Leukaemia Biology

Contacts: Professor Richard Lock, rlock@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 ethical considerations. Since 2005, our laboratory has been a Research Program in the Pediatric Preclinical In Vivo Testing Consortium, 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 Charles de Bock, cdebock@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 

Philadelphia chromosome-like acute lymphoblastic leukaemia (Ph-like ALL) is a recently identified leukaemia subtype with poor overall survival rates. Standard chemotherapy has low efficacy and can cause severe toxicity to healthy tissue. Antibody-drug conjugates (ADCs) enable targeted delivery of cytotoxic drugs to cancer cells and are rapidly growing in oncology. However, current ADCs, known as first/second-generation ADCs, have suboptimal properties, reducing efficacy against high-risk ALL and causing side effects.

We are addressing this challenge by developing a novel ADC with a multi-pronged therapeutic approach, tailored to the unique biology of Ph-like ALL. By optimising the antibody using site-specific conjugation and selecting effective payloads, we are creating a third-generation ADC with enhanced therapeutic activity. This ADC will not only target drug delivery but also disrupt a crucial cell-surface protein for Ph-like ALL survival and recruit the immune system against cancer cells. This research represents a shift towards precision medicine for high-risk ALL, improving patient outcomes and quality of life.

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

The most important prognostic factor for early relapse and therefore poor outcome in childhood acute lymphoblastic leukaemia (ALL) is the presence of minimal/measurable residual disease (MRD) in the bone marrow throughout treatment. Therefore early detection of MRD is vital for determining appropriate treatment options. However, standard MRD monitoring through repeated bone marrow biopsy is an invasive procedure which limits the frequency with which it can occur and does not inform about relapses in other organs.

We are therefore developing novel liquid biopsy methods for the detection of circulating tumour DNA (ctDNA) as a non-invasive “real-time” biomarker which will provide prognostic information throughout treatment as well as at progression. This paediatric focused study combines basic science analysing ctDNA in vivo with detecting MRD using personalised biosensors. Importantly, we are conducting Australia’s first prospective study to assess the prognostic value of ctDNA analysis to predict MRD in blood samples of paediatric ALL patients at Sydney Children’s Hospital. This project has the potential to shift the paradigm in MRD testing for high-risk childhood ALL from invasive bone marrow biopsy to blood sampling.

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 around 90 per cent, the rate for AML is only about 70 percent. It is clear that current treatments are not sufficient to overcome this gap in survival, and that novel therapies for paediatric AML are needed.

Our program is currently focused on two main approaches to solving this problem. First, we are developing new experimental models of AML that can be used to evaluate novel therapies for this disease. Our research program is currently utilising patient derived xenograft models of paediatric AML in combination with high-throughput drug screening and next generation sequencing analysis to identify novel therapies for the treatment of both individual patients (a precision medicine approach) and paediatric AML in general. 

Second, we are exploring the therapeutic potential of long non-coding RNAs (lncRNAs) in paediatric AML. 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.

Contact: Professor Richard Lock, rlock@ccia.org.au; Dr Charles de Bock, cdebock@ccia.org.au

Currently, the most potent indicator of long-term outcome in ALL is the measurement of minimal/measurable residual disease (MRD) following treatment initiation. Importantly, there is now evidence that MRD is the result of an acute adaptive response to drive chemotherapeutic drug resistance after which the residual MRD cells cause the emergence of a fully drug-resistant cell population. However, due to their scarcity, characterising MRD cells has been technically challenging.

Our group and collaborators have identified a pre-existing resistant state signature in patient samples using single-cell transcriptomics. The development of single cell multi-omics provides a unique opportunity to elaborate on this signature and correlate it with clinical outcome data for ALL patients to improve risk stratification. In an orthogonal approach, we will utilise combined single-cell transcriptomic and epigenetic analysis with our in vivo patient-derived xenograft mouse models to characterise the adaptive response in MRD cells after standard-of-care induction chemotherapy. Finally, we will use targeted in vivo knockout screens to identify new genetic vulnerabilities in MRD cells to reduce their adaptive response to induction therapy. In sum, our approach to characterising these adaptive changes in both clinical and xenograft models will provide a paradigm shift in the approach taken to treating children with ALL and identify new risk adapted therapeutic strategies.