The Kids Research Institute Australia researchers may have unlocked a vital key to reducing the progression of leukaemia in children, potentially prompting a change in thinking around the best way to target treatment.
In research published today in the Nature journal, Leukemia, a team led by The Kids Cancer Centre researcher Dr Laurence Cheung described how they had identified the mechanism of bone loss that occurred during the development of leukaemia – which, when treated, was able to reduce leukaemia progression.
Dr Cheung said the findings, although pre-clinical, were promising and suggested that targeting the microenvironment around leukaemia cells could not only help fight leukaemia, but simultaneously provide relief for one of its most common and painful side-effects, bone loss.
Acute lymphoblastic leukaemia (ALL) is the most common cancer among children and remains a common cause of cancer-related death before 20 years of age. Although long-term survival rates for children and adolescents with ALL have greatly increased in recent decades – now exceeding 85 per cent – outcomes in high-risk sub-groups remain poor.
Dr Cheung said the team’s study focused 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,” Dr Cheung said.
“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.”
The researchers wanted to discover what was causing the bone loss, and identified a signal produced by the leukaemia cells which instructed cells in the microenvironment – known as osteoclasts – to eat away at the bone.
“Then we thought, what if we stop the bone-eating cells from eating the bone away – will this have an impact on the development of leukaemia?” Dr Cheung said.
The team used a commercially available drug called zoledronic acid – already known to be safe for children and used to treat brittle bone disease – to target the cells in the microenvironment around the leukaemia cells.
“Importantly, we found that this not only compensated for the leukaemia-dependent bone fragility, but also reduced leukaemia progression,” Dr Cheung said.
He said although similar thinking had been applied previously to cancer in adults, the finding offered an exciting new treatment angle for children.
“To date, the main strategy for cancer therapy in children has focused on targeting malignant cells with chemotherapy, which is toxic for the leukaemia cells but also toxic for the patient.
“Our 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.”
Dr Cheung said the next step was 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 was 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.
The research was supported by the Children’s Leukaemia and Cancer Research Foundation, Western Australia, and Cancer Council Western Australia.
It was carried out in collaboration with the School of Pharmacy and Biomedical Sciences, Curtin University; the School of Pathology and Laboratory Medicine and the School of Medicine at The University of Western Australia; the Harry Perkins Institute of Medical Research; the Department of Pathology at St. Jude Children’s Research Hospital, USA; and the Department of Haematology and Oncology, Princess Margaret Hospital for Children.
The full paper, New therapeutic opportunities from dissecting the pre-B leukemia bone marrow microenvironment, can be read in Leukemia
