Starving cancer cells
Researchers are working on a new drug that can inhibit the growth of cancer cells 'C through starvation.
By JOSEPH LOH
THERE appears to be a ray of hope that can lift the gloom surrounding cancer. Researchers in Australia have developed a drug that inhibits the growth of cancer cells by starving them.
The drug, called PI-88, works by impeding the creation of new blood vessels to tumour cells, thereby curtailing its blood supply and preventing them from developing any further.
This is in contrast to current methods of cancer treatment that targets the tumours directly by radiotherapy or chemotherapy. Additionally, curtailing the growth of blood vessels effectively cuts off means for cancer cells to spread. Tests done on animal subjects so far have been successful and the drug is at an intermediate stage of clinical development.
The heparanase hurdle
The development of PI-88 has its roots way back in 1985 when Prof Chris Parish of the John Curtin School of Medical Research (JCSMR) at the Australian National University (ANU) in Canberra demonstrated that there were high levels of heparanase activity present in malignant cancer cells.
Heparanase is an enzyme that is normally present in the human body, and works during embryonic development, wound healing and inflammation. The enzyme works by facilitating white blood cell entry into damaged or developing tissue. The white blood cells degrade the walls of the blood vessels, which in turn invoke the body's natural healing process (utilising growth factors) to stimulate cell growth and hence aid tissue regeneration.
The abovementioned discovery found that cancer cells were hijacking the normal function of heparanase, and using it to promote its own growth and spread. One essential factor for the growth of cancer is the development of new blood vessels (known as angiogenesis) to the cancerous tissue. These not only supply blood to the affected tissue but also provide an easy method of transportation for cancer cells to invade the entire body though the bloodstream.
In 1991, Dr Craig Freeman joined the JCSMR, and began to study the heparanase enzyme in detail. There were several conflicting studies on heparanase at that time, according to him. 'We had to start from scratch and develop a new, quick and simple way to detect the presence of the enzyme, and this had been a major impediment to studying heparanase.'
Although heparanase was first described 30 years ago, it was thought that the enzymes found in cancer cells and normal tissue regeneration were different. 'We were one of the first to show that the various heparanase activities in cancer cells, immune system cells and probably in all cell types, were in fact the same. Much of the existing literature characterising heparanase activity was wrong!' explained Dr Freeman.
Cooking up the PI-88
Heparanase is essentially a degradative (or destructive, in not-so-accurate terms) enzyme that cells use to pass through blood vessel walls. Cell walls are supported by a membrane of a complex protein structure, which is bound together by a sulphated carbohydrate called heparan sulphate 'C think of it as bricks in a wall held together by cement.
Heparanase works to digest or break down the heparan sulphate, and with the glue holding the cell walls removed, the structure is destroyed and cells can pass through. Surrounding the blood vessel walls is a similar protein/heparan sulphate complex (the extracellular matrix), which contains growth factors that is released.
Normally, the body's healing process kicks in by stimulating cell growth and repair, but in instances of cancer, blood vessels that feed the tumour are formed.
The goal was therefore to come up with a compound that could mimic the structure of heparan sulfate and bind to the heparanase enzyme, thus stopping its adulterated function.
As Dr Freeman described, the breakthrough came in 1995, when they identified an oligosaccharide (essentially a carbohydrate), which could be easily obtained in large quantities from yeast cell walls, and chemically modified it, adding sulphate groups (a sulphuric chemical compound) to allow it to mimic the structure of heparan sulphate. 'This compound became known as PI-88 and was found to be a potent inhibitor of tumour growth by inhibiting heparanase activity and the action of the growth factors ' said Dr Freeman.
But the key advantage of PI-88 is that it has shown negligible toxicity levels in early human trials except for some small anti-coagulant activity. This is in contrast to side effects observed with other forms of cancer treatment.
Beyond cancer
PI-88 too has more potential than just a cancer drug. Many viruses such as HIV, herpes and dengue bind to cell surface heparan sulphates prior before invading the cells, and PI-88 or similar compounds can prevent this.
Dr Freeman added, 'We are also involved with collaborations on the role of heparanase and heparan sulphate in diabetes, kidney disease, Alzheimer's Disease and blood triglyceride levels.'
PI-88 was also shown to be an inhibitor of restenosis, which is the recurrence of narrowing in a coronary artery following the removal or reduction of a previous narrowing by balloon angioplasty.
A cure for cancer?
To provide funding to develop their initial discovery, ANU Enterprise, the commercial arm of the ANU, negotiated a deal with Progen Industries Ltd, an Australian biotechnology company to fund research which led to the development of PI-88. The company has provided A$4.3mil (RM12.2mil) over five years to JCSMR to support their work, and has guided PI-88 through several Phase I and II clinical trials, and is gearing up for the next stage, which will cost a staggering A$50mil (RM137mil).
More recently on May 16, Progen announced that it had received notification from the US Food and Drug Administration (FDA) guiding the accelerated development of PI-88. This essentially reduces the development timeframe of PI-88 by up to three years, which means that it could be available to the public earlier if the drug proves to be viable. But there's one thing for sure 'C a cure for cancer can never arrive too soon.
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