The anti-resorptive drug zoledronic acid used in osteoporosis, may have potential in the treatment of leukaemia in children, researchers in WA have shown.
Dr Laurence Cheung and co-researchers at the Telethon Kids Cancer Centre in Perth say they have identified the mechanism of bone loss that occurs during the development of leukaemia – which, when treated with zoledronic acid, is able to reduce leukaemia progression.
The pre-clinical findings suggest that targeting the microenvironment around leukaemia cells may not only help contain the malignancy but simultaneously provide relief for one of its most common and painful side-effects, bone loss.
The research published in the Nature journal, Leukemia focuses on the most common form of leukaemia in children, a subtype of ALL known as pre-B ALL.
“When we created a pre-clinical model replicating this kind of leukaemia, we witnessed substantial bone loss during the development of the cancer,” said Dr Cheung.
“We went back to the literature and found that more than a third of children diagnosed with pre-B ALL had symptoms of bone pain and skeletal defects at the time they were diagnosed – suggesting leukaemia cells can alter their surrounding environment.”
When investigating what was causing the bone loss, the researchers noted the number of osteoblastic cells was decreased in the bone marrow microenvironment.
In additionan leukemia cells produced high levels of receptor activator of nuclear factor κB ligand (RANKL), sufficient to cause osteoclast-mediated bone resorption.
Dr Cheung’s team then speculated on the potential of a drug that inhibits osteoclast activity. They used zoledronic acid to target the cells in the microenvironment around the leukaemia cells.
In animal models they found that zoledronic acid rescued leukaemia-induced bone loss, reduced disease burden and prolonged survival in leukaemia-bearing mice.
“Importantly, we found that this not only compensated for the leukaemia-dependent bone fragility, but also reduced leukaemia progression,” Dr Cheung said.
Although similar thinking had been applied previously to cancer in adults, the finding offered an exciting new treatment angle for children.
Dr Cheung said the finding that the cells surrounding the leukaemia cells can contribute to treatment failure or success has led to a paradigm shift.
“It means this potentially could be a powerful adjuvant therapy. It’s not going to replace chemotherapy, but we propose that using chemotherapy and treating the microenvironment at the same time will have more benefit than just the chemotherapy by itself.
“What it really shows is that it’s important to look at that whole picture, and not just the leukaemia cells, because the leukaemia cells and the cells in the surrounding microenvironment are all talking to each other.”
According to Dr Cheung the next step is to expand the study, using similar treatment on other sub-types of the same kind of leukaemia to see if a similar impact could be achieved; and to ensure that zoledronic acid is compatible with current chemotherapy agents.
“There’s quite a way to go yet, but it’s exciting to think about the paradigm shift this represents for children’s leukaemia, as well as the dual benefits it offers: both slowing the progression of the leukaemia, and mitigating this really common and painful side effect suffered by children with leukaemia, and that is the bone loss,” he said.