Caution raised over integrin inhibitors

When designing drugs to target and treat cancer, the last thing that you want to happen is for the agents to actually promote tumour growth. But this is what a study by scientists from the UK has found is the case when low doses of an experimental angiogenesis inhibitor were given to mouse models. However, there is hope that turning the findings on their head will help in the development of new ways to make these drugs as effective as possible. In the future, it may be feasible to combine these inhibitors with other drugs to maximise their effectiveness for patients.

Angiogenesis inhibitors are designed to block the supply of blood to the tumour to prevent it from growing. Some of these have proven successful in the clinic and gone on to be widely used, such as Avastin (bevacizumab) and Sutent (sunitinib), while others, such as those that inhibit the v3 and v5 integrins, have entered clinical trials but have generally been unsuccessful.

One such agent under development that targets integrins is cilengitide, which is thought to work by targeting the tumour and its vasculature. The agent is currently being investigated in a Phase III trial for the treatment of glioblastoma multiforme (GBM), as well as a number of Phase II studies in several indications, including advanced non-small cell lung cancer and squamous cell carcinoma of the head and neck. Now, scientists from the Institute of Cancer, Queen Mary's University London, the Institute of Cancer Research and the Beatson Institute for Cancer Research have 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.

The work, which was published in the 22nd March online edition of Nature Medicine (10.1038/nm.1941), showed that low concentrations of the drug promoted VEGF-mediated angiogenesis by altering v3 integrin and VEGFr-2 trafficking, thereby promoting endothelial cell migration to VEGF. The study found 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.

Cilengitide is being developed by Merck Serono (Merck KGaA), which in response to the Nature Medicine article issued a statement citing previous findings in numerous preclinical models of the drug in vitro and in vivo that diverge from the latest results. The company also countered with the fact that cilengitide has been studied in more than 750 patients in various long-term settings supporting its current development. Notably, the clinical data for cilengitide in the treatment of GBM, both as a single agent and in combination, have been encouraging. However, all current Merck Serono studies are investigating cilengitide in combination treatment (either radiotherapy and chemotherapy or chemotherapy and another targeted therapy), so there may be some truth in the fact that this class of drugs will not have utility as single agents. Only time will tell.

Matthew Dennis - Editor, Cancer Drug News