A new €5 million research programme aims to improve survival rates and quality of life for patients with advanced breast cancer. In particular, the Prism (Precision Oncology Research Initiative for Metastatic Breast Cancer) programme will study extremely hard to treat metastatic breast cancer tumours in the brain.
The pioneering four-year initiative, funded by Breast Cancer Ireland, Carrick Therapeutics, and the Research Ireland Strategic Partnership Programme, represents a significant step forward in the fight against advanced breast cancer. Led by the RCSI Cancer Centre, with Prof Leonie Young, scientific director of the Beaumont RCSI Cancer Centre serving as the programme director and Dr Damir Vareslija as co-director, key collaborators include University College Dublin, University College Cork, the University of Galway and Cancer Trials Ireland.
Prof Young explains that the tumours that form in the brain are particularly difficult to treat for several reasons. These include the plasticity of the tumours which allows them to adapt to quickly develop resistance to therapies used against them. The very aggressive nature of the tumours presents another challenge — in many instances, the patient will live for less than 12 months following diagnosis.
Another key issue is the blood-brain barrier. This is the layer of cells that defend the brain from harmful substances, germs and other things that could cause damage whilst also maintaining the brain’s delicate chemical balance. Unfortunately, it also has the effect of preventing certain drugs from getting through.
“It’s very tricky to treat,” says Young. “The pharmaceutical industry has been slow to take on these challenges because the short timelines involved make it difficult to demonstrate clinical efficacy. However, even three quality months extension to life would be beneficial to a patient. We know that if we understand the disease better, we can come up with new therapeutic targets.”
The Prism programme brings together a team of researchers and experts to carry out the first national longitudinal multiomic study for advanced breast cancer patients. This will use comprehensive genomic profiling to better understand and target the mechanisms of breast cancer spread (metastasis) and consequently, develop new, effective treatments.
In essence, the programme involves a four-year clinical trial during which the team will compare primary breast cancer tumours and secondary tumours which have developed in the brain to identify and understand the differences between them. This will assist in finding new therapeutic targets.
These targets can be genes or proteins expressed by the tumour which influence its behaviour in different ways. For example, by targeting a gene involved in the plasticity mechanism the tumour could be made more susceptible to existing therapies.
“We are looking for potential vulnerabilities,” says Young. “There are a lot of changes between primary and metastatic tumours, and we will investigate those changes to identify targets. For example, the brain is a very good environment for a tumour because it is rich in fats and so on. If you can break down the tumour’s communication system, it becomes an unsurvivable place for tumours.”
Young and Vareslija have been working with colleagues on breast cancer research for the past two decades and this has provided a very strong foundation for the Prism programme. “We are based in the RCSI Cancer Centre here in Beaumont Hospital which is also the National Centre for Neurosurgery. That gives us a unique advantage in terms of multiomic studies like this. We have been looking at tumours in the breast and brain and now have the world’s largest database on them. At the very heart of the programme is the multi-location clinical trial. Every patient seen at the different participating hospitals will be invited on to the trial. Samples will be shipped to us for omic assessment. If they do develop a metastatic tumour in the brain, we will assess that as well.”
The next step is the identification of targets. “Our approach is to take a target, validate it, develop a therapeutic, and demonstrate its efficacy in patient models. After that, we will look for partners to help develop it further. We will use the data along with computational and AI applications to design therapeutics.”
These therapeutics are likely to be highly specific. “Every tumour is different,” Varesliga explains. “We are getting to precision medicine. That’s the whole basis of our approach.” The programme could result in a suite of therapeutics with one or several of them being used on a particular tumour.
The second arm of the programme will see the team supporting Carrick Therapeutics, an oncology-focused biopharmaceutical company with its development of a new cancer therapy. “The company has just reached a first in-human trial stage for the new therapy,” says Young.
“We have four years of very hard work ahead of us and we have just started,” she concludes. “It’s terribly exciting and we feel we can make a real difference to this patient population.”