Old drugs give new hope in cancer

The 17 patients in an internation­ally novel clinical trial run from Hutt Valley did not live to see the promising results of the drug regimen they were testing.

But these patients live on, in that their experience is prompting further research on a regimen of medications repurposed for cancers.

The patients had an aggressive brain cancer with a poor prognosis – glioblas­toma, which is diagnosed in 180 to 200 patients in New Zealand each year.

All the patients in the Hutt Hospi­tal-based trial had relapsed following aggressive conventional treatment and had no more treatment options.

That made them eligible to partici­pate in the trial, led by the Gillies McIn­doe Research Institute, Wellington neurosurgeon Agadha Wickremesekera and Palmerston North radiation oncol­ogist Ramesh Pandey.

A phase I safety trial, it involved repurposing the common drugs pro­pranolol, aliskiren, celecoxib, curcumin, metformin, quinapril and aspirin. The drugs in phase II, testing for efficacy, will be the same as in phase I, except that aspirin will not be included this time around.

The patients taking part will start the trial earlier, when they finish their first cycle of chemotherapy (after surgery and radiation).

Institute director Swee Tan says phase II is ready to launch once funding is in place.

The beauty of the concept, Dr Tan says, is that the medications being tri­alled are well established, off patent, cheap and well tolerated.

One factor in favour of these prod­ucts’ potential in cancer is that many of them have been shown in the laborato­ry to have anti-cancer effects, he says.

Another factor is that cancer inci­dence tends to be lower in people who take these drugs, which are inhibitors of the renin-angiotensin system (RAS) and its converging pathways.

The report on the trial, in the Journal of Clinical Neuroscience, refers to epide­miological studies showing patients taking medications that modulate the RAS have a reduced risk of cancer and improved survival if they get cancer.

The RAS is critical in regulating blood pressure. But, earlier, Dr Tan and the team worked on infantile haemangio­ma (strawberry birthmark) and discov­ered that the RAS and stem cells are involved. Those findings underpin the use of beta-blockers and ACE inhibitors to treat this condition.

The RAS has an effect on cancer stem cells and the micro-environment of the tumour, Dr Tan says.

He says cancer stem cells are like the queen bees in the beehive. “They are the proposed origin of cancer and responsible for metastases and treat­ment resistance.”

Glioblastoma typically progresses rapidly and patients on average live only 15 months after diagnosis. But many of the trial patients maintained quality of life and some lived beyond the 15-month period.

The overall median survival was 19.9 months – a survival improvement of 5.3 months, which Dr Tan says is en­couraging even though, owing to the small number of patients, it did not reach statistical significance.

For the 10 patients who had full dose-escalation of the treatment, the average time from diagnosis to death was 23.8 months; for those who did not, it was 15.7 months.

The fully escalated group also did better on performance measures such as ability to take care of oneself and car­ry out normal activities.

The paper reports the case of one pa­tient who survived for 36 months and says, in some patients, tumour volume and metabolic activity reduced follow­ing treatment.

Dr Tan says the team is excited by the prospect of the phase II clinical trial confirming the phase I results.

He hopes phase II can start before year’s end. The aim will be to recruit 75 patients. Candidates can be referred by oncologists, neurologists and GPs.

Ethics approval has been obtained and a large proportion of the funding is in place, thanks to philanthropists and, in particular, Hugo Charitable Trust, which is donating $1 million of the required $1.5 million.

Dr Tan says the institute is hugely grateful the phase I trial was fully fund­ed by donations, including the services of organisations such as Pacific Radiol­ogy and Cyclotek Pharmaceuticals.

The drugs being tried for glioblastoma are:

• propranolol – beta-blocker
• aliskiren – renin inhibitor
• celecoxib – selective cyclooxygenase 2 (COX-2) inhibitor
• curcumin – natural polyphenol
• metformin – an antihyperglycaemic, and
• quinapril – angiotensin-converting enzyme (ACE) inhibitor.
• New drugs for cancer are few and far between and, for glioblastoma, the last breakthrough was temozolomide in 2005.

New oncology drugs have a 5.1 per cent likelihood of regulatory approval once entering safety trials, according to analysis released by industry groups last year.