Targeting cancer at the cellular level

With the global incidence of cancer expected to rise dramatically by 75 per cent to 35 million new cases annually in 2050, Associate Professor Paul Harris hopes to address what he believes is a “critical need” to develop new technology in cancer therapeutics.

“Cancer is increasing and they just seem to get harder and harder to treat. And while we have an arsenal of drugs to treat people, sometimes they just don’t respond,” he says.

Rather than using chemotherapy or radiation that can “flood the whole body”, Paul wants to restrict the lethal damage to tumours by using Boron Neutron Capture Therapy (BNCT), which places atoms of enriched boron-10 directly into cancer cells to absorb a neutron beam.

“Boron will decompose into a lithium and some gamma rays and other charged particles which are also toxic, so should hopefully kill cancer cells,” says Paul, who leads a passionate chemistry group within the School of Biological Sciences.

Not that the use of BNCT to treat cancer is anything new. Far from it. The therapeutic potential of boron-10 was recognised as far back as the 1930s, and Finland was one of the first countries to embrace the treatment – albeit with the downside that a hospital had to be located next to a nuclear reactor to provide neutron beams.

However, the “big game changer,” according to Paul, is the development of neutron accelerators powered by electricity which have opened up new avenues of treatment in Europe, the United States and Asia. “And hopefully we can be a part of that soon,” he says.

The more immediate challenge is to tackle some of the chemistry which has fallen behind because some of the boron compounds being used are not selective for cancer cells.

“There must be a better way of getting boron into the cancer cells rather than using indiscriminate chemotherapy-like drugs that attack the cancer cells but make you very ill in the process because they also target your healthy cells,” says Paul.

To that end, researchers in the Harris Peptide Laboratory are looking to develop a peptide consisting of a chain of amino acids that will effectively act as a “trojan horse” to carry boron-10 inside cancer cells.

“We’re targeting this particular cell surface protein that’s pretty much only expressed by cancer cells but not by healthy ones,” Paul says. “It’s almost like tricking the cancer cells to uptake a cargo that can then be irradiated.”

While BNCT has been a niche cancer therapy that targeted inoperable squamous cell head and neck cancers overseas, the Auckland project aims to develop peptide boron-10 carriers capable of achieving therapeutic delivery to multiple cancer types to achieve its full potential.

However, because peptides are degraded by enzymes when they enter the body, their half-life will need to be extended in order to find their cancerous targets. Nevertheless, Paul says that “once we have what we call in chemistry a ‘hit’ compound that works, we can work out where we’re going from there”. 

Given the various challenges involved, from peptide and boron chemistry to drug formulation and clinical radiation oncology, a transdisciplinary research team consisting of a mix of experienced, mid-career and young scientists has been assembled in five countries.

In addition to chemistry and biology research fellows Dr Renata Kowalczyk and Dr Jiwon Hong, who lead those areas respectively, the team includes an oncologist and formulation chemist in Auckland, a boron chemist in Sydney, and contacts at the University of Birmingham, which recently commissioned a scaled-down version of the UK’s first neutron accelerator.

“Hopefully we could go over there with our boron-containing compounds and see how they interact with cancer cells in real time,” says Paul.

Interestingly, the Birmingham facility, and another full-scale version in Finland – where Paul eventually hopes to conduct animal studies – were built by the US company Neutron Therapeutics which was co-founded by Auckland businessman Bill Buckley ONZM.

Well known as a world leader in the supply of precision electromagnets through his South Auckland-based Buckley Systems, the 81-year-old speedway fan who won a 2020 New Zealand Innovator of the Year Award “knows what we’re doing”, says Paul.

Earlier this year, Finland’s Helsinki University Hospital treated its first head and neck cancer patients using the Neutron Therapeutics nuBeam® device, and it’s hoped that the Kiwi connection will lead to the installation of a neutron accelerator in New Zealand.

Kick-started by an MBIE Smart Ideas grant in 2020, the project was initially interrupted by COVID and has since received additional funding from the University of Auckland’s Te Aka Centre for Cancer Research, which allowed PhD students to make boronated peptides.

Funding from the Maurice Wilkins Centre of Research Excellence has helped to set up biological assays, and a Health Research Council Explorer Grant will fund consumables and hopefully a trip to the UK to inspect the Birmingham accelerator.

But having drafted an ambitious ten-year pathway toward human clinical trials and commercialisation, Paul knows better than most about the trials and tribulations of achieving goals, which can take at least 20 years in some cases.

As the co-inventor of Trofinetide, one of only a handful of
drugs developed in New Zealand to gain all-important FDA approval, the
medication now marketed as DAYBUE was fast-tracked because it was the first
known treatment for Rett Syndrome.

That probably means the researchers will need to develop a peptide that targets a specific problem, such as lung cancer in the Māori population or a cancer with no other cure or very limited treatment options, to attract the interest of multinational pharmaceutical companies.

“If we have a really good peptide that goes inside cancer cells specifically and effectively, then big pharma may be interested and they can say we want to license this off you and we want to sell it to XYZ, and then we will generate royalties and support people in New Zealand.”

As always, gaining FDA approval and future funding will be key issues. However, Paul believes that instead of shipping our intellectual property overseas, a real opportunity exists for New Zealand to become a BNCT hub that supports local scientists and clinicians.

“Why can’t we bring everyone together including all the communities, academic researchers, Te Aka, Auckland Hospital, oncologists, imaging people, and get this moving as a big team. And then I think people will see there’s a future in doing some science in New Zealand.”

And while neither the boron nor the peptides are currently manufactured commercially in New Zealand, he believes that peptide manufacture could be done here. “In the end it’s just chemistry, time and people really, so there’s no reason we couldn’t do it here as long as there was a will and a way to fund it.”

Having lost both his parents to cancer after their condition deteriorated rapidly, Paul says there has to be other treatment options. “I’m not saying complete cure, but increase the quality or quantity of their life really.”

Rather than just making a new compound, he’s also motivated by doing chemistry for a purpose.

“It’d be nice to actually make a difference, not just in the lab but outside the lab and to see something progress further beyond just your day-to-day experiments you do with everyone.”