Suicide gene therapy kills bowel cancer cells

Cancer Research UK

An innovative type of gene therapy has for the first time succeeded in making bowel cancer cells commit suicide, according to a report in Cancer Research* this week.

The therapy, developed by Cancer Research UK-funded scientists at The Institute of Cancer Research, combines cutting-edge techniques to target tumour cells. Known as GDEPT (Gene-Directed Enzyme Prodrug Therapy), the treatment uses a virus to attack cancer cells.

But the researchers have added an extra gene to the virus. The virus is programmed to switch on the gene only if it reaches a tumour. When the gene is switched on, the virus produces a protein that activates an otherwise harmless ‘prodrug’, given separately.

Because this drug is only activated in tumours, it selectively kills only cancer cells. In normal tissue, the drug remains inactive, so healthy cells are not affected.

This is the first time such a therapy has proved successful at killing bowel cancer cells, albeit only in the laboratory. Cancer Research UK and The Institute of Cancer Research are supporting the development of the therapy, and hope to take it into early clinical trials in the future.

Lead researcher, Professor Caroline Springer of The Institute’s Cancer Research UK Centre for Cancer Therapeutics, said: “We have developed a smart method to selectively target cancer cells. Normal cells are spared because the virus doesn’t produce the protein that activates the drug unless it is inside a tumour.

"The beauty of our approach is that the cancer cells are made to commit suicide both by the virus and the activated drug - the two work in tandem. And once activated, the drug has the added bonus of causing the virus to produce more of the activating protein, which activates more of the drug, and so on. It’s the first time we’ve seen a ‘positive feedback loop’ like this in a GDEPT therapy."

The drug damages DNA inside the cancer cells to the point where the cells stop functioning. They have no choice but to shut down and die.

Another benefit of the therapy is that it doesn’t just kill only the cancer cells infected by the virus.

"We also see a significant 'bystander effect'," added Prof Springer. "This means the cells killed by the virus or the drug release signals into the tumour that tell neighbouring cancer cells to die too."

In lab experiments, mice with bowel tumours that received the therapy lived twice as long as those that did not. The researchers suggest their technique could one day be used as a treatment for advanced bowel cancer that doesn’t respond to standard chemotherapy.

Professor John Toy, medical director of Cancer Research UK, said: "GDEPT therapy has been in development for several years. But this study shows the technique - always a smart therapy - is becoming ever more sophisticated. For the first time it has been shown to be effective at killing bowel cancer cells in a laboratory model of human colon cancer. This is another stride towards the possible use of GDEPT for cancer patients."

ENDS

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Notes to Editor

* Cancer Research, Vol 67 Issue 10

GDEPT: an oncolytic adenovirus is injected into the bloodstream. The virus’s DNA contains an added gene for CPG2 (Carboxypeptidase G2) but the gene is controlled so that it is only translated in the presence of telomerase, an enzyme found in many cancers but much less so in normal tissue. When the virus reaches a tumour that is producing telomerase, the gene is translated and the virus produces the protein CPG2.

Meanwhile a "prodrug" is injected. A prodrug is an inactive form of a drug. In this case the prodrug, called ZD2767P, is activated by CPG2 - hence it is only activated in regions of the body where the virus is producing CPG2, i.e. in tumours.

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