Jamie Morton is the NZ Herald's science reporter.

New frontiers - The war against our biggest killer

New leaps in cancer research have landed promising blows against a what remains one of the most complex and wide-ranging diseases there is. Science reporter Jamie Morton discusses five key developments over with the University of Auckland's Distinguished Professor Bill Denny.
Professor Bill Denny. Photo / Paul Estcourt
Professor Bill Denny. Photo / Paul Estcourt

Despite billions of dollars worth of research by tens of thousands of leading scientists, cancer, in its many hundreds of forms, still remains one of the world's biggest killers.

In New Zealand, 60 people are diagnosed with it every day.

What hope do we have to stop such a varied, complex and aggressive scourge?

In the face of this immense challenge, we can point to a handful of new areas of research where the impacts could be game-changing.

And Distinguished Professor Bill Denny, director of the Auckland Cancer Society Research Centre at the University of Auckland, is encouraged by progress so far.

"I think it's fair to say that while we are not really sure where we are along the road, we have a clear pathway, finally, because we know what causes the disease in nearly all cases," he says.

"And at the molecular level, we've shown that we can develop specific agents that work."

Cancer has been such a confounding challenge for scientists because of the intricate and individualised nature of what it affects: our cells.

The body is made up of millions of them, all of which grow and are renewed in a controlled way that keeps us healthy.

It's when this control is lost - either through a cellular abnormality such as a genetic mutation, or exposure to a carcinogen, like the 70 within tobacco smoke - that cells begin to multiply unchecked instead of just renewing themselves.

Once there are enough to form a group, a tumour or growth is created.

The latest statistics showed that in 2013, there were 22,166 new cancer registrations - or an average of 335 for every 100,000 New Zealanders.

Among the leading causes of death of New Zealanders between 2010 and 2012, were one of the most common forms, breast cancer, and one of the hardest to treat, lung cancer.

Denny believes that as we come to understand more of the drivers of mutations and improve combination therapies to treat several at once, we may arrive at a place where more and more cancers can be treated as manageable, chronic diseases.

"That wouldn't happen in every case: for example, we know that with pancreatic cancer, it doesn't manifest itself until it's very late."

And he acknowledges that the personalised nature of cancers would continue to prove one of science's biggest hurdles. "Yet, although cancers are highly personalised, there's only going to be a limited number of driver mutations eventually and if we can get a handle on all of those we'll be well placed."

1. The '$1000 genome'

In 2001, scientists published the draft of the entire DNA sequence of a human genome, in an exercise that had taken a decade and cost billions.

Today, 12 years after the full genome was published, the cost has plummeted, opening up the fascinating possibility of affordable treatment tailored to our very own DNA.

Bringing sequencing costs down 100-fold to just around US$1000 per genome has been a key aim of the US-based National Human Genome Research Institute, which shares the advances of its programmes with laboratories around the world.

There are now countries running 100,000 cancer patient genomes through their systems every year, with goals of refining these down to the relatively small number of driver mutations behind most tumours.

"And there probably is only four or five hundred of them," Denny says.

Though a tumour, when diagnosed, typically contains many thousands of mutations, most are not important. This technology is allowing researchers to construct vast databases, from which the critical ones that still elude us will, hopefully, emerge.

"But then it's not that simple because, even though finding the right single gene mutation can make a huge difference to treating it, as is the case with most diseases, cancer a multi-factorial thing.

"What will be a really important part of it is looking at what happens when a cancer relapses, and then sequencing the genome again and comparing it with the original one and seeing what's changed. If that comes down to a relatively small number of genes, then it could be possible, in theory, to develop therapies against it, although this will be expensive and will take a long time."

He points out a range of new state-of-the-art, compact DNA-sequencing machines that can quickly decode a human genome.

One Mars Bar-sized device called the MinION, now being tested by the Wellington-based Malaghan Institute, can analyse a portion of our DNA in just a few hours and an upgraded version is expected to be fast enough to sequence our bacterial "meta-genome" in the same time.

It works by reading genetic sequences from a DNA sample as it travels through about 500 tiny pores in the device, with the data fed into a laptop via USB, allowing scientists to work with only around 16,300 bases, or nucleotides that are measurable sub-units of the DNA.

What will prove more difficult is actually interpreting the data, Denny says. "This won't ever be easy, but it would be a bold person who would predict we won't ever be able to get computer programmes that can just sort them out automatically - people are working on this but it's still in the very early days.

"You would hope that, ultimately, this technology would give us the ability to personalise things down to the single person as much as possible; even now it's helping in stratifying patients."

Scientists are involved in new research against cancer and the impacts could be game-changing. Photo / Getty Images
Scientists are involved in new research against cancer and the impacts could be game-changing. Photo / Getty Images

2. Editing out cancer

If sequencing technology has allowed us to view our DNA blueprint, the concept of gene editing suggests it's possible to tweak it.

Gene splicing and editing has been around for decades, but one new tool, with widespread buzz surrounding it, has seemingly endless potential.

When you hear scientists talk about "Crisper", they're likely referring to CRSPR/Cas9, short for "clustered regularly interspaced short palindromic repeats". It's a naturally-occurring process that draws on prokaryotic DNA containing short repetitions of base sequences.

Each is followed by short segments of "spacer DNA" that has previously been exposed to viruses so they can be employed the next time one attacks.

The second part of the picture, Cas9, is an enzyme that can enable a genome to be cut at any location.

Given CRSPR/Cas9's potential to effectively delete or edit out unwanted genes, and then introduce normal ones, commentators have discussed such giddy eventualities as curing genetic disease or creating designer babies.

In cancer, there is the obvious potential of editing out a gene carrying a mutation that was cancer causing.

"It has only been in the last 15 months or so that this came out, but now the accuracy of this has been improved to the point where you can pick out a single base pair, then take it out or replace it - and that has huge implications for everything," Denny says.

Though this is an encouraging theory, what isn't clear is how a cleaned-up cell could be used to eliminate a cancer, especially as the cancer is quickly proliferating from cell to cell, he says.

"Nonetheless, it's a fantastically specific tool for doing things and we are still learning what we can do with it."

3. Earlier detection can be 'blood simple'

Because tumours are invariably solid, extracting DNA from them requires a biopsy - which can be a very painful and expensive process.

It only gets more inconvenient when the monitoring of treatment demands further biopsies.

However, scientists have found an intriguing way around the problem and point to a way that could allow cancers to be detected much earlier.

"Most solid tumours shed tumour cells into the blood, but these have normally been below detection levels," Denny says.

"But now our detection levels are so good that we can pick them up."

At Otago University's Department of Biochemistry, Professor Parry Guilford has been exploring the potential of finding circulating tumour DNA (ctDNA) in blood.

These shed cells hold all the genetic information about the part of the tumour they came from and can be a valuable tool for tracking tumour development and responsiveness to treatment.

It takes just a quick blood test to capture ctDNA and testing can be done as often as desired, enabling more intense patient monitoring and faster clinical responses to any changes detected. Patients can also have any ineffective treatment stopped and quickly have their treatment plan adapted, potentially giving them a longer life, with a lower cost to the health care system.

"If you're prepared to have a deep biopsy done, you can do that, but the big barrier there is that can introduce infection," Denny says.

"So if it's something that can instead be done with a simple blood test, that's a very big step forward."

n New Zealand, 60 people are diagnosed with it every day. Photo / Getty Images
n New Zealand, 60 people are diagnosed with it every day. Photo / Getty Images

4. The immunotherapy drug revolution

Clinicians are increasingly turning to immunotherapy, designed to boost the body's natural defences and turn them against the cancer.

By using substances created either in a lab or within the body itself, the approach may halt or slow the growth of cancer cells, stop the spread of cancer or help the immune system better destroy cancer cells.

Researchers have been particularly excited by two forms of these drugs - immune system stimulants, which re-engage the body's defence system, and what are called checkpoint inhibitors.

At the heart of this new class of checkpoint inhibitor drugs is our understanding that cancer cells use certain enzymes to block the body's immune response by binding to - and then turning off - "T cells", whic patrol the body and are normally primed to kill cancer cells.

"These new compounds inhibit the ability for cancer to block the immune system."

Checkpoint inhibitors have so far proven incredibly promising at combating Hodgkin lymphoma and metastatic melanoma.

It was the latter cancer at which the drug Pembrolizumab was first targeted, before being tested against lung cancer, triple-negative breast cancer, gastric cancer and head and neck cancer.

It's better known by its trade name - Keytruda.

In trials, it was shown to be twice as effective as chemotherapy, halting and even shrinking tumour growth for 34 per cent of patients with advanced malignant melanomas.

The latest clinical trial results presented showed that 80 per cent of advanced melanoma patients who had received no prior treatment, experienced tumour shrinkage and 14 per cent had no detectable cancer, at a median follow up of 15 months.

The drug has been at the centre of debate in New Zealand, after a decision by drug-buying agency Pharmac not to fund it prompted a complaint by makers Merck Sharp and Dohme to Health Minister Jonathan Coleman.

Though Pharmac and Coleman have questioned its proven effectiveness, the Cancer Society is advocating the drug, which is approved for use in New Zealand.

Pharmac is instead in favour of funding the equivalent melanoma drug Opdivo.

Denny says checkpoint inhibitors often have the added benefit of longer-lasting effects against the cancers. "Not every one will get that longer-lasting response, but a significant minority do.

"They may only need therapy for two or three years or less, and remission will continue.

"While these drugs are still coming through the system, it's all still very exciting because 30 to 40 per cent of patients may respond to one of these compounds, and in five or six years, they'll still be looking good."

He says checkpoint inhibitors shouldn't be confused with immune stimulants, which re-stimulate the immune system after it has been shut down by a different process in cancer cells.

Denny acknowledges a key question surrounding these drugs is their cost. Patients who used Keytruda, for example, require a new cycle of treatment every three weeks and, at a cost of around $10,000 per patient, per cycle, depending on weight, the treatment remains out of reach for many.

"At the moment, there may be only one or two immunotherapy drugs on the market, but there's shortly going to be half a dozen and that will drive prices down."

5. It takes two: bio-markers and targeted drugs

Even with the plethora of cancer drugs at our disposal today, patients don't benefit from all of them.

How do we ensure the right drugs are targeted at the right patients?

Denny feels it is crucial to pair drugs with cancer bio-markers that detect whether a tumour secretes the molecule the drug is aimed at, and thus acts as an indicator of the body's specific response to the cancer.

For new drugs submitted to the US Food and Drug Administration (FDA) for approval, it is now almost mandatory that they come accompanied with biomarker tests.

"This is really sharpening up targeted therapies," says Denny.

"In the past, drugs have failed trials because not enough people responded, but if we'd known what the target was and we had a bio-marker for those drugs, they might have been successful."

The advent of bio-markers is helping stem what has been a high attrition rate of potentially effective drugs forced to undergo conventional assessments, while also providing a relatively clear picture as to how drugs might perform.

As so-called "surrogate endpoints", they could indicate the effects of a certain drug on cancer progression and survival, an approach which is being increasingly relied upon for drug development as it saves time, effort and money.

Though developing bio-markers for drugs is still relatively time-consuming, using it to screen potential patients is relatively straight forward. In New Zealand, the use of bio-markers is growing as clinicians use new agents that come with them. "They are keen as anyone to limit the number of drug treatments given to patients."

As with immunotherapy drugs, affordability would remain a big obstacle to patients seeking these specifically-targeted drugs. "If one drug costs $200,000, you won't take a cocktail of four ... so there will have to be some understanding of finances."

The biology breakthrough and the hurricane

Professor Mike Berridge of the Wellington-based Malaghan Institute. Photo / Malaghan Institute
Professor Mike Berridge of the Wellington-based Malaghan Institute. Photo / Malaghan Institute

It was one of the biggest scientific discoveries in New Zealand last year - but it might have been made years earlier had it not been for a strange twist of fate involving one of the deadliest hurricanes in history.

In leading journal Cell Metabolism, Professor Mike Berridge of the Wellington-based Malaghan Institute and Australian colleagues reported, for the first time, movement of mitochondrial DNA between cells in an animal tumour.

Unrelated to the nuclear DNA which creates our primary genetic profile, mitochondrial DNA encodes key proteins in the machinery which converts energy from food into a form of chemical energy that is particularly important for brain and muscle function.

Until that point, scientists had believed these genes stayed within cells, except during reproduction.

But Berridge was able to demonstrate that, after mitochondrial DNA was removed from breast cancers and melanomas in mice, replacement mitochondrial DNA naturally shifted from surrounding normal tissue.

After adopting the new DNA, the cancer cells went on to form tumours that spread to other parts of the body.

It was seen as a leap in the science of cellular biology, potentially ushering in a new field where synthetic mitochondrial DNA could be custom-designed to replace defective genes.

Only after the breakthrough did the scientists learn that researchers in New Orleans had been investigating the same possibility a decade earlier.

After being able to show mitochondrial transfer from human mesenchymal stem cells to lung cancer cells without mitochondrial DNA, researchers Scott Olson and Jeff Spees were developing similar mouse tumour cell lines.

They had planned to inject these into immune-deficient mice to determine whether mitochondrial transfer occurred in animals, but their work was cut short in August 2005, when Hurricane Katrina slammed into the Louisiana coast.

Most of the cell samples were lost when power was cut to the lab; a casualty among more than $215 million worth of funded health studies at colleges and universities affected by the hurricane.

Olson wrote up his PhD thesis and moved on, and attempts to resurrect his project were unsuccessful.

When the Cell Metabolism paper was published, he wrote to Berridge and his colleagues to offer his congratulations.

"Of course we did it without any knowledge of their involvement and that only came to light when Scott Olson emailed us to congratulate us and tell us the whole story," Berridge said.

"It was absolutely fascinating."

The tale showed that ideas - even those that led to breakthroughs - weren't unique.

"They had the idea with the same mouse cell lines that we picked up and worked with as our second option."

With a $840,000 Marsden Fund grant, Berridge is now investigating whether mitochondrial transfer is facilitated by mitochondrial DNA damage.

- NZ Herald

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