Leukaemia Biology

Contacts: Professor Richard Lock, rlock@ccia.org.au; Dr Cara Toscan, ctoscan@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 a Research Program in the Pediatric Preclinical In Vivo Testing Consortium (https://preclinicalpivot.org/about-pivot/), a US National Cancer Institute-funded initiative with the major goal of generating high quality preclinical testing data to inform new agent clinical decision making in paediatric cancers.

As the leukaemia testing site for PIVOT, and the only site located outside of the US, we use our experimental model of acute lymphoblastic leukaemia (ALL) to evaluate the preclinical activity of up to 10 new drugs and drug combinations per year. This has led to several drugs being prioritised for clinical trials and, just as importantly, reduced the number of likely ineffective agents being tested in patients who have already been heavily treated with conventional therapy.

Contacts: Professor Richard Lock, rlock@ccia.org.au; Dr Cara Toscan, ctoscan@ccia.org.au

Paediatric acute lymphoblastic leukaemia (ALL) can be broadly divided into B-lineage (B-ALL) and T-lineage (T-ALL). T-ALL is aggressive and exceptionally difficult to cure after relapse. We have recently demonstrated that T-ALL expresses significantly higher levels of the enzyme AKR1C3, albeit by currently unknown mechanisms. These findings were exploited using a first generation AKR1C3-activated prodrug, OBI-3424, now in a clinical trial for relapsed/refractory T-ALL. 

The next generation AKR1C3-activated prodrug, ACHM-025, has shown greater selectivity for activation by AKR1C3. Preclinical evaluation of ACHM-025 has shown superior efficacy compared to OBI-3424 and standard-of-care therapy. We are investigating the mechanisms regulating AKR1C3 gene expression in ALL, which will identify opportunities for novel drug combinations to enhance the efficacy of AKR1C3-activated prodrugs. Further preclinical testing of ACHM-025 alone and in drug combination efficacy experiments will inform future clinical trials of ACHM-025.

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.

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. These models will be utilised to improve personalised medicine approaches for the treatment of paediatric AML.

Long non-coding RNAs (lncRNAs) are a class of genetic molecules with key roles in cancer growth and therapy resistance. Consequently, lncRNAs have recently been discovered as attractive therapeutic targets for cancers that are high-risk or poorly serviced by current therapies. Current treatment options for AML frequently cause off-target toxicity to healthy cells and present a major limitation in AML treatment. Thus, there is an urgent need to discover new therapeutic targets specific to AML, however, almost no studies have explored targeting lncRNAs in AML.

We are currently undertaking a large-scale investigation into the function and therapeutic potential of lncRNAs in paediatric AML with the aim of developing new treatment options for children with AML.