The research, published in Scientific Advances, included the development of three mouse models to imitate how metastatic breast cancer spreads to the brain in humans. Using these models, US and Japanese scientists demonstrated that the stem cells successfully delivered the new therapy across the blood-brain barrier, resulting in prolonged lifespans for the mice.
'When breast cancer patients get metastasis to the brain, there's often not much we can do because therapeutics for brain metastatic cancer are scarce,' said corresponding author Dr Khalid Shah from the Harvard Stem Cell Institute in Massachusetts. 'Given the urgent need and magnitude of the problem, we set out to not only work on the development of a new therapeutic approach, but also to develop it in a way that maximises the likelihood that our findings will be clinically translatable.'
Between 15 and 30 percent of patients with metastatic breast cancer go on to develop brain metastasis. A subtype of breast cancer – called basal-like breast cancer – metastasises to the brain more frequently than other types of breast cancer. Patients with basal-like breast cancer brain metastasis tend to have a poor prognosis as the blood-brain barrier prevents therapies from reaching the brain. Testing any new drugs can also be difficult as animal models for breast cancer brain metastasis are limited.
By analysing patients' tissues from both breast and metastatic tumours in the brain, the researchers found that an excess of epidermal growth factor receptor (EGFR) and death receptors 4 and 5 (DR4/5) drive tumour growth. They genetically engineered a novel molecule that can target both EGFR and DR4/5 at the same time to induce cell death.
To test the new molecule, the researchers developed three different mouse models to reflect the different ways in which breast cancer can metastasise to the brain. The first model represented metastasis that forms a solid tumour in the middle of the brain, the second model reflected scattered metastasis, and the third model represented metastasis at the back of the brain.
The researchers then used stem cells, which can cross the blood-brain barrier and target tumours in the brain, to deliver the newly developed molecule to the brain metastases. They used donor tissue samples to create large batches of stem cells, meaning that these stem-cell delivery platforms can be produced efficiently and be readily available.
'Building these models was essential to testing our therapies because we wanted to mimic what happens in the patients,' Dr Shah said. 'We started our research by bringing findings in patients to mice, and now we are planning to go back to the patients.'
The US Food and Drug Administration is already reviewing a previous version of the researchers' novel therapy and the researchers hope that approval could pave the way for their newly developed stem-cell-delivered molecule.