Wednesday 1 December 1999
Super-powerful x-rays, 3D computer images and cancer chips have been used by scientists at the Institute of Cancer Research to develop the first of a new generation of drugs to block the effects of cancer genes.
The work comes from a major new £20 million development at the Institute of Cancer Research where scientists are using a multi-disciplinary approach - unique in Britain, but based on US models - and the latest technologies - to understand cancer genes and develop new therapies.
The drug, known as 17 AAG is the first step towards finding a new therapy for cancers which have so far eluded treatment. It is the only drug in a clinical trial to target a 'molecular chaperone' - Hsp90 - which helps activate many cancer genes.
17 AAG is the result of a new structural approach to drug development whereby biologists who look inside cancer genes to see how they work collaborate with chemists who develop the new treatments, and use cancer chips to monitor how the patient is responding.
Professor Laurence Pearl and his team of biologists at the Institute of Cancer Research worked out the 3D structure of the key parts of the Hsp90 molecule and put it onto the computer screen, and Professor Paul Workman is using this 3D image to understand how 17AAG works and to design yet more powerful drugs. This revolutionary new approach short-circuits the traditional trial and error technique on which conventional drug development is based.
Professor Pearl said: "Although the discovery of cancer genes is currently the 'hot topic' in terms of research, it can only be useful if their structure and functions are understood. That is why this new multi-disciplinary approach is so important and has the potential to revolutionise anti-cancer drug development."
The 3D image of Hsp90 was generated onto a computer screen by using powerful x-rays and the latest computer technology.
The molecules produced by a gene are too small to look at under a microscope, so they are extracted and crystallised in order to capture them as a structured form (like that of snowflakes or sugar) in a process called protein crystallography.
The crystals, which are only around 1/10th mm in width, are then x-rayed by a giant machine known as the 'Synchrotron Radiation Source'. The synchrotron takes sectioned x-ray pictures of the molecular crystals, using a very fine, intense beam no thicker than the lead of a pencil. When the crystal is placed in this beam, the x-rays bounce off the molecules and generate a pattern of thousands of spots that can be recorded on an electronic 'camera' and used to calculate the structure of the protein molecule.
Scientists can then examine the image on computer, wearing special stereo glasses which allow them to see the image in 3D. They can then work out how Hsp90 functions, how the changes occurring in cancer affect that function, and how drugs might block it.
Proteins from cancer genes need to change shape in order to cause the disease. 'Molecular chaperones' such as Hsp90 fold these proteins into the correct shape to cause cancer. By blocking Hsp90 with this new drug, scientists are preventing this shape change from taking place.
The first European clinical trial of 17AAG is being carried out at the Institute of Cancer Research and The Royal Marsden Hospital, and Professor Workman's promising lab results indicate that the drug could be active in solid tumours which do not respond to any other form of treatment.
By specifically targeting Hsp90 the drug 'switches off' the cancer process without damaging the patient's DNA - a risk of using high doses of conventional drugs. Also, because Hsp90 is responsible for the cancerous action of the proteins of several different cancer genes, drugs such as 17AAG which block its action could be effective in a wide range of cancers, and replace a cocktail of different drugs.
In order to determine the effects of the drug in humans, Professor Workman's team used cancer chips or microarrays to show which genes change in response to treatment with the drug, and so predict how individual patients will respond.
Professor Workman said: "The fact that we are working in a new way and blocking more than one pathway to cancer using one drug, gives us hope for those cancers for which there is no effective treatment, and for those which become resistant to existing drugs.
The structural biologists with their protein crystallography and 3D images have helped us to understand how 17AAG works to prevent Hsp90 from activating cancer genes. Cancer chips have provided us with markers to help ensure that the drug will work in the correct way in patients.
17AAG is the first of a new generation of drugs to result from a combination of these new technologies and we are using this knowledge to develop even better and more powerful treatments."
- ends -
For more information, please contact the Institute of Cancer Research press office on:-
Tel: 0207 970 6030
email: [email protected]
Notes to Editors
- The drug development work on 17AAG is funded by the Cancer Research UK.
Please note:
Unfortunately the press office are unable to answer queries from the general public. For general cancer information please refer to The Institute's cancer information page.