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New class of drugs effective against one of the toughest cancers to treat

Test tubes (Jan Chlebik for the ICR, 2011)

Scientists have discovered a promising new type of therapy for bile duct cancer – a deadly disease which in most cases is inoperable and incurable.

New Hsp90 inhibitor drugs, which work by destroying several cancer signals at once, were particularly effective at killing bile duct cancer cells when grown in dishes or transplanted into mice.

The team at The Institute of Cancer Research, London, also uncovered a marker indicating whether cancers were likely to respond well to the treatment.

Cancers that produced a small molecule of RNA called MIR21 seemed able to resist treatment more than those with low levels.

Testing for MIR21 could help judge whether a patient’s cancer was likely to respond to Hsp90 inhibitors, while future drugs that block MIR21 production could be used in combination with Hsp90 inhibitors to increase sensitivity in tumours with high MIR21.

Hsp90 inhibitors particularly effective

The study is published in the journal Gastroenterology, and was funded by The Institute of Cancer Research (ICR) itself, the European Union, and the NIHR Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and the ICR.

Scientists at the ICR – a research institute and charity – initially screened 484 prototype or existing drugs on cancer cells grown two-dimensionally in traditional flat dishes to pick out the ones that had any kind of cancer-killing ability.

They then tested the promising drugs on mini tumours formed from cells taken from biopsies of patients at The Royal Marsden and grew them in a gel so that they could form a three-dimensional shape.

These 3D ‘mini tumours’ resemble what happens inside a patient much more closely than conventional, flat cell cultures, and the researchers were able to look in detail at how tumours responded to drugs – such as patterns of gene activity and mutations, and what changes occurred that allowed the tumours to resist treatment.

Researchers found that as a class Hsp90 inhibitors were particularly effective against bile duct mini tumours.

They showed that cells that produced high levels of MIR21 were able to resist treatment, suggesting this could be used as a marker to judge the likelihood that patients could benefit from Hsp90 inhibitors, or to indicate that patients might benefit from combined treatment with a drug that targets MIR21 production.

Dr Chiara Braconi's research is aimed at understanding how non-coding RNAs may be exploited as targets for novel treatments and as clinical biomarkers in cancers of the liver, pancreas, gall bladder and bile duct.

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Personalising treatment for cancer patients

Hsp90 inhibitors are among several innovative new types of treatment which attack cancer indirectly, by destabilising multiple different proteins required for the growth and survival of cancer cells.

By destroying several cancer signals at once, they are designed to make it hard for cancers to escape the effects of treatment, giving them promise as potential ‘resistance-busting’ drugs.

Study leader Dr Chiara Braconi, Clinician Scientist at the ICR, and Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust, said:

“Bile duct cancer is an extremely difficult disease to treat. We desperately need new treatment options so we can offer patients precious extra time with their loved ones.

“We screened a large number of existing or potential drugs and chemicals in flat dishes and in 3D mini bile duct tumours taken directly from patients – and excitingly identified promising candidates to be explored further.

“Hsp90 inhibitors were particularly effective against bile duct cancers, and we found that high MIR21 levels were a marker for cancers that are more resistant to these drugs, and might also be a target for future drugs that would increase sensitivity.

“We found we could analyse the effect of drugs on mini tumours from inoperable patients after only six weeks. This technique could in future be applied to the majority of bile duct cancer patients who present at an advanced stage, and could be helpful to better personalise treatment for each patient.”


Chiara Braconi bile duct cancer HSP90 inhibitors
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