).

As Henry blogged about last year, there is a great deal of controversy among scientists as to exactly how anti-angiogenesis drugs work, and how they should best be used to treat patients.

Today, new research from Cancer Research UK scientists provides a possible explanation for this confusion – it’s all about the dosage.

The drugs (sometimes) don’t work

Writing in the journal Nature Medicine, Dr Andrew Reynolds and his colleagues have been studying an experimental drug called cilengitide, which is not yet licensed for use in patients.

Cilengitide was designed to block molecules called integrins, which help blood vessel cells to stick together and move – an important part of the angiogenesis process. This idea is that blocking these integrins will disrupt the formation of new blood vessels, slowing the growth of tumours.

This theory was backed up by promising lab experiments, suggesting it could have potential as a cancer treatment.

But early clinical trials of the drug have not been successful. Although a few patients with brain tumours responded to high doses of cilengitide, it doesn’t seem to work in most people.  But why should the results from the lab be so different from the results in humans?

Checking the levels

The researchers tested the effects of different doses of cilengitide on tumours, ranging from very high to very low. Intriguingly, they found that very low levels of the drug actually stimulated the growth of cancers, rather than blocking it.

Further tests showed that very low doses of the drug didn’t have a direct impact on cancer cells grown in the lab. But when they were grown alongside blood vessel cells, low levels of cilengitide caused a boost in cancer growth.

Further investigation revealed that low doses of the drug were switching on a molecule called VEGFR2, which ‘turns on’ angiogenesis and causes blood vessel cells to move towards a tumour. This explains why low levels of cilengitide promote cancer growth, rather than blocking it.

So now we know that low doses of an alleged anti-angiogenesis drug can actually have the opposite effect, and stimulate blood vessel growth, what does this mean for cancer treatment?

Implications for treatment

These findings are important because it is very difficult to control the levels of a cancer drug in the body. When a patient is initially given a drug, its level in the blood rise quickly, providing a big dose of the drug to the tumour.  But after a while, the levels start to fall as the body deals with the drug.

In the case of cilengitide, Reynolds and his team found that even though they gave high doses of the drug, levels in the blood dropped very low in just a few hours – down to the amounts needed to stimulate the growth of cancer rather than block it.

At last, this goes some way to explaining the poor results of cilengitide in clinical trials, as well as those seen for other anti-angiogenesis treatments.

It’s worth pointing out that these are still only early results from the lab, and they don’t suggest that drugs that are currently being used to treat cancer patients (such as Avastin or Sutent) will encourage cancers to spread. But they do suggest why angiogenesis inhibitors don’t work for everyone.

Where now?

This sounds quite disheartening and frustrating, as a potential new cancer treatment turns out to have the opposite effect.  But at least now we know why, and can try and find out how to use these drugs more effectively.

For example, there are various techniques that allow doctors to give a continuously high dosage of a drug to a patient, which would mean that levels don’t tail off.  And maybe researchers can develop a way to quickly get rid of the drug from the body once the dosage stops, so it doesn’t hang around at low levels for a long time.

As we often see with science, even a negative result can send researchers on a new avenue of investigation. Sometimes, figuring out why something doesn’t work can be just as important as finding something that does.

Kat

Listen to Dr Andrew Reynolds talking about his research.

Download mp3 file, 1.19 mins, 1.3 Mb.

References:

Ebos, J. et al (2009). Accelerated Metastasis after Short-Term Treatment with a Potent Inhibitor of Tumor Angiogenesis Cancer Cell, 15 (3), 232-239 DOI: 10.1016/j.ccr.2009.01.021

Pàez-Ribes, M. et al (2009). Antiangiogenic Therapy Elicits Malignant Progression of Tumors to Increased Local Invasion and Distant Metastasis Cancer Cell, 15 (3), 220-231 DOI: 10.1016/j.ccr.2009.01.027

Nabors, L. et al (2007). Phase I and Correlative Biology Study of Cilengitide in Patients With Recurrent Malignant Glioma Journal of Clinical Oncology, 25 (13), 1651-1657 DOI: 10.1200/JCO.2006.06.6514

Reynolds, A et al (2009). Stimulation of tumor growth and angiogenesis by low concentrations of RGD-mimetic integrin inhibitors Nature Medicine DOI: 10.1038/nm.1941