Promising experimental drug targets cancer 'Achilles heel'

In collaboration with the Press Association

A new drug called olaparib has successfully completed a phase I clinical trial at the Institute of Cancer Research and the Royal Marsden Hospital in London.

Olaparib was given to 60 patients who had an inherited form of breast, ovarian or prostate cancer that was caused by faulty BRCA1 or BRCA2 genes.

BRCA mutations block cells from repairing their DNA, and are thought to be responsible for about five per cent of breast and ovarian cancers, and about one to two per cent of early onset prostate cancers.

 

Early results from the AstraZeneca-supported trial, published in the New England Journal of Medicine, show that more than half of the patients saw their tumours shrink or be stabilised, despite the failure of previous treatments, and one patient is still in remission two years later.

The drug is now being tested in larger trials.

Olaparib is a new type of cancer treatment called a PARP inhibitor. It has been developed to block the action of a protein involved in DNA repair called "poly-ADP-ribose phosphorylase", or PARP.

It appears to be particularly effective in people whose cancers carry mutations in the BRCA1 or BRCA2 cancer predisposition genes - which are linked to inherited breast, ovarian and prostate cancers. The researchers also noted that patients experienced very few side-effects and many found it easier than chemotherapy.

When olaparib blocks the PARP protein, it causes the accumulation of many tiny errors in a cells' DNA. But in most cells, other DNA repair mechanisms kick in and repair this damage.

However, cancer cells carrying BRCA1 or BRCA2 mutations are highly sensitive to such drugs as they have serious defects in their existing DNA repair machinery.

When the PARP is blocked in these cancer cells, they're left with no way to repair their DNA and die. However, cells without mutations in the BRCA genes - such as non-cancerous body cells - are affected much less, as they are still able to repair themselves via a different pathway.

There is also evidence that PARP inhibitors may be effective in cancers with other DNA repair defects, including some non-inherited breast and prostate cancers and a significant proportion of ovarian cancers.

Dr Johann de Bono, an ICR scientist who led the phase I trial at the Royal Marsden Hospital and the Netherlands Cancer Institute, commented: "This drug showed very impressive results in shrinking patients' tumours.

"It's giving patients who have already tried many conventional treatments long periods of remission, free from the symptoms of cancer or major side-effects."

Joint lead researcher Professor Stan Kaye, who is supported by Cancer Research UK, added: "The next step is to test this drug on other more common types of ovarian and breast cancers where we hope it will be just as effective."

Dr Peter Sneddon, executive director of clinical and translational research funding at Cancer Research UK, which part-funded the trial, said: "It is very encouraging to see the development of 'personalised treatment' tailored to the requirements of the individual patient becoming a reality as it offers the opportunity to design new drugs that are truly selective.

"Although development of this drug is in its early stages, it is very exciting to see that it has the potential to work when other treatment options have failed. We look forward to further results to see if olaparib's early promise is fulfilled.

"Cancer Research UK has funded research into PARP inhibitors and their potential use in the clinic since the 1990s, and as well as supporting this trial, we are also funding a separate PARP inhibitor trial in seven UK centres, which involves treating women with advanced breast or ovarian cancer caused by BRCA1 or BRCA2 gene faults."

References

 Fong, P., Boss, D., Yap, T., Tutt, A., Wu, P., Mergui-Roelvink, M., Mortimer, P., Swaisland, H., Lau, A., O'Connor, M., Ashworth, A., Carmichael, J., Kaye, S., Schellens, J., & de Bono, J. (2009). Inhibition of Poly(ADP-Ribose) Polymerase in Tumors from BRCA Mutation Carriers New England Journal of Medicine DOI: 10.1056/NEJMoa0900212