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New hope for aggressive breast cancers as diabetes drug creates treatment ‘sweet spot’

24 Jun 2019

A drug commonly used to treat Type 2 diabetes can force breast cancer ‘stem cells’ to become reliant on sugar, opening up new ways to target aggressive forms of the disease, new research has found.

The study, funded by charity Breast Cancer Now, found that low-dose treatment with Type 2 diabetes drug metformin traps breast cancer stem cells in a glucose addiction – enabling scientists to target them using emerging drugs called CtBP inhibitors.

It is hoped the findings could now allow combinations of metformin and CtBP inhibitors to be developed and trialled in patients, leading to new ways to stop the spread of ‘triple negative’ breast cancers – a hard-to-treat form of the disease that is more common in younger women and lacks targeted treatments.

Over 8,000 women in the UK are diagnosed with triple negative breast cancer each year – so-named due to the absence of three key receptors that can be targeted in other forms of the disease. Survival outcomes for these patients are often poor, and it is thought that specialised cells called breast cancer stem cells are responsible for the disease spreading and becoming incurable.

Breast cancer stem cells normally rely on both oxygen and glucose for the energy they need to grow and survive.

However, a special feature of these cells is their ability to alter how they produce their energy depending on their surroundings.

They can shift their metabolism to rely more heavily on glucose, which they break down into smaller energy units in a process called glycolysis.

In a new study published in Carcinogenesis, researchers at the University of Southampton found that long-term, low-dose treatment with metformin – commonly used to treat Type 2 diabetes, a condition resulting in high glucose levels in the blood – altered the metabolism of breast cancer stem cells in the lab.

To survive the metformin treatment, the cancer cells switched their metabolism to become more reliant on glucose – which created a new treatment ‘sweet spot’.

These sugar-dependent cells had higher rates of glycolysis and increased activity of proteins called CtBPs, which fuel cancer growth, meaning that the cells were more sensitive to CtBP inhibitors.

The team, led by Dr Jeremy Blaydes, found that the sequence of treating cancer cells with low-dose metformin followed by silencing the CtBP genes led to a significant reduction – of up to 76% – in the growth of breast cancer stem cells.

Breast cancer stem cells that had changed the way they produce energy in response to metformin treatment also showed increased expression of several genes.

It is hoped that some of these genes could in future be used as biomarkers to indicate that cancer stem cells have shifted their metabolism, which could help identify the patients that would benefit most from CtBP inhibitors.

The team at the University of Southampton now plan to develop and refine molecules that can target CtBPs in breast cancer stem cells and stop them spreading – and hope that exploiting the metabolism of cancer cells in this way could lead to new treatment options for patients with breast cancer, and potentially other types of cancer.

Lead author Dr Jeremy Blaydes, Reader in Cancer Cell Biology at the University of Southampton, said:

“Our work has given us the first glimpse into how changes in metabolism can alter the behaviour of breast cancer stem cells and reveal new targets for therapy. We are only beginning to scratch the surface in this area of research, and we now need to push forward the development of CtBP inhibitors as breast cancer drugs. We hope these could lead to new treatment options for breast cancer patients who most need it.”

Baroness Delyth Morgan, Chief Executive at Breast Cancer Care and Breast Cancer Now, which funded the study, said:

“It’s really exciting that a diabetes drug could force breast cancer stem cells to change their energy supply to help us treat aggressive ‘triple negative’ tumours in the future.

“With patients still lacking targeted therapies, and these tumours being more common in younger women, triple negative breast cancer remains one of the greatest areas of unmet need in breast cancer."

“Breast cancer stem cells are thought to be central to the disease spreading around the body, where it becomes incurable, and so it’s incredibly promising that these early findings could lead to a new way to outsmart these elusive cells."

“We look forward to further studies to develop and trial combinations of metformin and CtBP inhibitors in patients. By creating a new treatment ‘sweet spot’ in aggressive tumours, we hope this research could take us closer to our goal that by 2050, everyone who develops breast cancer will live, and live well.”

Source: Breast Cancer Now