Scientists find genes that make brain tumours resistant to treatment

1st April 2013

Scientists at The Institute of Cancer Research (ICR) have pinpointed two genes that can predict whether patients with a deadly brain tumour will respond to the gold standard treatment, according to a study published this week in Cancer Research.

Scientists have previously found another gene linked to resistance to the drug Temozolomide, but it could not explain all patients’ failure to respond. This study - supported by funding from Cancer Research UK, The Oak Foundation and La Fondation de France -identifies two new genes and the biological mechanism that can lead to drug resistance for glioblastoma patients.

Lead author Dr Chris Jones from the ICR says: “Temozolomide is a chemotherapy drug and its side-effects can have a potentially serious impact, including a drop in white blood cells that can lead to increased infection risk, potential loss of fertility, anaemia, fatigue, nausea and occasionally hair loss.

“Finding these genes will help us identify patients who are unlikely to benefit from Temozolomide, so they don’t suffer side-effects unnecessarily. Understanding the mechanism of resistance will also guide our efforts to overcome this resistance and discover new drug targets in resistant tumours.”

Glioblastoma is an aggressive type of brain tumour with a median survival after diagnosis of just 14 months. There has been little success over the past 40 years in improving patients’ poor prognoses; however Temozolomide has emerged as a new standard of care that gives a modest improvement in survival in some – but not all – patients. The drug, which is taken orally, works by crossing the blood-brain barrier and damaging tumour cells’ DNA, triggering their death. However, some tumours are able to repair this type of DNA damage and in these patients the drug has little effect.

In some patients, this drug resistance is predicted by high levels of a protein called MGMT, which allows the tumour to repair the DNA damage the drug causes. In glioblastoma samples that were drug resistant without high levels of MGMT, the scientists found high levels of proteins from two other genes - called HOX9A and HOX10A.

Both HOXA9 and HOXA10 were associated with drug resistance and shorter survival in children with glioblastoma. The research team further showed that the genes are overexpressed in response to a pathway called PI3 kinase. Treating cells with a drug that inhibited this pathway reduced the amount of HOXA9 and HOXA10 protein present and overcame resistance to Temozolomide. This raises the possibility that resistance to this drug could be overcome, however further testing would be required to confirm this.

Dr Lesley Walker, Cancer Research UK’s director of cancer information, said: “Being able to match patients to drugs with much greater confidence about the outcome will transform cancer treatment over the next 20 years. This research, on a drug which Cancer Research UK discovered, is heartening and raises the possibility of more targeted treatment with temozolomide as well as the future possibility of broadening its use by overcoming drug resistance.”

The work was a collaboration between scientists at the ICR, at the Institut de Cancérologie Gustav Roussy in France and the Life and Health Science Research Institute (ICVS), Universidade do Minho, Portugal.

Gliomas are tumours that develop from brain cells called glia - account for about 80 per cent of primary malignant brain tumours (cancer that originates in the brain). Glioblastomas are a type of aggressive glioma that are often fatal. In the UK, about 4,550 adults and 350 children are diagnosed with brain tumours each year. Brain tumours can be very difficult to treat successfully and sadly only 14 per cent of people diagnosed with a brain tumour are alive after five years.

HOX genes are essential in the developing embryo and are known to be involved in cancer including giloblastomas.

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