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Two is better than one: new combination approach halts breast cancer spread

December 18th, 2016

NBCF-funded breast cancer researcher, Dr Samantha Oakes from the Garvan Institute has identified a new driver in the spread of breast cancer to other tissues.

Dr Oakes and her research team showed for the first time in mice that a well-known ‘survival protein’ (MCL-1) is important in the spread (metastasis) of breast cancers – and that blocking MCL-1 can decrease cancer spread. Importantly, blocking MCL-1 can ‘turbo-charge’ the anti-metastatic drug dasatinib, suggesting possible future combination therapies to combat metastatic breast cancer.

Many forms of breast cancer respond well to therapy – but stage 4 (metastatic) breast cancer, which has already spread to other sites in the body, does not. Essentially incurable, metastatic breast cancer accounts for almost all disease deaths[i].

“Every year in Australia, approximately 3000 women and men will die of breast cancer. As far as I’m concerned that’s unacceptable and we urgently need better therapeutic interventions to stop these patients from dying. And that’s why I’m excited about our latest research – because it suggests a promising way to turbo-charge the effects of an existing anti-cancer drug that targets advanced cancer,” says Dr Oakes.

In the new research paper, ­Dr Oakes and her team show that the protein MCL-1 drives the spread of breast cancer to other tissues. Dr Oakes said the finding took the team by surprise.

“MCL-1 is well known as a ‘survival factor’ ­that can flick the switch between life and death in cancer cells – but until now no one has ever shown that it helps cancers to spread. First, we were testing the effect of MCL-1 on cells derived from triple-negative breast cancers – the type of breast cancer that frequently develops resistance to treatment and spread to other organs. When we turned the protein off, we saw cancer cells dying in many cases.

“But we weren’t prepared for what we saw next. We used a state-of-the-art approach that faithfully replicates how human breast cancer escapes from the breast and spreads throughout the body – and we saw that, by turning off the MCL-1 protein in invasive breast cancer cells, we could largely suppress the spread of cancer.”

The researchers went on to explore how MCL-1 drives the spread of cancer through the body. They showed that, in cancer cells, MCL-1 regulates proteins called ‘Src-family kinases’ – which are extremely important for cancer progression and spread in many types of cancer.

The next surprise came when the research team blocked the action of MCL-1 while treating with dasatinib (Sprycel), an anti-metastatic drug that, like MCL-1, affects Src-family kinases.

“We found that blocking MCL-1 could ‘turbo-charge’ the effects of dasatinib; that is, the two approaches together blocked the progression of breast cancer much more effectively than either approach alone.”

Crucial funding for the research came from NBCF, through an Early Career Fellowship awarded to Dr Oakes. Dr Oakes’ research has been supported by NBCF since 2008.

Dr Alessandra Muntoni, Director of Research Investment at the National Breast Cancer Foundation, congratulated Dr Oakes and said that the findings are important for Australian breast cancer patients. “This is a landmark study for the progression of breast cancer research in Australia,” said Dr Muntoni. “It also highlights the National Breast Cancer Foundation’s strong focus and research investment in preventing and treating metastatic breast cancer.”

Dr Oakes says, “These findings have implications that could reach far beyond triple-negative breast cancer and in fact beyond all breast cancers. This is because we know MCL-1 is a crucial survival factor in a wide range of cancers, and Src-family kinases are hugely important for cancer spread in a great many cancers.

“For this reason, we believe that this type of dual therapeutic approach, which we have tested successfully in pre-clinical models, could hold great promise for the many cancers that rely on MCL-1 and Src-family kinases to survive and spread.”

The Garvan, with the assistance of patent attorneys FB Rice, has now filed a provisional patent with IP Australia, the Australian Government’s office of intellectual property that will assist the development of this new dual breast cancer therapy involving dasatinib and MCL-1 blockade towards clinical use.

The findings have just been published in the journal Breast Cancer Research.

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