Researchers pinpoint drug for the treatment of an aggressive type of childhood leukaemia
February 26, 2015
Children’s Cancer Institute researchers have identified a drug as a potential treatment for a particularly aggressive, chemotherapy-resistant type of paediatric leukaemia.
Published online this month in Blood, the study reveals the effects of a clinically approved small molecule drug against a sub-type of very high-risk acute lymphoblastic leukaemia. Known as early T-cell precursor acute lymphoblastic leukaemia (ETP-ALL), this destructive disease has a survival rate of less than 20%*, compared to the overall survival rate of about 90% for childhood acute lymphoblastic leukaemia^.
Acute lymphoblastic leukaemia, the commonest childhood cancer, is characterised by the overproduction of immature white blood cells (known as lymphoblasts). Lymphoblasts can be of T-cell or B-cell lineage.
ETP-ALL was first described in a study published in The Lancet Oncology in 2009 as a particularly aggressive, chemo-resistant subset of T-cell ALL*. That study reported that patients with ETP-ALL responded poorly to conventional chemotherapy. More recently ETP-ALL has been found to contain faults in the enzymes that play a key part in transmitting information, known as kinases.
Kinases are an area of expertise of Dr Sibasish Dolai, Research Officer in the Leukaemia Biology team at Children’s Cancer Institute and equal first author on the study. “These ‘early’ T-cells were found to have a mutated type of kinase, known as Janus kinase (JAK),” said Dr Dolai.
“JAK is a critical part of the signalling pathway that transmits information from chemical signals outside of the cell – so once it became known that this mutation was present in ETP-ALL cells, we decided to try and target this pathway to stop it.”
Professor Richard Lock, Head of Children’s Cancer Institute’s Leukaemia Biology Program and equal senior author on the paper, conducted an initial drug screen with his team within the Institute’s ACRF Drug Discovery Centre and found a pre-approved drug called Ruxolitinib to be very effective at blocking the JAK pathway and killing the ETP-ALL cells. This extended to a collaborative study with researchers at the Children’s Hospital of Philadelphia (USA) and San Francisco Benioff Children’s Hospital (USA), highlighting the potential of the drug against ETP-ALL.
“Ruxolitinib has already been clinically approved for other types of bone marrow disorders in adults, which is a significant benefit,” said Prof Lock. “The process a new drug needs to go to before it is approved for use can take years – and for such an aggressive disease as ETP-ALL, we don’t have time to wait.
“We know what this drug does and we know how it works, so we’re very excited to have identified it as a potential treatment for paediatric cancer with our collaborators.”
This pre-clinical study marks an important step towards Children’s Cancer Institute’s vision of reaching a 10 out of 10 survival rate for acute lymphoblastic leukaemia.
Dr Dolai is supported by a grant from the National Health and Medical Research Council and Professor Lock is supported by a Fellowship from the National Health and Medical Research Council.
*Coustan-Smith E, Mullighan CG, Onciu M, Behm FG, Raimondi SC, Pei D, et al. (2009). Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia. Lancet Oncol 10(2), 147-156; DOI: http://dx.doi.org/10.1016%2FS1470-2045(08)70314-0
^Ching-Hon Pui, Charles G. Mullighan, William E. Evans, Mary V. Relling; Pediatric acute lymphoblastic leukaemia: where are we going and how do we get there?, BloodAug 2012,120(6)1165-1174; DOI: http://dx.doi.org/10.1182/blood-2012-05-378943
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.