Cancer's ‘Achilles’ heel’

A new concept for cancer therapy could lead to treatments personalised to each patient’s tumour without any side effects, says Professor Thomas Helleday, who is pioneering the idea at Oxford University [watch a video describing this work].

He believes cancer may have an ‘Achilles’ heel’: The genetic damage that builds up in cancer cells and the subsequent escape from the body’s normal controls on growth may also make them very susceptible to treatments that block repair of DNA.

‘DNA damage is a prerequisite for most cancers,’ explains Professor Helleday of the Gray Institute for Radiation Oncology and Biology at Oxford University. ‘Whether that damage is a result of the tar in cigarettes, toxins or genetic and environmental factors, it can result in mutations that alter genes. That genetic instability drives cancer.’

Normal cells have many pathways and mechanisms to correct and repair DNA breaks and damage as they occur. These are crucial to maintain the normal functioning of the cell. If the damage is too great, the cells are either killed by a process called apoptosis or their growth and division is arrested so that the damage doesn’t go any further.

Many cancers have defects in one or more repair processes which enables them to sidestep these controls. ‘We can exploit these defects,’ says Professor Helleday. ‘If we can block the remaining repair systems, the body will knock out the cancer cells. Normal cells with a full set of repair kits will be fine.’

Such treatments, designed to each patient’s individual cancer, should mean patients experience few, if any, side effects from the treatment. It would be a great advance over standard chemotherapy techniques which are toxic to all dividing cells.

Professor Helleday’s group have studied defects in the BRCA1 and BRCA2 genes which predispose women to developing breast and ovarian cancer. In these cancers, a pathway that repairs mistakes when DNA is replicated no longer works, and the cancer cells are reliant on a different process based on a protein called PARP for survival.

The researchers showed that these breast and ovarian cancers could be targeted using an existing drug that inhibits the PARP protein. The idea has now been licensed to Astra Zeneca and phase II clinical trials of the drug involving a few hundred patients began in May 2007.

‘The results are better than expected,’ says Professor Helleday. ‘I thought we might see the cancers in these people stop growing. But in many cases the drug is killing off the cancer cells. The tumours have shrunk substantially and the patients report no serious side effects.’

Professor Helleday is sure this can be a general concept for tackling many cancers: ‘If there are two possible pathways for repairing damage and one is lost in a cancer, we can target the second one. This is called synthetic lethality as the drug is not toxic on it own – only for the cancer cells with this extra defect.’

‘In the future, you could imagine screening a patient’s cancer for defects, picking out the precise inhibitors to target the remaining DNA repair pathways, and treat that person’s tumour in a very targeted way.’

‘We know of thousands of these pathways in yeast. We want to extend this knowledge into humans so we can exploit them and come up with selectively toxic therapies with no side effects and no damage to normal tissue,’ he says.

http://www.ox.ac.uk/media/science_blog/