SickKids-led research team discovers mechanism that leads leukemia cells to trigger bone loss, identifies a potential therapy to prevent it in lab models
Survival rates in children with leukemia have improved significantly over the last several decades due to great improvements in chemotherapy. The most common paediatric cancer, B-cell acute lymphoblastic leukemia (B-ALL), has a five-year survival rate in children of 85-90 per cent.
However, many children and youth with B-ALL also experience long-term effects of the cancer and treatment, including significant pain and fractures due to osteoporosis (reduced bone mass) and osteonecrosis (death of bone cells).
In a new study led by The Hospital for Sick Children (SickKids), published on September 16 in Science Translational Medicine, researchers have discovered a process that may trigger this bone loss in patients with childhood B-ALL, and also identified an antibody that helped to prevent it in the lab.
The research team, led by Dr. Jayne Danska, Senior Scientist in the Genetics & Genome Biology program at SickKids, found that leukemia-related bone loss and fragility occurred in an animal model of acute leukemia. They discovered that the bone destruction is associated with an interaction between a protein called RANKL on the surface of leukemia cells that grow in bone marrow, and its receptor, called RANK, on the surface of bone-degrading cells.
They went on to show that this same mechanism occurs when patient cells are transplanted into a specialized mouse model. When they administered a type of monoclonal antibody (a lab-created protein used as an immunotherapy) to the mice that had been transplanted with human leukemia cells, it blocked the RANK-RANKL interaction and prevented bone damage.
Danska says she hopes the findings will lead to clinical trials to see if using a similar approach is effective in protecting the bones of children and youth with leukemia. RANK-RANKL antagonists are currently being used in clinical trials for post-menopausal osteoporosis as well as breast and prostate cancer bone metastases in adults. Because the clinical safety data is already available for use in adults, this information could allow for a shorter path to clinical trials using such drugs in children and adolescents receiving chemotherapy for B-ALL.
About 15 per cent of children and youth with B-ALL have evidence of bone fractures at the time they are diagnosed, suggesting that bone damage can be caused by the leukemic cells themselves. In addition, high doses of corticosteroids, a key part of current treatment protocols for leukemia, are known to cause further damage to their bones.
“Bone loss is a big problem for young people with leukemia. It can be devastating because a 12- or 13-year-old patient going through chemotherapy in those critical growth years may never reach the adult height they would have achieved, and may require joint replacements early in life,” says Danska, who is also Associate Chief of Faculty Development and Diversity at SickKids Research Institute and Professor in the Departments of Immunology and Medical Biophysics at the University of Toronto.
“We hope the next step will be to use this bone-protective therapy in clinical trials with adolescents and young adults, in combination with the chemotherapy they receive for the leukemia, to see if it reduces bone loss without compromising the incredible efficacy of anti-leukemia therapy,” she says.
Danska’s research team included Dr. Sujeetha Rajakumar, a post-doctoral fellow, Dr. Cynthia Guidos, Senior Scientist in the Developmental & Stem Cell Biology program, and Dr. Johann Hitzler, Staff Haematologist and Senior Scientist in the Developmental & Stem Cell Biology program, all from SickKids, as well as Dr. Mark Minden, Senior Scientist at Princess Margaret Cancer Centre, University Health Network (UHN).