A novel Phase II AstraZeneca drug is able to attack tumours directly and simultaneously boost the effectiveness of radiotherapy, according to new data presented at last month's International Conference on Molecular Targets and Cancer Therapeutics in San Francisco.

AZD6244 is a small molecule inhibitor that targets MEK1/2, a key part of the MAPK signalling system.  MAPK is itself downstream of the key Raf pathway, which in tumour cells is constantly switched on leading to uncontrolled cell growth. Constant Raf activation is a key feature of many cancers including those of the lung, pancreas and colon. Manchester University researchers led by Dr Aoife Shannon showed that in a human lung tumour model, AZD6244 inhibited the pathway in both the cells and in the mouse tumour model and that treatment with either AZD6244 or radiotherapy alone slowed tumour growth.

More significantly, however, when they combined the two therapies they observed an additional therapeutic effect, as tumour growth was inhibited to a much greater degree by the combination than by treatment with either AZ6244 or radiotherapy alone - and without any noticeable side effects in the animals.

Dual-pronged attack
The studies suggest that AZD6244 may have made both the tumour cells and tumour vessel cells "more susceptible to the effects of radiation treatment in a double-pronged attack", Dr Aoife said.  "This is something we are currently looking at in more detail."

"We think the preclinical data with AZD6244 and radiotherapy are highly encouraging and warrant further investigation, and this combined approach offers the opportunity to affect a large patient population if you think that around 50% of all cancer patients currently receive radiotherapy at some stage in their treatment," she said.

Up until a few years ago, the general opinion was that the new generation of targeted drugs should show anti-tumour activity when used as single agents. "However, it has now become clear that much greater improvements in therapeutic activity will be achieved by combining these agents with conventional therapies that are already in use in the clinic," Dr Shannon said. "By combining these drugs with radiation therapy in the right way it might be possible to significantly improve their efficacy – and their cost effectiveness," she added. By Michael Day