Paradox of cancer drugs gives clue to why some treatments fail

Cancer Research UK

Cancer Research UK funded scientists have found that some types of cancer drugs called angiogenesis inhibitors can encourage tumour growth rather than stunt it - according to research published in Nature Medicine* today (Sunday).

These drugs are designed to block the supply of blood to the tumour to prevent it from growing. This research focused on an experimental angiogenesis inhibitor called cilengitide that has not yet been licensed for patients.

The scientists based at The Institute of Cancer, Queen Mary, University of London**, the Institute of Cancer Research (ICR) and the Beatson Institute for Cancer Research found evidence to suggest that low doses of cilengitide in laboratory studies can have the opposite effect to what was expected and promote cancer growth***.

Study author, Dr Andy Reynolds, from the Breakthrough Breast Cancer Research Centre at the ICR, said: "Our study revealed a previously unknown mechanism through which drugs such as cilengitide behave. It showed that while higher concentrations of cilengitide can block angiogenesis, lower concentrations can actually stimulate the supply of blood to the tumour and can promote its growth. These results may explain why initial results from early stage clinical trials have not been as promising as hoped.

"Knowledge of this mechanism will help us develop new ways to make these drugs as effective as possible. In the future, we may be able to combine these inhibitors with other drugs to maximise their effectiveness for patients."

Dr Lesley Walker, director of cancer information at Cancer Research UK said: "Drugs redirect the body's complex signalling systems. Sometimes very subtle alterations to the way a drug is administered, or subtle changes to a drug's structure, can have a huge impact on its effectiveness.

"This study is important because it may help to explain the mixed results previously seen in patients and turn around disappointing results so people may still benefit from the drug without the potential harm."

"Other anti-angiogenesis drugs like sunitinib (Sutent) and bevacizumab (Avastin) have proven effective enough for use in the NHS but there is still need to understand why they can sometime fail. It may be that there are similar mechanisms at work."

ENDS

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To listen to an interview with Dr Andy Reynolds click here: http://media.cancerresearchuk.org/media/press/reynolds0309/Andrew_Reynolds_0309.mp3

Notes to Editor

*Stimulation of tumor growth and angiogenesis by low concentrations of RGD- mimetic integrin inhibitors. A Reynolds et al. Nature Medicine. March 2009.

**The study was led by Dr. Kairbaan Hodivala-Dilke based at The Institute of Cancer, Queen Mary, University of London.

***The scientists showed through laboratory studies that angiogenesis inhibitors which target integrins can alter the way in which integrins and VEGF receptors move inside blood vessels. By altering the movement of integrin and VEGF receptors inside the blood vessel, they promote cell movement and angiogenesis.

This study coincides with the publication of other lab-based research published in the journal Cancer Cell this month showing that other types of angiogenesis inhibitors already on the market, such as sunitinib (Sutent), can sometimes encourage tumour growth rather than stunt it. It is possible these findings might help to explain why this can happen although this study did not seek to do that. These papers are:

Accelerated Metastasis after Short-Term Treatment with a Potent Inhibitor of Tumor Angiogenesis. Cancer Cell. John M.L. Ebos. DOI 10.1016/j.ccr.2009.01.021

And Antiangiogenic Therapy Elicits Malignant Progression of Tumors to Increased Local Invasion and Distant Metastasis. Cancer Cell. Marta Pa` ez-Ribes. DOI 10.1016/j.ccr.2009.01.027

The pharmaceutical company which manufactures cilengitide has independently published phase II clinical trial data suggesting that the drug cilengitide can have a positive effect in treating brain tumours. You can read some of these results here.

Linking the two studies, Cancer Research UK's chief clinician, Professor Peter Johnson, said: "The research on cilengitide published in Nature Medicine (Stimulation of tumor growth and angiogenesis by low concentrations of RGD- mimetic integrin inhibitors. A Reynolds et al. Nature Medicine. March 2009) gives us interesting information about the biology of tumour growth, but the laboratory work it is based on is a long way from the situation in the clinic. The early results for patients taking cilengitide appear positive and although we need to remain vigilant, there is nothing to suggest that this drug actually encourages the growth of human brain tumours.

"Cancer Research UK continues to fund research into angiogenesis inhibitors as well as other treatments that have shown the potential to help people survive cancer longer."