Leukaemia Biology

Contacts: Professor Richard Lock, rlock@ccia.org.au

Glucocorticoids are one of the most active classes of drugs used to treat childhood acute lymphoblastic leukaemia (ALL) and other lymphoid malignancies. However, resistance to these drugs develops in some children, leading to treatment failure. The mechanisms that ALL cells use to develop glucocorticoid resistance are not well defined. We are making significant advances in understanding glucocorticoid resistance using our unique experimental model of ALL, a living model of leukaemia developed in the laboratory which closely mimics the disease in children.

We have 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 different responses to glucocorticoids, and are investigating this further using techniques such as ATAC (Assay for Transposase-Accessible Chromatin) sequencing and 3C (chromatin conformation capture).

Using gene expression profiling and high-throughput screening, we have identified several compounds able to sensitise glucocorticoid-resistant ALL to glucocorticoid treatment. We are investigating the mechanism of action of the most potent of these compounds 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.

Contacts: Professor Richard Lock, rlock@ccia.org.au; Dr Cara Toscan, ctoscan@ccia.org.au; Dr Keith Sia, ksia@ccia.org.au; Kathryn Evans, kevans@ccia.org.au

There are many drugs developed for adult cancers that potentially hold promise as treatments for childhood cancers. However, the clinical evaluation of these drugs 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.

As the leukaemia testing site for the PPTC, and the only site outside the US, we use our experimental model of acute lymphoblastic leukaemia (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 many drugs being promoted to clinical trials and, just as importantly, reduced the number of ineffective agents reaching the clinic.

Drugs found to be effective are investigated further in the lab, where we determine mechanisms of action and assess rational combination treatments to further increase drug efficacy. Using this approach, we recently identified a drug combination potentially effective against early T-cell precursor (ETP)-ALL, a particularly aggressive leukaemia subtype, and are now using our experimental model of ALL to test this combination against an expanded panel of patient samples.

Contact: Professor Richard Lock, rlock@ccia.org.au; Dr Patrick Connerty, pconnerty@ccia.org.au 

Acute myeloid leukaemia (AML) is less common than acute lymphoblastic leukaemia (ALL) in children but is also generally much less treatable. While ALL has a 5-year survival rate approaching 90 per cent, the rate for AML is only about 75%. We have 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 recently found a drug combination which targets transcriptional elongation machinery and shows great promise against a subset of AML with MLL-translocations, genetic alterations associated with chemotherapy resistance.  We are now working to identify the exact mechanism behind the synergy to identify determinants of response.

Contact: Professor Richard Lock, rlock@ccia.org.au; Dr Narges Bayat, nbayat@ccia.org.au 

The treatment options for high-risk acute lymphoblastic leukaemia (ALL) are far from optimal, and patients are frequently treated with intensive chemotherapy leading to severe short- and long-term side effects as the drugs affect both healthy and cancer cells. Therefore, there is an urgent need for novel targeted approaches to improve therapy and to reduce side effects.

Through collaboration with national and international research institutes, we are developing novel nanotechnology-based approaches for effective treatment as well as early and non-invasive minimal residual disease (MRD) detection for high-risk paediatric leukaemia. 

We are utilising the unique properties of nanoparticles (defined as particles of matter between 1-100 nanometres) including their large surface area to volume ratio to conjugate favourable quantities of drugs, imaging agents, and targeting moieties against high-risk paediatric leukaemia. As drug carriers, nanoparticles can improve bioavailability, decrease dose and dosing frequency, as well as improve the solubility of the chemotherapeutic drugs.

Moreover, the most important prognostic factor in childhood ALL is the presence of MRD in the bone marrow where leukaemia cells are less sensitive to the effects of chemotherapy and thus can lead to relapse and poor prognosis. Therefore, early detection of MRD can determine appropriate treatment options and evaluate early response to therapy leading to improved patient outcome.  However, the frequency with which MRD can be monitored is limited, especially in children, due to discomfort as well as practical difficulties posed by bone marrow aspiration. Therefore, we are developing novel liquid biopsy methods for the detection of circulating tumour DNA (ctDNA) and microRNA (ct-miRNA) as non-invasive “real-time” biomarkers which will provide prognostic information before and during treatment as well as at progression.