It’s the end of an era at the country’s most successful cancer drug discovery laboratory, with the retirement of three of its most distinguished scientists. Now questions are being raised about its future. Donna Chisholm reports.
Every year, in the United States alone, about $10 billion is spent researching cancer cures. Every year, worldwide, around 10 million people who can’t be cured will die. Many battles have been won, the latest of which has been the revolution in immunotherapy that has changed the direction of medicine research globally, but the war rages still.
In New Zealand, the most successful hothouse for new cancer drugs is the Auckland Cancer Society Research Centre (ACSRC), which has a team of 80 scientists who populate a rabbit warren of offices and labs at Auckland University’s Medical School, above the former site of the city’s morgue. Established in 1956, it became less than 30 years later the first laboratory in the southern hemisphere to take an anti-cancer drug from discovery into clinical use.
But now, with the retirement of the centre’s three most decorated researchers, who have largely controlled the direction of its investigations for more than 40 years, the centre is at a critical crossroad. Can it mutate and survive, or will it lose its identity – and possibly its life?
There were none of the fancy fume hoods they have these days to ventilate the labs and ensure the scientists don’t breathe in toxic vapours from the chemicals they cook up – just a plastic sheet separated Cain’s office from the fumes. “It was fairly third-world,” Emeritus Professor Bruce Baguley says of the set-up when he joined Cain in 1968 after two post-doctorate years working in cancer research in Switzerland.
That year, Cain had just ordered a plastic model of the DNA double helix, which arrived about the same time as Baguley. It was a full 15 years after Cambridge University scientists Watson and Crick had described the structure of DNA, with the crucial contribution of New Zealand-born molecular biologist Maurice Wilkins, together with Rosalind Franklin, who produced the first X-ray images of DNA. But now, for the first time, says Baguley, you could build something chemically and see if it fitted into the structure of the DNA, heralding the birth of rational drug design.
Cain started out using native flora as anti-tumour agents. But he had read widely on all aspects of anti-cancer drug development, and his own research was based on the concept that drugs designed to interact in some way with DNA might be useful, especially if they didn’t interact with any other molecules. He was one of the first scientists in the world to use molecular modelling, designing the drugs to fit the shape of the biological molecule he wanted to target. Today, molecular modelling is done by powerful computers. In Cain and Baguley’s time, they tested their drug designs with a kind of molecular Lego. Cain’s early studies focused on drugs that bound in the “grooves” formed by the turns in the spiral staircase of the DNA helix, before turning his attention to drugs that slotted between the individual steps – the “base pairs” within DNA that make up the coded blueprint for our bodies.
The result, in 1970, was anti-leukaemia drug amsacrine, the first drug of its kind to be successfully trialled, and, in 1983, marketed. Given only 5% of cancer drugs that enter phase 1 trials make it to market, it was an astounding achievement, but it came too late for Cain, who died of a heart attack in 1981, at just 50 years old.
Professor Rod Dunbar, a cancer immunology researcher who heads the Maurice Wilkins Centre, one of the country’s Centres of Research Excellence, was a medical student when he heard about amsacrine. “It was astonishing. I couldn’t believe it was possible to make drugs in New Zealand that would go into people. They were true pioneers and they inspired a generation of researchers.”
The man appointed to step in to the void left by the inspirational Cain’s death was Baguley, who’d just turned 40. “Fifty years ago, I think we were much more optimistic in terms of finding something that would work,” says Baguley. “Bruce Cain would say organic chemistry is an infinite science and therefore it must be able to come up with something that stops cancer cells from growing.” If the goal of scientists is to render cancer a chronic (rather than terminal) disease, we’re about 10% of the way there, he says.
Baguley, who’s multilingual and plays the cello, led the team with Professor Bill Denny as a co-director for 30 years. In 2013, he stepped aside and Denny took over, with Professor Bill Wilson as a co-director. Denny was inducted into the American Chemical Society Division of Medicinal Chemistry Hall of Fame in 2016. Dunbar describes him as the chemistry equivalent of a gold medallist in successive Olympics – “the kind of person we would have knighted ages ago if he wasn’t a scientist” – but one who shunned the limelight.
At the end of this year, Denny and Wilson join Baguley in retirement, taking with them their brilliance, their international reputations and their rainmaker abilities to attract research grants in an increasingly competitive space.
In August, Auckland University, which runs the centre jointly with the Cancer Society, appointed Associate Professor Michael Hay to the directorship, ending an at-times acrimonious debate over whether an international candidate should have been headhunted for the job, but also signalling the university’s long-term plan to integrate its cancer research and clinical arms under the wider leadership of a professor of cancer sciences. Those ambitious plans have some questioning whether – or how – the research centre will adapt to survive in the new environment.
Wilson was at the forefront of demands for the university to launch a global search for the new director. “We have something unique here, and that is academic drug discovery that doesn’t sit easily in most university environments. It’s distinctly different in flavour from the kind of drug discovery that is done in industry. It can afford to take a longer-term perspective, to investigate some of the hard issues that industry skirts around. It makes a really important contribution internationally and locally, and it is being put at risk by the fact we are not getting investment by the university at that leadership level.”
Hay, a 30-year veteran of the centre, a respected scientist and popular with staff, was regarded as the natural successor internally. But as he himself admits, “I’m not the rainmaker people have been saying we must have. Other people are going to also have to stand up and become leaders. It’s not for me to hold up the whole sky on my own.”
With 75% of the centre’s budget so-called “soft money” from research grants that must be renewed, it’s still a daunting task. But he says the “young saplings who’ve underpinned the mighty totaras” are now seeing the light. “We are stepping up and maintaining, at least to some degree, the flow of money that keeps this place alive.”
Wilson says the centre’s directors all wanted to recruit an overseas candidate with a stellar reputation to replace Denny. When the university demurred, largely because of the cost, Wilson believes, Denny agreed but Wilson kept up the fight. The dean of the university’s faculty of medical and health sciences Professor John Fraser told North & South he’d received “flaming emails from Bill” on the subject, before adding, “We don’t normally let retiring professors dictate to us.”
Fraser says identifying an international candidate to parachute in to the centre is “a very, very big ask” and hadn’t worked with some other appointments. The centre directors also hadn’t nominated anyone for the university to approach.
It’s a critical period for the ACSRC, with four leaders leaving at the same time – Emeritus Professor Lynnette Ferguson left last year – and Wilson admits the quartet have “sort of formed a canopy that’s made it difficult for the understory to come away”.
Wilson says although he’s not opposed to the idea of an integrated cancer sciences centre, the ACSRC’s unique culture has to be protected. “It’s been innovative because of the close communication between the medicinal chemists who know how to make molecules, and the cancer biologists who have ideas about new targets and new approaches in cancer treatments.” These mini-teams, which began with biologist Baguley and chemist Cain, followed by biologist Wilson and chemist Denny, and then Wilson and Hay, among others, are crucial but, Wilson believes, at risk under the new model. “Putting together a university-wide network is a valuable thing to do, but it won’t deliver the kinds of outcomes we have.”
Hay, however, has a far rosier take. He says uncertainty about Denny’s succession and the future plans had been corrosive and demoralising, but he doubts an integrated cancer centre would be bad for the ACSRC and says it could be “transformational”. “We have the potential to be a cornerstone rather than being subsumed,” he says.
He acknowledges, though, that the battle for funding dollars has always been tough and is getting tougher. The centre’s scientists attract about $6 million-plus a year in research grants, together with contracts from pharmaceutical companies that license new drugs to take to trial.
It is clear, he says, that big funding bodies such as the Health Research Council want to see research money having much more impact in patients, particularly Māori. “When you are in the lab making molecules, you are three or four miracles away from engaging with real-life people and it’s a very long bow to say, yes, we are going to impact on health generally or even Māori health, in particular.”
Attracting research money in that environment will require scientists to look beyond the walls of the lab – and into the wards across the road. That’s one of the reasons the university wants to integrate its cancer clinicians and its scientists under the leadership of someone with what Fraser calls a “broad interest” in cancer. “We have 14 professors in the faculty whose primary interest is in cancer. The university now has a phase one clinical trials unit, a tissue bank and is invested in genomic cancer research. There are a lot of areas of cancer research that are just flourishing at the moment… really, really important, which to be honest I think has left the ACSRC a little bit behind.”
If that is true, it may be partly the result of the centre’s decades-long focus on its holy grail: finding cancer drugs to target the oxygen-deprived parts of tumours. Its initially high hopes have suffered a string of frustrating setbacks and a declining interest from the big pharmaceutical companies whose deep pockets are essential to take new drugs to clinical trial.
“Pharma is never interested in something until someone gets it to work,” says Wilson. “It had zero interest in immunotherapy until scientists discovered T-cell checkpoint inhibitors [the mechanism of drugs such as the ground-breaking Keytruda] and showed they worked. It’s now a multi-billion dollar industry. The same is true in hypoxia – it won’t happen until someone makes it work.”
Hypoxia (oxygen deficiency) matters in cancer cells because it makes them resistant to radiotherapy, chemotherapy and immunotherapy. The problem is, first, identifying patients whose tumours are resistant because of hypoxia without expensive or invasive screening tests, and then delivering the drugs to the right place, given the regions of hypoxia change. In clinical trials, patients haven’t been selected according to the likelihood of a response, which has led to marginal results.
While the hypoxia problem hasn’t yet been cracked, scientists’ approach to it has evolved, say centre investigators Adam Patterson and Jeff Smaill (another biologist-chemist team), who’ve set up two biotech companies to work in the space Big Pharma has vacated.
“Originally, it was simply that the lack of oxygen caused radiation resistance so you could make molecules that mimicked oxygen and correct the problem,” says Patterson, an Oxford graduate attracted to Auckland by Wilson’s hypoxia work in 2000. “The next stage is whether we could make drugs that can kill those hypoxic cells. And then you could go one beyond that and say, well, those hypoxic cells could generate a toxin and kill more than themselves. Or say, hang on, those hypoxic cells could then release a growth factor inhibitor. Or you could go one step further and look at its effect on the outcome of immunotherapy.”
Smaill and Patterson’s tarloxotinib is the first hypoxia-activated drug of its type to enter human clinical trials, in partnership with start-up biotech company Rain Therapeutics, in non-small cell lung-cancer patients. “It’s taught us something very important,” says Patterson, “which is that hypoxia is a moving target, so it’s like whack-a-mole. It fluctuates from seconds to days – in terms of where it is, how many hypoxic cells there are, and the spatial arrangement of those. It’s constantly changing.”
They acknowledge the contribution of Denny, in particular, and the others to the centre’s ability to attract research dollars. “When Denny is on a grant,” says Patterson, “he brings a CV with 500-plus papers – he’s a powerhouse and you have a much bigger chance of winning. They are internationally renowned… absolute giants, so their ability to pull in money when it is a very scarce resource is better than ours.”
But Smaill says he doesn’t accept the implication that the centre might struggle to stay scientifically relevant. “As good as they are, we have been doing this for 25 years and for most of that time our work has been independent of them scientifically.” Smaill and Patterson have run their own team for the past decade and, says Patterson, “we’ve never had to let anyone go because we can’t afford them”.
Another of Wilson’s chemist collaborators is Moana Tercel, who, with post-doctoral fellow Ben Dickson, developed what Wilson calls a “state of the art” molecule, the best hypoxia-activated prodrug so far. A prodrug is one which starts working only in certain conditions, and this one releases a potent anti-cancer cytotoxin within tumours. The new drug has been dubbed Benomycin, after Dickson.
The competition for research grants makes it difficult for post-docs like Dickson to have any long-term security. A medicinal chemist, he made Benomycin for the first time in 2014, about a year into his tenure, by slightly adapting an existing molecule “recipe” he and Tercel were working on – partly to solve another problem of linking the molecules’ left and right sides.
“It wasn’t a compound we intended to make,” says Dickson, “but during testing it kept showing better and better behaviour. The first time we saw it knock out a tumour model [in a mouse] was probably where it was exciting. I was going, ‘Oh my gosh, this is one of the leading compounds in this project.’ It was a Kiwi-made drug, so we were thinking of naming it Moana-mycin or Marmite-omycin, but at some point Moana said Benomycin. I thought it would be a bit awkward – imagine being at a dinner party and someone says they’re getting treated with Benomycin and you’re like, ‘Hi!’”
The 16 drugs the centre has taken from invention to clinical trial is one of the best “conversion rates” in the world, says Dr Jonathan Koea, a cancer surgeon and chair of the society’s board.
“It doesn’t sound a lot, but in that world it’s huge. I didn’t realise how good they were until I started going to North American cancer meetings. That lab is legendary in the US.” It’s also a big draw for donors, who like the thought their contributions are helping to find cancer cures. They’re less keen, he says, on funding expensive professorial chairs, which can cost many millions of dollars to establish.
Koea believes the university’s plans to establish a mega cancer-science centre is probably a good one, mirroring the model of the Centre for Brain Research, and the Liggins Institute in perinatal research.
“The ACSRC has shown that even with all our funding problems, you can be a world-leading unit in New Zealand. American cancer labs might have three or four times the funding, but their output is in fact inferior.”
Observers such as Dunbar believe the legacy of Cain, Baguley and Wilson – and particularly Denny in medicinal chemistry – must not be lost. “It is one of the jewels in the crown of biomedical research in New Zealand.”
Cures and prevention
So, what are the prospects of a cure or cures for cancer, given scientists have long since abandoned hopes of the mythical magic bullet? We asked the ACSRC scientists to crystal-ball gaze.
Retiring ACSRC director Professor Bill Denny: “People still need to help themselves more than they do. We all know what the majority of carcinogens are and nobody takes any notice. There is no question about alcohol, no question about tobacco, no question about fatty foods and that sort of thing. If everyone lived properly, we would have only half the burden we have now. There is unfinished business, but it is going to be unfinished for a while. If you look at 10-year cure rates for adult cancers in New Zealand, when I first started, it was 24%, now it’s 58%, and it’d be nice to see it at 70%.”
Emeritus professor Bruce Baguley: “There is a lot of hype at the moment, and a lot of bucks, in immunotherapy. The overstatement is to say that cancer in principle can now be cured by it, because a lot are not. The big challenge is to find out for an individual whether immunotherapy will work or not, and it is still not clear what tests you should do to find that out. One of the problems with precision medicine is that it assumes all the cancer cells are the same, that they will all have the same defect and can all be treated with the same drug, but cancer cells are quite heterogeneous. A little group like us can’t make an impact internationally by copying what everyone else is doing, so the challenge is to see the gaps that others have missed.”
Biologist Professor Lai-Ming Ching: “There could be lots of magic bullets; it won’t be just one. I think a lot of people still see it as one disease, and think there might be one cure for cancer. It’s not. Every cancer in every person is a little bit different and that makes it a complex task. Cancer cells are very cunning and can adapt. In immunotherapy, the important thing is not finding out why 75% (of patients) don’t respond, but what was it about the 25% that do. What are the biomarkers that will allow us to select those who will respond so you save others from being given a horrible treatment that won’t benefit them.”
Biologist Associate Professor Adam Patterson: “Adding things to immunotherapy is the way the world is going to go. If you go into a boardroom and try to partner a drug, the first question they’ll ask is, what does it do to the immune system? It can’t be immune-suppressive to start with or you are dead and buried. At international conferences, you see the change in emphasis of large pharma – it pretty much changed on a dime and 90% of their effort has switched to immunotherapy. This year at ASCO [the American Society of Clinical Oncology], the posters and adverts were around promising a chemotherapy-free future. Before that, it was targeted therapy and kinase inhibitors, but that switched about 10 years ago – now they’re lucky to be on the last day, after four days of immunotherapy.”
To market, to market
The Auckland Cancer Society Research Centre has developed anti-cancer drugs acting in innovative ways, of which 16 have made it to clinical trial and two to market, in four main classes:
Topoisomerase inhibitors, such as amsacrine. When cells divide – as cancer cells do very frequently – they need to copy their DNA accurately for each of the two “daughter” cells to survive and grow. Amsacrine molecules insert themselves into DNA and prevent the DNA from being copied correctly, causing the death of newly divided cancer cells. Like other DNA-targeting drugs, amsacrine can also affect fast-growing cells in normal tissues, such as gut and hair cells, causing the familiar chemotherapy side effects of nausea, vomiting and hair loss.
Anti-vascular agents, such as vadimezan (DMXAA), which limit the blood supply of tumours. Vadimezan made it to phase three clinical trials in non-small cell lung cancer, with the first patients enrolled in Auckland. But the drug failed; it was found to work on anti-tumour immunity in mice, but not in humans.
Kinase inhibitors, such as dacomitinib, which block a type of enzyme called a kinase. Kinases help control cell signalling, metabolism, division and survival, and scientists think blocking them might stop cancer cells from growing, and block the growth of new blood vessels that tumours need to grow. Dacomitinib, developed by the ACSRC in partnership with Pfizer, was this year approved for use in the US, EU and UK in non-small cell lung cancer.
Hypoxia-targeted prodrugs. These are drugs activated in hypoxic or oxygen-deprived parts of solid tumours. Several, including CP-506 and tarloxotinib, have gone to clinical trial but none have yet made it to market.