A new detailed molecular portrait of central nervous system leukemia cells developed by Princess Margaret Cancer Centre researchers has found a possible "Achilles heel" for the illness, which could pave the way to a new treatment for patients.
The team of scientists, including study co-first authors Dr. Robert Vanner, University of Toronto Medical Oncology resident and Dr Stephanie Dobson, University of Ottawa pediatrics resident, made the discovery using pre-clinical models of acute lymphoblastic leukemia and performing targeted DNA sequencing and transcriptional and proteomic profiling of paired leukemia infiltrating cells in the bone marrow and the lining of the brain and spinal cord.
The study delves into the different gene expression programs within those cells in each area of the body and found distinct differences in the cellular production of proteins. That distinction could mean the cancer cells in the brain are potentially vulnerable to a new drug therapy.
The study, from the lab of PM Senior Scientist Dr. John Dick, shows that a drug currently available but previously believed to be ineffective as a treatment for acute lymphoblastic leukemia – omacetaxine mepesuccinate – could potentially make a difference to those who have the illness spread to the central nervous system, and could have less harmful side-effects for patients.
Leukemia treatments to the brain have advanced to a stage where they are initially very effective, but can leave damaging side-effects in patients. The central nervous system is a common site of leukemia relapse and because there are currently no treatments that specifically target the biology of these leukemia cells, it has a poor prognosis.
This research could change that.
"We created a comprehensive molecular portrait of the leukemia cells that invade the central nervous system," says Dr. Vanner. "And that led us to the pathway of mRNA translation as a therapeutic vulnerability, or 'Achilles heel' for these cells.
"We could only have discovered it by showing that cells invading the central nervous system depend on different factors than leukemia cells growing elsewhere."
The results were published recently in the journal
Blood Cancer Discovery. Dr. John Dick, Senior Scientist at the Princess Margaret, is senior author of the study.
Dr. Dick says the difference in the leukemia cells may lie in the way they translate mRNA into proteins. In the brain, where the cells are not exposed to the same nutrient-rich environment as in the bone marrow, the cells must adapt.
"It means that the cells are under more stress in that environment and they need to tune themselves up to try to deal with it," he said. "It's not just a coincidence that these cells have upregulated mRNA translation, but they're actually using it to survive."
Dr. Dick says the study builds on previous work conducted by his lab at the Princess Margaret and it could help pave the way to further precision-medicine for patients.
"Treatment of CNS disease involving injection of chemotherapy drugs into the spinal fluid has improved and that has been an important advance in increasing survival in leukemia, particularly for children," Dr. Dick says. "The problem is that comes at a cost to brain development.
"If there is a way to give the same effect, with less cost, less invasive treatment and other secondary effects, this could be a very important new therapy."
This work was supported by the Princess Margaret Cancer Foundation, Ontario Institute for Cancer Research, Terry Fox Research Institute, Canadian Institutes for Health Research, Canadian Cancer Society.
