Cancer research: at the frontline

Australia's biotechnology industry is tiny by comparison with its US and European counterparts, but it offers glimpses of what a future in which most cancers will be curable, or ideally, preventable.

Professor Tony Burgess, director of the Ludwig Institute for Cancer Research in Melbourne, believes the advent in 2000 of Glivec, a new treatment for chronic myeloid leukaemia developed by multinational pharmaceutical company Novartis, marked a sea change in cancer therapy.

"The drug inhibits the enzyme that drives the disease," Burgess said. "It was first trialled in 50 US patients who were resistant to the usual cancer drugs and had dangerously high levels of white blood cells. The blood cell counts of all but one patient returned to normal after treatment with Glivec, a potent inhibitor of an enzyme with a key role in cell division, a tyrosine kinase.

"It was the first truly targeted therapy, and it changed the industry's vision. If you know what's going on, you can turn it off, and you've got a winner."

Brisbane-based biotech company Progen Industries has one of the world's most promising angiogenesis inhibtitors: PI-88. By inhibiting the growth of new blood vessels, angiogenesis inhhibitors like Genentech's Avastin, recently approved by the FDA, starve fast-growing tumours of oxygen and nutrients.

PI-88 targets a biological glue, heparan sulfate, that binds cellular communities together, and forms the tough, plastic-like membrane that surrounds organs and blood vessels.

The cells that create the new plumbing for tumours come from the lining of existing vessels. They must digest their way through the confining heparan sulfate membrane with an enzyme, heparanase.

PI-88 plugs the receptors to which heparanase normally attaches, rendering the confining membrane impermeable to cells seeking to escape and form new blood vessels. As a bonus, PI-88 also seals off lymph vessels, trapping vagrant cancer cells before they can spread.

"We're purely testing PI88's effect on the growth of tumours, not their spread. It's difficult to conduct clinical trials on metastases, because by the time they appear, it's usually too late to stop them,” said Progen's Vice President of R&D, Dr Robert Don.

Turning back time

During childhood, naïve killer T-cells arising in bone marrow migrate the thymus, a fist-sized gland in the chest. There, they learn to distinguish between normal and mutant proteins before they go out to patrol the body. Activated T-cells will destroy any mutant cells displaying mutant proteins on their surface.

But in teenage, surging sex hormones shrink the thymus to walnut size, slowing the flow of new T-cells to a trickle. Mutant cells displaying unfamiliar proteins now escape detection, so the risk of cancer rises with age.

In Melbourne, Monash University researcher Dr Richard Boyd has shown the thymus can be restored to full activity with drugs that block gonadotrophin-releasing hormone (GnRH).

Produced by the pituitary gland in the brain, GnRH stimulates production of the sex hormones that cause the thymus to atrophy. GnRH blockers switch off sex-hormone production, quenching the patient's sex drive in the process - a Faustian bargain that most cancer patients accept. Melbourne medical technology company Norwood-Abbey, which is commercializing Boyd's discovery reported in July 2003 that several men with advanced prostate cancer were in remission after taking a GnRH -blocker.

Forward guard

Ian McKenzie's research team at Melbourne's Austin Research Institute has found a very different way to stir the immune-system into vigorous, belated action.

They took blood from10 volunteers with advanced kidney, prostate, breast, or ovararian cancers, and processed it to extracted dendritic cells -- the forward sentries of the immune system. Dendritic cells detect potentially hostile molecules and call other immune-system cells to the fray.

The ARI team primes the patient's dendritic cells with a cocktail of cellular growth factors before adding them to a test tube containing purified MUC1, a protein over-expressed by 50 times normal in many cancer cells.

After an hour, the ARI researchers infuse the MUC1-primed dendritic cells back into the patients - with dramatic results. "Ten out of 10 patients made excellent immune responses," McKenzie said. "And in four patients, the tumours stopped growing".

To McKenzie's relief, one of the star responders was his friend, Bruce Tayler.

The Austin team's advance is being commercialized by Cancer Vac, subsidiary of Melbourne biomedical company Prima Biomed. At Sydney's St Vincent Hospital, medical oncologist and researcher Associate Professor Robyn Ward has taken another novel approach to immunotherapy, by targeting a mutant protein found on the surface of many tumours. Like many oncologists, Ward knew that a rare few patients with advanced cancers fare much better than others - - their multiple tumors simply shrink away.

She began screening the serum of large numbers of patients with colorectal cancer, and found some were responding to antigens on the surface of their tumors from a gene called P53.

All cells have a small arsenal of genes that actively suppress tumours -- P53, dubbed 'the guardian of the genome', is the most important.

The P53 protein is normally active only in the cell nucleus, and invisible to the immune system. But P53 is as vulnerable to "knockout" mutations as any other gene. When it loses function, mutant proten fragments drift to the cell's surface and become potential targets for the immune system.

As humans age, the immunosurveillance system becomes increasingly inept at detecting novel, mutant proteins, and P53-marked cancerous cells go undetected.

Ward's aim is to use a vaccine -- based on protein fragments replicated from cancer patients - to prime the immune system to recognize mutant P53 molecules.

In Nature Medicine several years ago, US researchers reported that the technique protects laboratory mice against certain cancers - but will it help save the lives of aging humans who already have cancer? Ward says it's too early to tell. A Phase II clinical trial is being conducted for the prototype of this Pentrys vaccine by Perth-based biotechnology company Australian Cancer Technology.

Devil’s apple

Therapeutic gold can be found in the most unlikely places. Former Perth mining company Britannia Gold, reincarnated as Solbec Pharmaceuticals, has found a remarkably potent cocktail of cell-killing alkaloids in a common weed in Australia, a thorny horror from the nightshade family called Devil's apple (Solanum linnaeanum). The weed had an anecdotal reputation for curing skin cancer in horses and cattle.

In the plant's original brew of eight alkaloids, Dr Bruce Robinson's research group at the University of Western Australia, found two compounds that, used in combination, killed 160 different tumour cell lines in vitro.

The drug, SBP002 enters the cancer cell via an as-yet undisclosed receptor that is over-expressed in nearly all solid tumours. Once inside, it kills cancerous cells in an unusual way, causing death by necrosis rather than apoptosis.

SBP002 also appears to induce the immune system to attack tumours, and suppresses production of interleukin-6 (IL-6), implicated in nausea and weight-loss.

Researchers in Florida who have administered SBP002 to patients with advanced metastatic melanoma and mesothelioma lung cancer have reported that it variously slowed, stabilized or shrunk patients' secondary tumours -- in several seriously ill patients, tumours have actually vanished, and they remain well.

Solbec is hoping to get SBP2000 fast-tracked under the Food and Drug Administration's Orphan Drug Program.

Vaccine quest

At the University of Queensland, Dr Ian Frazer's research team has developed a vaccine that may prevent cervical cancer, often triggered by human papilloma virus.

Melbourne biotechnology company CSL has acquired the commercial rights to Frazer's anti-HPV vaccine, and on-licensed it to international pharmaceutical company Merck. It is currently in Phase 2 trials in female volunteers.

The Cooperative Research Centre for Vaccine Technology has developed another experimental vaccine against Epstein-Barr Virus (EBV), the agent of glandular fever. In developing nations, EBV infections can trigger lethal cancers like Burkitt's lymphoma and nasopharyngeal carcinoma.