Researchers at the University of Sheffield have received new funding to investigate if radium-223 (Ra-223), currently used to treat bone metastases in prostate cancer, might also help in bone spread from metastatic breast cancer.
The £142,714 award, from charity Breast Cancer Now, will enable a team led by Penelope Ottewell, professor of cancer biology at the University of Sheffield, to investigate the potential efficacy of the drug in combination with other agents.
In prostate cancer, Ra-223 given by injection rapidly concentrates in bone to release a small dose of radiation that only affects cells within the immediate vicinity, so it has minimal side effects. However, clinical trials have not shown similar success in bone metastases from breast cancer. In announcing the new funding, Breast Cancer Now said that the reason was believed to be that breast cancer cells are very good at repairing their DNA when it gets damaged.
Professor Ottewell's research is focused on advanced breast cancer, with particular emphasis on bone metastasis, aiming to identify specific molecular determinants involved in tumour cell intravasation, homing to bone, and colonisation of the metastatic site. She hopes to use this information to develop and apply new therapies to treat breast cancer bone metastasis. The team now plan to test Ra-223 in combination with other drugs that target DNA repair mechanisms, in the hope that this will improve efficacy.
Research Aims to "Unlock Potential" of Radium-223 in Breast Cancer
Speaking of the new research funding, she said: "Although Ra-223 is already used to treat prostate cancer that’s spread to the bone, it’s not been as successful in clinical trials for breast cancer. We hope by combining radium-223 with other drugs, we can unlock the potential of this treatment and help thousands of women with secondary breast cancer."
Prof Ottewell explained to Medscape News UK: "Ra-223 is thought to work better in prostate cancer than breast cancer as prostate cancer bone metastases are blastic (form bone), whereas breast cancer bone metastases are lytic (reduce bone)." In addition, "When Ra-223 binds to bone it kills cells that are a few mm away, therefore in breast cancer it was thought the majority of the tumour was too far away from the bone for the Ra-223 to be active."
She told us: "We are using an array of DNA Damage Repair Inhibitors (DDRi) including those that inhibit the DNA damage repair pathways: ATM, ATR, PARP, PARG, and DNA-PK. We will test each in combination with Ra-223, using the relevant DDRi alone and Ra-223 alone as comparators.
Breast Cancer Cells More Sensitive to Combination Therapy
"We previously found that giving an ATMi before administration of Ra-223 increased killing of large tumours, therefore we hypothesised that adding a DDRi to Ra-223 would do the same thing in breast cancer. Furthermore, when we looked in breast and prostate cancer cell lines, we found that breast cancer cells were more sensitive to the combination of ATMi and Ra-223 compared with prostate cancer."
At this point her team applied to Breast Cancer Now for funding to see which DDRi agents would work best in breast cancer when combined with Ra-223, she said, and to test whether combining DDRis with Ra-223 kills tumours in more complex breast cancer bone metastasis models.
They have eight drugs planned for initial in vitro testing, some existing anti-cancer agents and some drugs still in development. Those that work best alongside radium-223 will then be tested in mice to assess the ability of the combination to prevent secondary breast cancer from arising, or to shrink or eliminate bony metastases that are already present.
No Curative Treatment at Present
The charity estimated that there are more than 61,000 people with secondary breast cancer in the UK. In 70-80% of women so affected, the disease spreads to the bone, meaning that between 42,700 and 48,800 women have bone metastases, for which there is currently no curative treatment.
Dr Simon Vincent, Breast Cancer Now’s director of research, support and influencing, said: "With 11,500 women dying from breast cancer in the UK every year, it’s vital we continue to fund research to understand and treat this devastating disease.
"Breast Cancer Now is delighted to fund this new research that we hope will lay the groundwork for clinical trials into new treatment combinations for secondary breast cancer in the bone. And even help to stop secondary breast cancer developing in the bone in the first place."
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