Targeting the drivers of difficult-to-treat breast cancers

Wednesday, 4 February, 2015
One quarter of breast cancer cases belong to two subtypes that are difficult to treat. EU-funded researchers are identifying new therapeutic targets for these patient groups. The research has already led to new diagnostic tools, while patients are already being enrolled for clinical trials.

World Cancer Day - 4th February 2015

Most breast cancers are characterised by the presence of receptors within cells, which are known to drive cancer and can be targeted by drugs. In the first subgroup, triple-negative breast cancer – which accounts for around 15% of all breast cancer cases – these receptors are missing, making traditional drugs ineffective. The second subgroup, invasive lobular carcinoma, accounting for around 10% of breast cancer cases, is relatively poorly understood and has limited treatment options.

A common link between these and other cancers are kinases. A type of enzyme, kinases are also at the heart of the RATHER project. There are around 500 within the human genome and they are known to be key drivers of cancer. The specific kinases behind cancer vary from one subtype to the next and identifying them is essential to developing treatments.

The RATHER team has been analysing 300 samples from breast cancer patients. Comparing samples enables the researchers to establish which kinases have been altered, and at which layer (DNA/RNA/protein).

Molecular profiling was used to spot alterations. This did not involve looking at thousands of glass slides under a microscope, as would have been done in the past. Instead, the team turned to digital pathology tools developed by one of the project partners, OncoMark. The innovative technology allows a computer to help the pathologist identify these alterations, saving significant time in the process, explains project co-coordinator William Gallagher of University College Dublin in Ireland.

Separating the culprits from the casualties

An altered kinase does not necessarily mean that it is responsible for the cancer – the alteration could be a result of the cancer. To make the distinction between the culprits and the casualties, the RATHER researchers took tumour cells, grew them, removed the enzyme and waited to see what would happen. “If changes occur when the gene is taken out, it could be a driver,” says Gallagher.

These studies led to a shortlist of cancer driver suspects. “We now need to prune it back a bit further,” says Gallagher.

But the team has already identified one very promising kinase, often altered in breast cancer sufferers and known as PI3K. It was identified early on in the project, so the team is already preparing for clinical trials to test drugs targeting this kinase. The trials are some way ahead of schedule: “The original plan was to start the enrolment of patients by the end of the project, but we actually hope to complete most of the patient recruitment during the lifetime of RATHER,” says Gallagher. The first patients will be enrolled in the coming weeks.

“We’re very excited about this,” says Gallagher. “This will be one of the first investigator-led clinical trials of its type in Europe.” Another EU-funded project, the EurocanPlatform Network of Excellence, is also providing support and resources towards the ground-breaking clinical trial.

In addition to the planned clinical trials and new diagnostics tools, the RATHER team is also very proud of its molecular portrait of the human kinome (the complete set of more than 500 kinases that make up its genome) in invasive lobular cancer. The portrait will be published before the end of the project.

Addressing both basic clinical research and the development of state-of-the art diagnostic tools, the RATHER project is quite unusual. But the breadth of topics covered will ensure that we won’t have heard the last of RATHER when the project comes to an end. Gallagher expects spin-off projects that will showcase the fruits of RATHER: the molecular portrait of invasive lobular cancer, new therapeutic options and further validation of these options.


Rational Therapy for Breast Cancer: Individualized Treatment for Difficult-to-Treat Breast Cancer Subtypes
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