Leukaemias account for approximately one-third of all paediatric malignancies and cause the greatest number of cancer-related deaths in children.
The Leukaemia Biology program increases our understanding of high-risk leukaemias by using cutting-edge techniques alongside clinically-relevant preclinical testing models. The lab’s research has a strongly translational focus, from bench to bedside, with a large collection of paediatric acute lymphoblastic leukaemia (ALL) samples available to represent the considerable diversity of childhood leukaemia. Our research includes:
- examining mechanisms of resistance to conventional chemotherapy drugs
- identifying and testing novel therapies for high-risk patients.
Our funding sources include grants from Cancer Council NSW, National Health and Medical Research Council (NHMRC), National Cancer Institute (USA), CRC for Cancer Therapeutics (CTx), The Kids Cancer Project, Cancer Institute NSW, The Balnaves Foundation, and the Anthony Rothe Memorial Trust.
Glucocorticoids are one of the most active classes of drugs used to treat childhood acute lymphoblastic leukaemia (ALL) and other lymphoid malignancies in children and adults. However, resistance to these drugs develops in some children, leading to treatment failure. Glucocorticoid resistance in childhood ALL generally indicates poor treatment outcome.
The mechanisms ALL cells use to develop glucocorticoid resistance are not well defined. We’re making significant advances in understanding glucocorticoid resistance using our unique experimental model of ALL. This is a living model of leukaemia developed in the laboratory which closely mimics the disease in children.
We’ve successfully identified a number of previously undiscovered ways in which leukaemia cells develop glucocorticoid resistance. We recently identified epigenetic mechanisms contributing to glucocorticoid response using a model system of paired ALL samples that share a similar gene expression pattern but exhibit considerably different response to glucocorticoids. This is being further investigated using techniques including ATAC (Assay for Transposase-Accessible Chromatin) sequencing and 3C (chromatin conformation capture).
We’ve used gene expression profiling and high-throughput screening to identify several compounds able to sensitise glucocorticoid-resistant ALL to glucocorticoid treatment. We’re investigating the mechanism of action of the most potent compound with a view to taking a proteomics-based approach to identify its cellular target. This will provide the basis for developing clinically effective combination therapies.
Professor Richard Lock
There are a large number of drugs, developed for adult cancers, which may have promise against paediatric malignancies. However the clinical evaluation of these is hampered by small patient populations and considerable ethical considerations. Since 2005, our laboratory has been part of the Pediatric Preclinical Testing Consortium, a US National Cancer Institute-funded initiative aimed at prioritising effective drugs for clinical evaluation in paediatric cancers. The PPTC uses clinically relevant criteria to stringently evaluate drug efficacy.
As the leukaemia testing site for the PPTC, and the only site outside the US, we use our experimental model of ALL to evaluate preclinical efficacy of up to 10 new drugs and drug combinations per year, with those deemed effective put forward for clinical evaluation. This has led to a number of drugs being promoted to clinical trials. Just as importantly, testing has highlighted drugs ineffective against paediatric ALL, helping reduce the number of ineffective agents reaching the clinic.
Effective drugs are usually investigated further in the lab, determining mechanisms of action and assessing rational combination treatments to further increase drug efficacy. This has recently identified a drug combination potentially effective against early T-cell precursor (ETP)-ALL, a particularly aggressive leukaemia subtype. Given the large number of patient samples available for our experimental model of ALL, drugs showing specific activity against a particular subtype are typically investigated further against an expanded panel of samples for that subtype.
Professor Richard Lock
Acute myeloid leukaemia (AML) is less common than acute lymphoblastic leukaemia (ALL) in children, but is also generally much less treatable. The 5-year survival rate is only about 65% per cent.
We’ve been developing new experimental models of AML subtypes that can be used to evaluate novel therapies for this disease. A key component will be incorporating humanised mouse-strains into this testing.
We’ve recently found a drug combination which shows great promise against a subset of AML with MLL-translocations, genetic alterations associated with chemotherapy resistance. This drug combination targets transcriptional elongation machinery. We’re working to identify the exact mechanism behind the synergy to identify determinants of response.
Group LeaderProfessor Richard Lock
SENIOR RESEARCH OFFICER
Dr Duohui (Vincent) Jing
Dr Narges Bayat
Dr Patrick Connerty
Dr Keith Sia
Dr Cara Toscan