Treatment for ovarian cancer by gene targeting

Mar 22 2004

Targeting and inactivating a key gene could be a subtle and effective treatment for certain types of ovarian cancer, Scottish researchers suggest in a study published in Clinical Cancer Research.

Cancer Research UK scientists at The University of Edinburgh found that blocking a gene called Raf-1 can halt the growth of some ovarian cancer cells while leaving others largely unaffected. Their findings could lead to selective cancer therapies tailored for individual patients.

Researchers also gained important clues about why targeting the gene was effective in some types of cancer but not in others, paving the way for a test to predict which patients would benefit from the treatment.

The Raf-1 gene is switched on in over 90 per cent of ovarian tumours and scientists believe it plays an important role in the disease's development. Like other genes it is controlled by the molecular equivalent of a dimmer switch and the cancers where it is turned up highest tend to have the worst survival. Scientists believe Raf-1 helps to trigger the process of cell division, allowing cancer cells to ignore the normal controls on their growth and to divide much more quickly than usual.

Researchers from the Cancer Research UK Edinburgh Oncology Unit, Western General Hospital, cultured cells from 15 ovarian tumours in the laboratory. They used short stretches of DNA called antisense oligonucleotides to interfere with the activity of Raf-1 and measured the effects on cell growth.

In some cell types, blocking the gene reduced the rate of cell growth by over 90 per cent and caused widespread cell death. But in others treatment had only a moderate effect, with growth falling by just 10-40 per cent.

Lead researcher Dr Simon Langdon, of the Cancer Research UK Edinburgh Oncology Unit, says: "Ovarian cancers often become resistant to conventional chemotherapy, so there's a real need to develop new, more subtle therapies that attack cancer cells in new ways. Our study highlights the potential of the Raf-1 gene as an exciting target for future cancer drugs. It looks as though therapies aimed at Raf-1 might be highly specific for a particular group of ovarian cancers and would hopefully leave healthy tissue relatively unaffected."

Researchers believe it should be possible to test ovarian tumours to see if they are likely to respond to treatments aimed at Raf-1.

The gene has a couple of relatives called A-Raf and B-Raf which work in a similar way and also help to trigger cell division. Scientists suspected that the more cancer cells relied on Raf-1, rather than its relatives, the more they would be affected by Raf-1 targeted therapies.

Genes exert their effects by producing specific protein molecules, so researchers measured the Raf-1, A-Raf and B-Raf proteins in different ovarian cancer cells. Cells with the highest proportion of Raf-1 were the most sensitive to treatment, providing the basis of a test to identify patients who would be best suited to therapy.

Dr Langdon adds: "It's crucial with selective cancer therapies that we have a way of picking out the patients who would benefit most, so that doctors have a rational basis for giving patients a particular treatment. Our results certainly suggest it would be possible to select patients for Raf-1 therapy." Clinical studies with anti-Raf-1 therapies are underway and scientists believe their greatest areas of promise may be in combination with conventional chemotherapy.

Professor Robert Souhami, Cancer Research UK's Director of Clinical and External Affairs, says: "The future of cancer treatment lies in selective therapies, which target only the cancer cell, and often only certain types of cancer cell, while leaving healthy tissue unharmed. "While this research is still at an early stage, it is laying important groundwork for the development of selective and more effective treatments for a particularly insidious form of cancer."