Do cheap off-the-shelf drugs hold the key to treating some of our most deadly cancers? By Peter Griffin
As cancers go, glioblastoma is one of the worst types you can be diagnosed with. The aggressive tumours emerge rapidly from astrocytes, the star-shaped cells that make up much of your brain's mass.
Some tumours spread out like tentacles, hitchhiking on neural pathways and often affecting speech and coordination as they advance. The way they embed themselves in the brain makes surgery to remove them a dangerous undertaking.
Only about five out of every 100 people with glioblastoma survive for five years or more. The average life expectancy for a patient who is treated for the illness, through surgery, radiotherapy, chemotherapy, or often a mix of the three, is just 14.6 months following diagnosis.
While an estimated 200 people are diagnosed with high-grade brain cancers such as glioblastoma in New Zealand each year, scientists have few if any promising options on the table to deal with it.
"Glioblastoma is a horrible cancer," says Dr Swee Tan, the soft-spoken plastic surgeon, researcher and executive director of the Gillies McIndoe Research Institute.
Above a blood bank in Newtown, Wellington's hospital district, Tan and his small research team use philanthropic grants to conduct studies into cancer treatments. His focus is on the worst of the worst cancers, the ones for which there is no cure.
"There's nothing really on the horizon that can help patients with glioblastoma," says Tan.
The last advance in treatment happened 15 years ago and improved life expectancy by two months.
Cancer, Tan points out, is a leading killer globally, accounting for nearly 10 million deaths in 2020. The World Health Organisation in 2018 estimated that 18.1 million new cancer cases are newly diagnosed each year, more than 25,000 of them in New Zealand. The economic burden of treating cancer is huge – $1 billion a year in this country alone.
"For 100 years, we have been pursuing novel drugs, which cost a fortune and take a long time, over a decade, to develop," says Tan.
New cancer treatments do hold great promise. Immunotherapy has become a major focus of clinical trials and new treatments in the past decade. The aim of it is to train the immune system to recognise and attack cancer cells.
Chimeric antigen receptor (CAR) T-cell therapy involves genetically engineering a person's white blood cells, called T cells, to kill cancer cells. But it is hugely expensive – about $1 million to treat one person.
There has to be a better way, and Tan believes there is. He's part of a research movement around the world exploring the repurposing of cheap, commonly prescribed drugs to treat cancer. In December, Tan and his colleagues published a paper in the Journal of Clinical Neuroscience reporting results of a three-year, phase I clinical trial that involved 17 patients aged between 20 and 85 that showed some promising results.
Everyone in the cohort had exhausted all other treatment options for glioblastoma. Tan put them on a regime of numerous off-the-shelf drugs, including aspirin, the anti-inflammatory celecoxib, diabetes pill metformin, beta-blocker propranolol, renin inhibitor aliskiren and the angiotensin-converting enzyme (ACE) inhibitor cilazapril. The drugs were phased in over a number of weeks.
Ten patients survived long enough to complete the treatment. Overall, the trial had a median survival time among patients of 19.9 months – 5.3 months longer than the norm with conventional treatments.
Only minimal side effects were reported. The small size of the trial means its results aren't "statistically significant". But they are encouraging enough for the independent monitoring committee overseeing the trial to recommend that Tan progress to a phase II trial.
That will take place over four years with 75 patients, including Māori, Pasifika and disadvantaged minorities. Tan will also start their treatment earlier, introducing the drugs over a shorter period once they've started their first cycle of chemotherapy.
"Because we know that every patient gets a recurrence, why wouldn't you?" he says. "The brain is in a fixed cavity and once the tumour starts to grow, it squeezes the brain and the patient just doesn't have time to get the benefit of the treatment."
Tan is optimistic that he can replicate the results in a phase II trial, which would boost the prospects for the development of a cheap polypill that could be given to those with glioblastoma to give them some extra time and a decent quality of life.
Tan imagines cancer as being like a beehive. The mass of worker bees crawling around the hive are the equivalent of cancer cells.
"When you look deeper you find the queen bee, the equivalent of cancer stem cells and the proposed origin of cancer," he says. "They are responsible for cancer recurrence and spread and cancer resistance to radiotherapy, chemotherapy and immunotherapy. The queen bee makes the worker bees. They are pluripotent and can self-renew."
To get rid of all the worker bees, you ultimately need to take out the queen. Most cancer treatments have targeted the cancer cells – a war involving radiation, chemicals and scalpel to destroy the tumour. Tan believes there's an alternative that is less painful to endure, cheaper, and ultimately more effective.
"What we need to do is to think about how to manipulate the renin-angiotensin system [RAS] to control the cancer stem cells – the queen bees."
The RAS is a hormone system that regulates blood pressure as well as fluid and electrolyte balance in the body. A significant body of research shows that by blocking the RAS at a local level, you can reduce or stop tumour growth.
Tan's novel strategy is to cut off the constant supply of cancer cells by controlling the cancer stem cells using this built-in control system that can be regulated with these off-patent, oral medications. But it isn't quite that simple.
"The buggers can get around it," says Tan. His team discovered inbuilt bypass loops of the RAS and other important pathways, which converge on the RAS in cancer. That explains the need for a combination of medications, to block different steps of the RAS simultaneously.
Drug repurposing is a growing movement in medicine that has received a lot of attention during the Covid-19 pandemic. Scientists found that Remdesivir, an antiviral medication developed over a decade ago to treat hepatitis C, could work on some of the same molecular pathways associated with the new Sars-CoV-2 virus.
"Cancer is even more urgent than this virus," says Tan, who is already responsible for a breakthrough in drug repurposing.
He's best known internationally for his research on strawberry birthmarks, or haemangiomas, clusters of blood vessels that grow on or under a baby's skin and can develop into large, if benign, tumours.
Tan and his team discovered that the RAS system could be targeted to control stem cells in the birthmarks to kill the growth. While he was unravelling the role of the RAS in strawberry birthmarks, two separate French groups serendipitously found that propranolol, a beta-blocker medication prescribed for high blood pressure, caused accelerated regression of the benign tumours. Propranolol subsequently became the go-to treatment for strawberry birthmarks worldwide in 2009.
No new drug development was required – it relies on cheap off-patent medicines and avoids the need for surgery. "It costs next to nothing, a $5 prescription, and you don't go to hospital, you are treated at home," says Tan.
A trial he undertook at Hutt Hospital in 2012 found that captopril, an ACE inhibitor that modulates the RAS, achieved the same outcome for strawberry birthmarks with fewer side effects, helping build the case for the use of these drugs to treat brain cancers.
The phase II glioblastoma clinical trial will cost $4.8 million to run and go ahead only if the Gillies McIndoe team can secure the funding, which may again need to come from philanthropists because the Government hasn't funded drug repurposing. Tan's funding application to the Health Research Council to support the phase II trial was rejected. In a submission to the review of government drug-buying agency Pharmac, he proposed a contestable $40 million fund over four years for drug-repurposing research. But there was no mention of it in the interim review, which came out in early December.
The drugs for Tan's clinical trials cost about $4000 per patient each year, a fraction of the cost of the conventional treatment of glioblastoma of about $60,000 a year.
"We've got to get away from these expensive treatments," says Tan. His dream is that he can develop a polypill made up of cheap drugs that can shrink and contain tumours and extend the life of brain-cancer patients. There are years of cancer trials ahead, but if Tan is on the right track, the most horrible of cancers may not be cured but tamed, so that their sufferers can live with them long-term.
Jonathan Densem is having a swimming pool installed at his home in Christchurch. It's a rare luxury for the 52-year-old musician, actor and music teacher, who was diagnosed with terminal brain cancer at the end of 2015.
It followed a year during which he continuously felt ill, regularly having to put down his violin in the middle of a music class, or pull over to the side of the road if he was driving. Densem knew something was wrong with his body.
A neurologist who undertook an electroencephalogram (EEG) test, which records the small electrical signals produced by the brain, found that Densem was having hundreds of minor, partial epileptic seizures a day.
But it was New Year's Eve, 2015, when his cancer journey began, with a stint lying in a magnetic resonance imaging (MRI) scanner.
"Straight after I had that, we took the kids to Margaret Mahy Playground," remembers Densem. "Then, 15 minutes later, the phone rang. They said, 'Can you go and see your doctor today?' That's not a good sign."
That evening, Densem ended up at the emergency department of Christchurch Hospital – the best way, he was told, to guarantee a quick path through to the neurology ward as the hospital prepared for an influx of New Year's party casualties.
Another scan led to the diagnosis: grade IV astrocytoma – a glioblastoma brain tumour.
Densem was 46. Two weeks later, surgeons attempted, unsuccessfully, to remove the tumour. Only about 5 per cent of the mass was carved out. "The neurosurgeon said that if he took out any more, it might affect some of my functions, like breathing," says Densem, who, with his floppy hair and thick-rimmed glasses, has the look of British documentary-maker Louis Theroux and possesses a similarly dry sense of humour.
Radiation therapy and chemotherapy followed. He describes the cancer diagnosis – if not the debilitating side effects of the cancer treatment – as "weirdly energising".
"I thought, there are things I haven't done that I am going to do now. There's crap I'm used to putting up with that I won't put up with any longer," he says.
It was in this weird period of stasis, as Densem began to plan what he would do with the rest of his uncertain life, that his mother, Prue, called from Wellington and urged him to enrol in a clinical trial that was treating patients with late-stage glioblastoma.
Densem joined Tan's trial and began receiving the daily concoction of drugs he has maintained ever since – 12 pills in the morning, five at night. Densem is the only surviving member of the trial cohort. But his remarkable story isn't featured in the scientific paper outlining its results.
In June, Densem received word that following genetic analysis of the pathology samples taken during the attempt to remove his tumour, his cancer had been reclassified as a grade III astrocytoma. It is still a high-grade brain cancer with only a marginally better prognosis than glioblastoma.
"It was definitely an umpire's call by the doctors at the time," says Densem, who admits to being a little disappointed that he doesn't feature in the study results.
"I recall them saying it wasn't as active as the worst ones they'd seen. But the structure of the way it was growing and the way the tentacles were heading towards the centre of my brain – they thought it was really dangerous and I'd probably have only about 10 weeks if they didn't do something."
Despite the downgraded diagnosis, he maintains his faith in the trial's drug regime. "I feel so much better for having been on that trial. There could be a bit of the placebo effect there. But I think I know my body well enough to know when something is having an impact on me."
He still gets hit by the afternoon "tireds" two or three times a week, but maintains a busy schedule teaching music and recording his own compositions. When he was trying to process his diagnosis, Densem thought about all the things he hadn't done in his life. One thing stood out: he had been writing songs for decades, but never recorded them. In 2016, his wife, Emma, started a Givealittle crowdfunding campaign for him, which raised about $50,000 – enough to not only record an album but ensure it received top-notch production.
Densem found himself in Auckland's Roundhead Studios, the recording base of Neil Finn, sitting behind a Steinway grand piano and working with top musicians. The resulting album, I'm Saying It Now, was released in 2017. It features the song Cape Reinga, the first tune Densem ever wrote, and one that has Finn's pop sensibility all over it.
“If I hadn’t got the tumour, I very likely wouldn’t have made my album,” says Densem, who has made peace with the fact he’s an outlier, one of a tiny handful of people still alive years after being diagnosed with a high-grade brain cancer. “In my subconscious, this tumour is not going to get me, it’s just a part of me,” he says. “It’s not a friend, it’s the neighbour I’m happy to tolerate.”
