Progen heartened by melanoma therapy trial

Three US patients with advanced, metastatic melanomas -- one of the most aggressive and rapidly lethal forms of cancer -- remain alive 22 months after being treated with PI-88, an experimental cancer therapy developed by Brisbane-based biotechnology company Progen.

All three patients had been categorised as terminally ill after their tumours became unresponsive to conventional chemotherapy and radiotherapy.

The three patients have been receiving monthly injections of PI-88, which inhibits the growth of blood vessels that supply solid tumours with oxygen and nutrients for rapid growth. In two patients, secondary lung tumours have actually regressed in size, while in the third, the patient's tumours have stopped growing.

Six other terminally ill patients among the 32 enrolled in the Phase I/II trial have also experienced stabilisation of advanced, melanomas and other solid tumours. These patients commenced the treatment up to seven months ago.

Progen's vice-president of R&D, Dr Robert Don, described the results as "heartening." He says several patients had died, but PI-88 was not a factor in their death -- their cancers were already too advanced for them to survive.

PI-88 inhibits blood vessel growth by neutralising the enzyme heparanase, which normally breaks down the carbohydrate compound heparan sulphate, which is an integral component of the basement membrane that forms the protective 'skin' around major organs -- and rapidly-growing tumours.

By breaking down the basement membrane, heparanase clears the way for new blood vessels to grow and penetrate the tumour mass, supplying cancerous cells with nutrients and oxygen to fuel their rapid growth and division. Heparanase also has a role in metastasis, allowing cancerous cells to detach from tumours and migrate elsewhere in the body.

Don said PI-88 also inhibited fibroblast growth factor (FGF), which stimulates cells lining the walls of blood vessels to detach and form new blood vessels.

Don said tumour stabilisation was becoming "a new paradigm" in cancer treatment. If tumours could be stabilised early, before they metastasised, patients could learn to live with their disease; tumours would become, in effect, superfluous but relatively harmless "organs".

Don said that if PI-88 was successful in stabilising or regressing tumours, an important role would be in giving cancer patients time to recover from the severe effects of aggressive chemotherapy.

He said chemotherapy was "brutal" on patients, who needed time to recover before they could be treated again. During this vulnerable interval, PI-88 might inhibit the growth of any surviving tumours -- with PI-88 in this backup role, patients could be treated even more aggressively.

Stabilisation was a useful result in its own right, Don said: "Getting rid of a tumour is a very long process. The existing blood vessels stay there, and it's a matter of the tumour slowly turning necrotic as its growth is halted. We don't expect with PI-88 alone, that tumours will regress radically."

Synergies

Don said the future of cancer therapy may lie in synergies between conventional chemo- and radiotherapy, and angiogenesis inhibitors like PI-88, in much the same way that multi-drug therapies are now prolonging the lives of HIV-AIDS patients.

Progen is already conducting a Phase I trial in the US with a combination therapy involving PI-88 and low doses of the established chemotherapy drug Taxotere, to determine the safe dose of PI-88 in this combination.

Six patients with non small-cell lung-cancer Phase I trial have already undergone therapy, and shown no adverse results.

Progen and its Taiwanese ally Medigen are also planning a Phase II trial in the post-operative treatment of primary liver cancer.

Progen is involved in another Phase I trial of its second lead compound, PI-166, in patients with inoperable primary liver cancer, or hepatoma. The drug has a different mode of action to PI-88, so there is potential for synergies between the two drugs in treating liver cancer.