Researchers uncover new leukemia cell invasion pathway into central nervous system
Researchers at The Hospital for Sick Children (SickKids) and University Health Network (UHN) have identified a previously unknown entry route for leukemia cells to invade the central nervous system (CNS), as well as a possible approach to prevent it. The discovery has the potential to contribute to more targeted treatment options to combat acute lymphoblastic leukemia (ALL) invasion of the CNS, according to Dr. Jayne Danska, lead author of the study and Senior Scientist in the Genetics & Genome Biology program at SickKids.
Danska and her team had previously identified a process in which ALL cells ‘drill’ through the bone from their origins in the bone marrow, which can result in bone fractures, osteoporosis and cell death. In this latest study, published on December 21, 2021 in Cell Reports Medicine, they show that leukemia cells may also enter the CNS by ‘drilling’ through bone that separates the marrow cavities in the skull or the vertebrae to enter the brain and spinal cord.
Previous research led by Danska illustrated how leukemia cells contribute to bone loss and fragility, and identified a monoclonal antibody that helped prevent it in lab models. They discovered that ALL-driven bone destruction is associated with an interaction between a protein called RANKL on the surface of leukemia cells in bone marrow, and its receptor, called RANK, on the surface of bone-degrading cells. By administering an immunotherapy antibody to a mouse model with patient ALL cells, they were able to block the RANK-RANKL interaction and prevent bone damage.
Danska’s latest research now shows that the antibody treatment to block the RANK-RANKL interaction also reduced ALL-mediated damage to bone of the skull and vertebrae, preventing these cells from entering the CNS.
Lessening the burden of CNS-chemotherapy
ALL is the most common childhood cancer. ALL patients are often treated with chemotherapy directed to the brain and spinal cord to prevent CNS leukemia, a particularly difficult to treat form of the disease.
Survival rates for ALL have improved significantly over the last several decades, thanks to treatment advances including CNS-directed chemotherapy. However, due to the effect of chemotherapy on the developing brain, paediatric patients may experience damage to the brain resulting in neurocognitive changes such as slower processing speeds, difficulties with comprehension and problems with motor skills.
“For many children who survive leukemia, the long-term effects of chemotherapy treatment can include neurocognitive and psychosocial deficits, endocrine disorders, and increased risk of secondary brain cancers,” says Danska, who is also Associate Chief of Faculty Development and Diversity at the SickKids Research Institute and Professor in the Departments of Immunology and Medical Biophysics at the University of Toronto.
“To improve these outcomes, we need to understand how these cells enter the CNS and use this knowledge to identify effective, targeted treatment for CNS leukemia.”
Exploring RANK-RANKL interaction for future paediatric clinical trials
Danska’s team found that antibodies that block RANK-RANKL interaction (known as antagonists), which are in use for post-menopausal osteoporosis as well as breast and prostate cancer bone metastases in adults, could have therapeutic benefit to not only protect the bones of children and youth diagnosed with ALL, but to also prevent the leukemia cells from creating passages in the skull and vertebrae bone to enter the CNS altogether. Because RANK-RANKL antagonist antibodies can be used safety in adults, they may have a shorter path to be considered for clinical trials for children and young adults with ALL, says Danska.
By targeting this specific RANK-RNAKL pathway of leukemia entry into the CNS, it may be possible to reduce the intensity on CNS-targeted chemotherapy, and thereby lessen the long-term side effects of ALL treatment.
Danska notes that a limitation of their research was the in-depth analysis of a small number of ALL patient samples her team studied through mouse models. The team’s next step is to analyze a larger number of ALL patient samples to find out if these results are generalizable to a larger population and can be used to support future clinical trials.
Danska says she foresees this work supporting future cancer treatments rooted in precision medicine to specifically target each patients’ disease and limit negative effects on healthy cells, particularly bone and brain for ALL patients.
“If you understand the mechanisms, you can test each patients’ cells for which of these molecules they express to tailor the available treatments,” says Danska. “That’s the kind of precision we’re seeking.”
This research was a collaborative effort of SickKids investigators, including first author Dr. Sujeetha Rajakumar, a post-doctoral fellow in Danska’s group; Ildiko Grandal; Dr. Johann Hitzler; Dr. Cynthia Guidos; and Dr. Mark Minden from University Health Network (UHN). The research was supported by the Leukemia and Lymphoma Society of Canada, the Ontario Institute for Cancer Research and SickKids Foundation.