Early inspiration still drives angiogenesis guru

Affectionately known as the father of angiogenesis, Prof Judah Folkman, from Harvard Medical School, visited Australia for the first time last month to attend the AHMRC congress at which he gave an inspiring plenary about angiogenesis and his latest foray into the emerging class of anti-cancer or anti-angiogenic drugs.

At the age of 72 Folkman continues to conduct research and has vision that anti-angiogenic therapy will provide clinicians of the future with a routine way of controlling or regressing tumours.

A tumour can grow to 1-4mm in size without its own blood supply -- this is about how far nutrients and oxygen from surrounding tissues can penetrate.

An 'angiogenic switch' is then required to enable the tumour to grow its own blood vessels and obtain the supply of nutrients and oxygen it needs to grow larger.

Most people live with microscopic or in situ tumours that remain harmless throughout their lifetime. Too small to be detected with any current imaging techniques, these tumours do not switch to the angiogenic phenotype.

"Only one in a thousand of these [in situ tumours] will undergo the angiogenic switch in a lifetime," says Folkman.

The body's endogenous anti-angiogenic defence mechanisms prevent or block angiogenesis from occurring in these tumours, thus preventing them from growing uncontrollably.

"We are beginning to think that the safest anti-angiogenesis inhibitors may be those in the body, the endogenous inhibitors," says Folkman.

Folkman's team has driven the search for these endogenous anti-angiogenic compounds since 1980, and two that they have discovered include endostatin and angiostatin -- both are currently in clinical trials.

The discovery of endostatin arose from Folkman's hankering for correlating clinical observations with causal outcomes.

In recalling his days as a medical student, when he was told the reason why people with Down syndrome have a much lower incidence of cancer than the general population was because they die young, Folkman realised that individuals with Down syndrome no longer die so young -- most live to 60 or 70 years-of-age, yet they still have a very low incidence of cancer.

"They don't get brain, breast or prostate cancer, and only one report of pancreatic cancer exists," says Folkman, although individuals with Down syndrome do suffer the same incidence of testicular cancer and a form of mild leukemia. They also have the same rate of diabetes, but suffer no diabetic retinopathy and no atherosclerosis.

In pursuing the reason for this, Folkman's team found that individuals with Down syndrome carry an extra copy of the gene for collagen 18 (COL18AI), which encodes for the protein collagen 18 of which the anti-angiogenic protein endostatin is an integral component. Individuals with Down syndrome end up with ten times the normal level of endostatin.

There are now at least 17 endogenous angiogenesis inhibitors known and, according to Folkman, there are probably many more.

Anti-angiogenic drugs are less toxic than conventional chemotherapy, have a much lower risk of drug resistance, produce no side effects and Folkman is enthusiastic about using them in combination therapies for treating tumours.

"Changing the schedule and using low dose or metronomic chemotherapy and anti-angiogenic drugs together has a good effect on reducing the size of tumours," Folkman says.