SECOND STRIKE Professor Leonie Young and her colleagues at RCSI are discovering crucial differences between primary and recurrent tumours in breast cancer, and developing new strategies to target those cancers that return. Dr Claire O’Connell reports
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ancer is a diagnosis that nobody wants to receive. But for some people, they hear it more than once. Around the world, hundreds of thousands of women each year learn that the breast cancer they were treated for has returned, often in other parts of their bodies. These recurrent tumours can be highly resistant to the original treatment, and this is where Professor Leonie Young and colleagues at RCSI are on a mission to develop more targeted medicines to tackle them. “Our main interest is in advanced disease where the cancer has recurred, the tumour has come back locally in the breast or in another organ,” explains Professor Young. “We are very much interested in looking at the difference between that primary tumour, the first tumour, and the tumour that returns. These returning tumours are usually more aggressive, they are harder to treat and there is a lack of targeted therapies out there for this recurrence. If we can find differences between the primary and recurrent tumours, this opens up new opportunities for new ways of targeting them.” The vast majority of women, around 70 per cent, who are diagnosed with breast cancer initially have a type of tumour that is studded with large numbers of estrogen receptors, and such tumours can be treated with estrogen-receptor blocking medications. But in about 40 per cent of those cases – approximately half a million women each year – the disease will come back and may spread.
Concerted approach
To find out what is going on requires a concerted approach involving scientists, surgeons and patients. Professor Young, an expert in cell and molecular biology, works in tandem with clinical experts in Beaumont Hospital, including Professor Arnold Hill, Professor of Surgery and Head of the School of Medicine, RCSI. “We are very lucky to be working so closely with our clinical colleagues, as they are treating patients and have a deep understanding of the clinical side of breast cancer and its recurrence,” she says. As a group, they are working with Clinical Trials Ireland on a large clinical trial across all the cancer-treating hospitals in Ireland. The trial recruits consenting patients when they present with primary breast cancer that is estrogen-receptor (ER) positive, and collects blood samples from those patients before and after surgery to remove the tumour, as well as surplus tissue from the primary tumour and from any later recurrent tumour.
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Professor Young’s research is focused on uncovering networks involved in SRC-mediated resistance in breast cancer to both tamoxifen and aromatase inhibitors. In doing so, these investigations will identify markers that predict these outcomes and importantly develop new therapeutic targets. The research focuses on SRC-1 and takes a high-level view to harness data from high throughput experimental methods, molecular studies, functional models and translational studies and capitalises on translational research, in particular making use of primary breast cell cultures derived from patient tumours and large clinical datasets. By modelling the mechanism(s) of resistance associated with SRC-1, this research has defined new predictive markers and therapeutic targets suitable for commercial development and clinical trial interventions that could improve patient outcomes.
Professor Young’s lab then analyses these samples for patterns in DNA structure and how genes are switched on or silenced: they compare and search for small but potentially important differences between how the primary and later tumours go about their biochemical business. “It involves a lot of data integration,” she explains. “We are looking at pathways that are changing and opportunities where we might have to intervene.” So far, almost 2,500 women have been recruited onto the study, building up a biobank of patient samples and data that now includes 21 cases where a primary tumour in the breast later spread to the brain. “We have the largest biobank in Ireland for this disease,” says Professor Young. “And we also collaborate with colleagues internationally, sharing and comparing data to see if we can spot similar patterns across different groups of patients. We are looking to see if there are common pathways that extend over local issues, such as slightly different treatment regimes.”
Searching in the bigger picture
Their search is turning up interesting findings, including a protein called Ret, which crops up in relatively large amounts on the surface of recurrent tumours in the brain. That discovery has led to Professor Young working with an industry partner – a company that makes a molecule to block Ret – to see if jamming the protein could diminish these recurring tumours. As well as looking at the effects of blocking Ret in laboratory models, Professor Young continues to look at the bigger picture of what is going on in the patient
