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Sunday December 7, 2008
By DR JOHN LOW SENG HOOI
A new paradigm in cancer therapy – drugs that stop the blood supply to tumours.
IT was the autumn of 2005, in Philadelphia, at the 47th American Society and Therapeutic Radiology & Oncology (ASTRO) Annual Scientific Meeting. Every year, cancer specialists from around the world gather in this meeting, where new technologies are unveiled and doctors share their experiences and listen to experts in various fields of cancer therapy.
At the 2005 meeting, Prof Judah Folkman gave his plenary lecture on cancer and angiogenesis. It was my first and last encounter with Professor Folkman. He passed away on the January 14, 2008. He was 74 years of age.
Prof Folkman was the first to postulate on the importance of blood supply in tumour growth more than 30 years ago while he was still a surgical resident.
He published a seminal paper in the 1971 New England Journal of Medicine. His work cumulated to the discovery of an entirely new class of drug that specifically targets the development of new blood vessels in tumours, cutting off nutrients and further growth signals to the tumour, practically “starving” the tumour to death.
This new class of drug, typified by a compound called bevacizumab, has been shown to be effective in the treatment of various types of solid tumours including lung, breast and colon cancers, adding to the growing armamentarium of drugs of the practising oncologist.
Theoretically, a tumour cannot grow to more than a certain size on its own, generally 1-2mm, due to the lack of oxygen and other essential nutrients. When the tumour starts growing, it needs more oxygen and nutrients which can be supplied through blood vessels.
Therefore, the tumour will send out a signal to the blood vessels nearby seeking supplies – this is called “tumour angiogenesis”. This process is mediated by a factor called vascular endothelial growth factor, in short VEGF.
As this process continues, more and more blood vessels will be formed, thereby allowing the tumour to grow even further. These new blood vessels connect to the main bloodstream from where the tumour can spread to other organs such as the liver and lungs.
Therefore, we need a substance that stops tumour angiogenesis. Bevacizumab was found to specifically target VEGF, causing the breakdown of existing blood vessels and preventing the development of new blood supply to the tumour.
Besides stopping the development of new blood vessels, bevacizumab leads to normalisation of the blood vessels, hence improving the delivery of chemotherapy drugs to the cancer cells.
In this manner, bevacizumab can be combined with various types of chemotherapy, working hand in hand without significantly increasing the toxic effects of the treatment.
This hypothesis has been proven in recent large clinical trials, revolutionising the treatment of colon, lung, breast and other solid cancers.
For example, in the treatment of advanced lung cancer which has not had much success for the past decades, the addition of bevacizumab to chemotherapy has significantly increased the life expectancy of lung cancer patients.
This drug has also been used successfully to prolong the survival of colon and breast cancers patients.
Numerous trials are ongoing to test this drug in combination with other chemotherapy agents in various other cancers. This is very encouraging and it is without doubt that the role of blocking this important pathway in tumour growth and spread will increase in importance.
Indeed, several other new drugs are on the horizon that specifically target the development of new blood vessels (angiogenesis).
The treatment of cancer has changed dramatically over the last decade, manly due to a better understanding of cancer biology. A whole new generation of cancer drugs has been developed through the understanding of how cancer cells grow and spread and the signals that control their proliferation.
Oncologists are trying novel combination of various drugs that specifically target certain pathways of cancer growth, which reminds us of the saying of Sun Tze – “Know thy enemy and in a hundred battles you will be victorious”.
Chemotherapy kills cancer and normal cells indiscriminately, leading to a multitude of side-effects, including hair loss and the risk of severe life threatening infection when the immune system is severely compromised. By targeting a specific pathway of the underlying mechanisms that drive the cancer to grow, we can avoid some of these side-effects.
More importantly, these new classes of drugs can be combined with conventional chemotherapy and radiotherapy, improving their effectiveness without adding to the side-effects.
With continued research and the elucidation of more signalling pathways in cancer cells, newer and better targeted therapies will be developed, bringing new hope and cure for cancer patients.
As I sat and listened to Prof Folkman in the Philadelphia Convention Centre in the autumn of 2005, there was a sense of great admiration and awe for this silver haired, soft-spoken gentleman. Known widely in the medical fraternity as the father of angiogenesis research, he was a caring doctor and a brilliant teacher.
It took more than 30 years, from a hypothesis to laboratory research, countless clinical trials and finally the development of an effective new class of drug to treat cancer.
There is no short-cut to medical progress. In science, more important than brilliance are diligence and perseverance, without which there will be no success.
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