Solving Global Problems With Molecular Focus

As research has shown, cancer is not just one thing, and to imagine we will find a single silver bullet solution for it simply does not do service to the complexity to be found in this killer group of diseases – each with its own characteristics, risk factors and causes. This inherent variability of cancer though, has over the last century, lent itself to the growing field of precision and personalised medicine, the hope of which is that treatments will one day be tailored to the genetic changes to each person’s cancer.

Within New Zealand, we live with the sobering fact that cancer is the single biggest cause of death, with most us having some experience of it, either personally or through a relative or friend. We also suffer from one of the highest rates of breast cancer in the world, which is responsible for more than 600 deaths and over 3,300 women being diagnosed every year. Furthermore, around one in five women with breast cancer will exhibit the notorious triple-negative tumour, which possesses devastatingly unique molecular profile.

Alongside such startling cancer statistics, researchers around the world, including a hotbed of New Zealand scientists, are starting to unlock the potential of molecularly targeted approaches to the most aggressive breast cancers. Dr. Lisa Pilkington is one such scientist pushing the boundaries for a cutting-edge treatment specifically for that most aggressive and difficult-to-treat variant of breast cancer – triple-negative. “As a scientist, personally, you look for where the greatest need is, and also where your research can have the greatest impact and potentially achieve the greatest good,” says Pilkington. “Breast cancer is such a devastating disease and it is really important to try and target, in particular, triple-negative breast cancer.”

The unique molecular signature of triple-negative, as the name implies, is such that it tests negative for all three receptors – oestrogen, progesterone and HER2 – which traditional therapies will ordinarily zero-in on to get at the Achilles heel of the tumour. Consequently, there are no specifically targeted solutions to attack the unique vulnerabilities of this particular form of breast cancer, leaving chemotherapy as the only systemic therapy for patients. “With triple-negative, you can only treat it through those very broad, systemic cancer treatments, which basically target any fast-growing cells. These agents can’t distinguish between a cancer cell and a healthy cell; they just go for any fast-growing cells, which is why it also goes for your hair and things like that, and why you have such devastating side-effects,” says Pilkington. “Triple-negative can be treated this way but that is not necessarily the most effective way, and so what we’re trying to do now is to target more specific responses as we start to understand the biology of these cancers more – that has definitely been the drive in more recent years and also where I think you typically get the most successful cancer treatments.”

Pilkington has her own personal connection with cancer through her aunt being diagnosed with breast cancer when she first started university, as well as experiencing her own brush with a rare form of cancer in her salivary gland just as she was finishing her Honours degree and embarking on her PhD in organic and medicinal chemistry. “I’ve seen first-hand what it’s like to go through breast cancer. My aunt’s suffering was huge, but the people around her also suffered too – cancer has such a big impact. So, this cause is very personal. To me, breast cancer is a disease you can put a face to.”

Her personal experience with the disease has only served to heighten her drive to make a difference, offering hope to that subset of triple-negative patients who have few effective treatment options and often face a poor prognosis. “Having your own personal connection provides very much a different perspective to what you’re doing. For me, it is extremely personal and it’s extremely motivating. When you’re looking at the data or you’re working towards something, there is added meaning behind it,” says Pilkington. “As a scientist, you obviously have to focus on the problem at hand but I know for me and many colleagues and other people who are in the same situation, there is that knowledge in the background that you don’t ever forget – that there are real people who are suffering and there is a potential for having such an amazing impact on those people who are suffering. It’s extremely motivating and it’s extremely humbling as well.”

Pilkington’s brush with cancer involved surgery followed by radiation therapy every day for six weeks during which time she continued going to the lab, determined to not let the treatment and its side-effects affect her life and work. Fortunately, the treatment was successful though the experience has left its mark in more ways than one. “I still have effects from the cancer. I have no feeling in my ear and the lower left side of my face as a result of the treatments, particularly as they had to cut very close to the nerve during surgery. I still get a dry mouth, and I have to be very careful in the sun,” says Pilkington. “It was terrifying being faced with my own mortality. There is a chance the cancer could come back and that’s something I still live with every day. I’ve had a couple of scares… It’s always at the back of my mind.”

The lack of effective treatments in the triple-negative subtype of breast cancer is not lost on New Zealand’s largest non-government funder of breast cancer research, Breast Cancer Foundation NZ, with whom Pilkington has forged a relationship that continues to build on the organisation’s connection with the public, the scientific and medical communities, and the people she could potentially be helping with her work. “I think Breast Cancer Foundation NZ is an extraordinary organisation, providing people with something they can’t get anywhere else,” says Pilkington. “I’m so impressed with all of the different ways the organisation connects with the public – from the pink caravan to the nurses, who know exactly what people are going through and the issues they face.”

This has led to Pilkington being awarded the not-for-profit organistion’s Ronald Kay Science Fellowship to the tune of $80,000 to carry out her specialised research in triple-negative breast cancer. “It was an honour to be awarded the fellowship, it’s a privilege. Meeting the Breast Cancer Foundation NZ team was very special for me,” says Pilkington. “It was lovely seeing everyone working towards this common goal. I feel a real connection with the charity and the people who support it. And I feel a sense of responsibility to do the best that I can because it’s such an important field of research I feel very passionate about.”

The funding reflects Breast Cancer Foundation NZ’s steadfast commitment to supporting ground-breaking research projects that push for new frontiers in early detection, treatment and support, and to ultimately improve outcomes for breast cancer patients. “Breast Cancer Foundation is that bridge between the funding, the science and the research but also, they are frontline with the patients and those offering support to families,” says Pilkington. “And there is also this really big drive to not be afraid of breast cancer and of being very aware. I know how hard they work to support people and to raise awareness – they also have their Breast Cancer Awareness Month in October – so it is actually motivation for me on top of the fact that I am a sufferer of cancer.”

Pilkington’s latest research has shone a light on a previously identified enzyme called PC-PLC that could offer a viable target for uniquely treating triple-negative breast cancer, in that it has been found to promote the growth of triple-negative breast cancer. “The [PC-PLC] enzymes are basically little engines in the cells and what has been shown is that this enzyme seems to be up-regulated – it seems to work at a higher rate in these triple-negative breast cancer cells,” says Pilkington. “Compared with normal cells, this enzyme is going a bit haywire and this might be one of the reasons why this triple-negative breast cancer has developed. In going a bit haywire, it is causing this very fast cell growth, and these cells are triple-negative breast cancer cells. They’ve mutated into something not good – not a normal, healthy cell.”

With this hyperactive enzyme in mind, Pilkington and her team have gone on to identify a promising new class of molecules that is important for killing triple-negative breast cancer cells and stopping their growth – new compounds that have the ability to inhibit the PC-PLC enzyme and in turn, have the potential to lead to effective treatments for triple-negative cancer. “Essentially, the compound goes into a sort of a pocket in the enzyme and deactivates it or slows its function down,” Pilkington explains. “And if you slowed down the workings of this PC-PLC enzyme, it would mean that it would slow the growth of triple-negative breast cancer or it would stop the function of these cells and ideally, hopefully treat these cells and treat the patient.”

The ultimate challenge, however – and what the impetus behind the Ronald Kay Science Fellowship funding is – lies in the fact that these special molecules are unstable. They are unable to survive for very long in any new kind of system that mimics the body, degrading in seconds and rendering them incapable of reaching their target, the PC-PLC enzyme, to ultimately kill the triple-negative cancer cells. “What we’re trying to do is make the molecules remain stable to the body environment. We’re aiming to make slight modifications to the structure, so they can get to where they need to go and inhibit the enzyme,” Pilkington explains.

Since embarking on a career in scientific research, specialising in pushing the boundaries of cancer knowledge, Pilkington is no stranger to failure, it being an essential, frequent and inescapable aspect of experimental research and scientific discovery. “As with all research, there are big challenges. You know, research is 90 percent failure and ten percent success – probably more so,” says Pilkington. “I know I take – and I think a lot of people take – failure very personally. But I think in the end, it’s about being comfortable with failure and knowing that it is – particularly in research but also in general – part of the process to success because you can’t have success without failure. She adds, “I always say to people, if they’ve had something go wrong in the lab or the research is not going well, ‘You know what? It’s going to make it all the more sweeter and all the more satisfying when you get that success.’”

A big part of Pilkington’s drive in the scientific research arena is also in serving as an inspiration for younger women and girls showing an interest in STEM, as well as a mentor for young people already in STEM with their research and career paths. “I am very passionate about getting more young women into science. I’ve been invited into schools and to STEM holiday camps to talk about what it’s like to work in this field. It’s such a joy to give kids a face and an example of someone who works in science,” says Pilkington. “I hope when I go to STEM programmes, they look at me and say, ‘Oh, she’s quite cool. I think I want to be like her.’ I hope that by being the best I can be, along with others, that people can see really good, strong role models,” says Pilkington.
While occupations in science, technology, engineering and mathematics are expected to experience rapid growth in the coming decade, a gender gap in STEM persists with fewer women than men represented at senior levels in science, often beginning in education and fuelled by stereotypes and expectations regarding “women’s work.” Pilkington has experienced these die-hard sentiments first-hand but feels optimistic about a shift for the better in years to come. “When I tell somebody what I do, if they don’t know me, you get this look of ‘Oh!’ – of surprise and shock – like, ‘You don’t look like the normal scientists that I have in my head,’” says Pilkington. “I think it’s just about breaking perceptions, not only of people within academia or university or research, but just in general because kids grow up in that kind of environment. I think there are some really positive female science role models out there and I think it’s improving, so by the time that I’m near the end of my career, it could be that everything is 50-50 and there are women represented at every level in a very equitable way. I don’t think we’re there yet, but I have hope for the future that it will be the case.”

Pilkington and her team’s ground-breaking research is right at the forefront of the intense and burgeoning interest of scientists around the world in identifying what fuels the growth of triple-negative breast cancer and of finding that holy grail in a targeted therapy to treat it in the future. “Now I want to do research that makes a difference,” Pilkington enthuses. “I want to work towards something that has meaning and impact for people. I’m attracted to this cause because I’ve seen how much it affects people’s lives. Knowing that what I’ve done might one day contribute in some way to someone’s life is what motivates me to go to work each day.”

Breast Cancer in New Zealand:

Breast cancer is the most common cancer for Kiwi women and the third most common cancer overall.
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More than 3,300 women across the country are diagnosed with breast cancer every year (that’s nine women a day). One Māori woman a day will be diagnosed. Twenty-five men are diagnosed each year too.
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We still lose more than 650 Kiwi women a year through breast cancer.
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The ten-year survival rate if breast cancer is detected by a mammogram is 92 percent, compared with 75 percent if a lump is the first sign.
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Breast cancer is most treatable when it’s found early. Women should be breast aware from age 20, which means you need to know the normal look and feel of your breasts, so you can tell your doctor if there any changes.
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BCFNZ recommends considering annual mammograms from 40 to 49, then every two years from 50. Free mammograms through BreastScreen Aotearoa are available when you’re 45 to 69, and the Government has committed to extending the age to 74.
breastcancerfoundation.org.nz

Ways to get involved for Breast Cancer Awareness Month:

Pink Ribbon Walk in Auckland, Wellington, Christchurch & Queenstown
Walk five or ten kilometres for the ones you love, sign up at pinkribbonwalk.co.nz

Pink Ribbon Street Appeal
Grab a bucket and donate two hours of your time to be a collector in your community on Friday 30th or Saturday 31st October, sign up at
pinkribbonvolunteer.co.nz

Pink for a Day
Join the hundreds of workplaces that go pink during Breast Cancer Awareness Month and start conversations about breast health and wellbeing.