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26 Jul 2018

A world-first study has revealed that triple negative breast tumours can be treated with a drug that cuts the communication between normal cells and tumour cells.

Triple negative breast tumours are the most aggressive and have the fewest treatment options, but Australian researchers were part of a team that has found what is described as a secret hotline between breast cancers and the normal cells surrounding them.

This two-way communication was uncovered in mouse models of disease and investigated further in people. In a Phase I clinical trial, a drug known as SMOi was used to block the communication, resulting in promising clinical responses in several breast cancer patients.

The findings have been published in international journal Nature Communications and are the result of a collaboration between researchers at the Garvan Institute of Medical Research in Sydney, the Centre for Cancer Biology in Adelaide, and GEICAM, a translational breast cancer research group Spain.

The research focused on triple negative breast cancer, where treatment options lag far behind other breast cancer types. Triple negative breast cancer is hard to treat because its cells lack crucial landmarks that are used as targets for medical treatment in other breast cancers.

The researchers investigated the role of non-cancerous cells, which along with cancer cells are a part of every breast tumour. They then analysed the genetic output of thousands of individual cells within the tumour.

Importantly, they found that cancer cells send signals to neighbouring non-cancerous cells (known as cancer-associated fibroblasts or CAFs).  And CAFs talk back: they send back their own signals that help the cancer cells become drug-resistant and to enter a dangerous state the researchers call stem-like.

The researchers disrupted the hotline between CAFs and cancer cells by using the drug, which targets CAFs and stops them from pushing tumour cells towards a stem-like state. In mouse models of triple negative breast cancer, treatment with the drug reduced the spread of cancer, slowed tumour growth, increased sensitivity to chemotherapy and improved survival.

Following the success in mice, The Garvan Institute’s Associate Professor Alex Swarbrick, who led the research, worked with the Spanish translational breast cancer group GEICAM to carry out a Phase I clinical trial in 12 triple negative patients, in which several patients saw measurable responses to the drug.

One patient, who had an aggressive, metastatic triple negative breast cancer that was unresponsive to several other treatments, achieved a ‘complete response’ – her metastatic tumour shrank and became undetectable.

Professor Swarbrick said the research has led to a major step forward in our understanding of how CAFs can drive aggressive cancer.

“It’s the stem-like cells in breast tumours that are particularly bad players, as they can travel to distant parts of the body to create new tumours and are resistant to treatment,” he said.

“We knew that CAFs played a role in turning cancer cells into a stem-like state, but now we know exactly how they communicate with tumours – and how to stop them talking to one another.

“We found that when they received signals from cancer cells, CAFs produced large amounts of collagen, a protein that forms a dense scaffold in the tumour, which increased its stiffness and helped to maintain the stem-like state of the cancer cells.

“When we disrupted the hotline in our models and also in our patients, collagen density was reduced, and the cancer cells weren’t as stem-like anymore.”

Phase I clinical trials in a small number of patients are now complete. The results have been so promising that Professor Swarbrick and his medical collaborators are currently working on designing and funding Phase II trials to test the effectiveness of this treatment in a larger group of patients.

This work was supported by funding from the National Health and Medical Research Council, Love Your Sister, John and Deborah McMurtrie, the National Breast Cancer Foundation, RT Hall Trust and Novartis.

The Centre for Cancer Biology is an alliance between the University of South Australia and SA Pathology.



Published: 26 Jul 2018