For children with the most common childhood cancer, resistance to treatment has remained an enigma – until now
December 17, 2018
Research published last week in the prestigious journal, Cancer Cell, by scientists at Children’s Cancer Institute in Sydney, has discovered why one of the most successful classes of drugs used to treat acute lymphoblastic leukaemia (ALL), glucocorticoids, fails to work in 15% of children with the disease.
Each year, around 150 Australian children are diagnosed with acute lymphoblastic leukaemia (ALL), the most common childhood cancer. Around 15% will have an aggressive subtype that is less responsive to therapy and more likely to relapse.
A team of researchers at Children’s Cancer Institute, led by Dr Duohui Jing and Professor Richard Lock, has discovered a novel mechanism of glucocorticoid resistance in ALL, opening up the possibility of a 100% cure rate for the disease.
Steroid hormones are naturally made by our bodies in very small amounts, and control many normal bodily functions. However, at higher doses steroids can also be used as drugs to treat ALL. Steroids used to treat ALL are usually a type called corticosteroids. These are man-made versions of the hormones produced by adrenal glands just above the kidneys.
Dr Jing and his team, working in animal models, wanted to understand why a class of corticosteroids, the glucocorticoids, work so well in most patients with ALL, but not in the proportion of patients who are resistant to the treatment.
By looking at samples from patients with both the glucocorticoid-sensitive and resistant forms of ALL, Jing and his colleagues found an abnormal folding of DNA in glucocorticoid-resistant cells that hides the glucocorticoids’ targets. “It’s a very clever way that the cancer has developed to avoid being killed,” he said. This reveals a fundamental mechanism that explains why some ALL patients fail to respond to the treatment.
Importantly, the researchers, having uncovered how the glucocorticoid-targeted DNA regions were hiding, used a drug that would expose the DNA regions. When they combined this drug with glucocorticoids in animal models representing the 15% of patients resistant to glucocorticoids, they found a significant improvement in response.
According to Professor Lock, the results are a significant advance for children with ALL who currently do not respond to glucocorticoid treatment. “We now understand how a fundamental mechanism of resistance occurs, which has the potential to lead to a treatment that reverses the resistance and improves patient outcomes,” he said.
About Children’s Cancer Institute
Originally founded by two fathers of children with cancer in 1976, Children’s Cancer Institute is the only independent medical research institute in Australia wholly dedicated to research into the causes, prevention and cure of childhood cancer. Forty years on, our vision remains unchanged – to save the lives of all children with cancer and to eliminate their suffering. The Institute has grown to now employ more than 220 researchers, operational staff and students, and has established a national and international reputation for scientific excellence.
Our focus is on translational research, and we have an integrated team of laboratory researchers and clinician scientists who work together in partnership to discover new treatments which can be progressed from the lab bench to the beds of children on wards in our hospitals as quickly as possible. These new treatments are specifically targeting childhood cancers, so we can develop safer and more effective drugs and drug combinations that will minimise side-effects and ultimately give children with cancer the best chance of a cure with the highest possible quality of life.
We are currently leading the establishment of the Zero Childhood Cancer national child cancer personalised medicine program for children with the most aggressive cancers, in partnership with the Sydney Children’s Hospitals Network. This program will revolutionise the way treatment decisions are made, with the aim of improving survivorship for those children at highest risk of treatment failure from their disease.