Team Leader
What we do
Survival rates are now approaching 90% for children diagnosed with acute lymphoblastic leukaemia (ALL). However, current treatment often results in severe chronic health conditions, and outcomes for children with relapsed ALL remain poor.
There is now an increasing amount of “omic” data being generated through large scale sequencing efforts, such as within the Zero Childhood Cancer Program (ZERO). This includes whole genome sequencing, whole transcriptome sequencing, and whole methylome sequencing, as well as our own efforts to undertake single cell sequencing analysis, that together give us unprecedented resolution of the genetic and epigenetic changes that underly ALL.
In our group, we are using this information to understand the molecular aberrations that underpin the development and progression of ALL, with the ultimate aim of developing novel therapeutic approaches tailored to the unique genetics (mutational signature) of each child’s cancer.
As part of our ongoing efforts, we use both cell line and in vivo mouse models together with CRISPR-Cas9, ChIP-seq, ATAC-seq, nanopore-sequencing and RNA-seq base technologies to model how these different mutations cooperate with one another and drive disease. It is hoped that this, in turn, will help us design more targeted therapies.
Research projects
Molecular characterisation of relapse-initiating acute lymphoblastic leukaemia cells for targeted therapy
Contact: Dr Charley de Bock, CdeBock@ccia.org.au
Acute lymphoblastic leukaemia (ALL) is the most common childhood cancer and remains one of the most common causes of death from disease in children. Risk-stratified chemotherapy has led to substantial improvements in clinical outcome but when children with ALL relapse, survival can drop to below 30% due to limited treatment options. Currently, the most potent indicator of long-term outcome in ALL is the measurement of minimal 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.
The development of single cell multi-omics provides a unique opportunity to test our hypotheses: (1) chemotherapeutic drug resistance emerges de novo from drug tolerant persister cells; and (2) characterising the genetic dependencies of persister cells will in turn identify new therapeutic targets for drug development and prevent relapsed disease. Our preliminary single-cell transcriptome data have identified a pre-existing resistance signature, which we will correlate with clinical outcome data for ALL patients to improve risk stratification. In an orthogonal approach, we will characterise the adaptive response in MRD cells using combined single-cell transcriptomic and epigenetic analysis, utilising in vivo patient-derived xenograft (PDX) mouse models after standard-of-care induction chemotherapy. Finally, we will use a targeted in vivo knockout screen to identify new genetic vulnerabilities in MRD cells to reduce their adaptive response to induction therapy.
Our approach to characterising these adaptive changes in both clinical and PDX models will provide a paradigm shift on the approach taken to treating children with ALL, and identify new risk adapted therapeutic strategies.
Team
Team Leader
Postdoctoral Scientist
Dr Jackie Huang
Dr Hansen Kosasih
PhD Students
Yashna Walia
Zahra Sheybani
Honours Student
Kristy YeatsNews & blogs
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