What we do
Cancer is a disease driven by changes – ‘mutations’ in the normal genes of cells. These changes can cause cells to multiply when they shouldn’t, resist normal constraints on where and how they grow, and live longer than normal. The result is cancer. The science of genomics lifts the lid on cancer cells and allows us to read the code of the genes. This provides us with a new way to understand cancer, by understanding how the mutations in the genes drive the disease.
Our Group models and studies the genetic changes in tumours, many discovered through the analysis done as part of the Zero Childhood Cancer Program (ZERO) national clinical trial. The goal is to understand how these altered genes cause cancer, and how new therapies can specifically target these altered functions. Our fundamental hypothesis is that a detailed understanding of how gene changes cause cancer is the key to more effective, less toxic therapies.
We work closely with the Computational Biology Group to analyse the cancer cells’ genomes, discover the unique features in childhood cancer cells and decipher how they function.
Our research aims are to:
- Conduct genomic analysis of samples from children enrolled on the ZERO national clinical trial, to identify the best treatment options.
- Investigate novel findings arising from this genomic analysis, using the molecular biology toolkit to probe the function of mutated genes and how they might be more effectively targeted by treatments.
- Develop models of paediatric cancers to explore the molecular pathways that are altered in cancer − a major way we can identify potential new therapeutic options.
Investigating the biology of novel homeobox gene fusions in paediatric cancer
Contact: A/Prof Paul Ekert, PEkert@ccia.org.au
Cancer in children, as in adults, is a disease caused by the accumulation of somatic mutations in previously normal cells. In many paediatric malignancies, a frequent event is the fusion of two genes to form a novel active oncogene, which then drives the phenotypic traits (hallmarks) of cancer cells including unregulated proliferation and a resistance to cell death (apoptosis). We have identified several novel fusions which, as a common feature, drive the expression of homeobox genes normally expressed during early development and which are thought to regulate gene expression programs controlling differentiation.
In this project, we will use the tools of molecular and cellular biology to determine the mechanisms by which these novel homeobox oncogenes function to drive proliferation, repress cell death, regulate differentiation, and activate oncogenic signalling pathways. The broad aims of the project include:
- Determining how these fusions regulate differentiation programs using in vitro and in vivo model systems.
- Identifying where in the genome the fusions bind, the molecular complexes in which they function, and the changes in gene expression they induce.
- Using high-throughput drug screens to identify potential targeted therapies.
Biological modelling of FGFR1-altered paediatric cancers to identify effective therapeutic strategies
Contact: Lauren Brown, LBrown@ccia.org.au and A/Prof Paul Ekert, PEkert@ccia.org.au
Recurrent alterations − including single nucleotide variants, gene fusions and intragenic deletions − that affect the fibroblast growth factor receptor 1 (FGFR1) gene in a range of paediatric cancer types have been identified in the Zero Childhood Cancer Program. FGFR1 encodes a receptor tyrosine kinase, which when activated in cancer typically results in activation of intracellular signalling pathways, including PI3K/AKT and RAS/MAPK, driving cell proliferation and survival. FGFR1 may be therapeutically targetable with tyrosine kinase inhibitors, but further understanding of how specific variants drive cancer is needed to implement these therapies clinically.
This project aims to develop and use biological models to understand the mechanisms by which FGFR1 oncoproteins drive cancer and identify rational therapies to treat patients with FGFR1-altered cancers.
The experimental work will include analysis of a broad range of FGFR1 variants to identify signalling mechanisms and drug susceptibilities that are common and unique to different FGFR1 variant classes. In addition, unbiased screening methods including phosphoproteomics and high-throughput drug screening will be used.
Immune profiling and immunotherapy for high-risk paediatric tumours
Contact: Dr Rachael Terry, RTerry@ccia.org.au; Associate Professor Paul Ekert, PEkert@cciia.org.au; Dr Emmy Fleuren, EFleuren@ccia.org.au
There is a distinct lack of targeted and effective treatments for children with high-risk tumours. Outcomes remain poor for these patients, with <30% chance of survival. This project aims to improve treatment of these high-risk paediatric cancers by harnessing a patient’s own immune response to improve their survival and quality of life.
The project includes an extensive and deep analysis of the immune microenvironments of high-risk patients enrolled in the Zero Childhood Cancer Program, combining DNA and RNA sequencing analysis with multiplex immunohistochemistry. The goal is a comprehensive understanding of the immune profiles of high-risk paediatric tumours, identifying subsets of immune-inflamed ‘hot’ and non-inflamed ‘cold’ tumours, and pinpointing the most clinically relevant and targetable immune checkpoints.
This data will be used to inform the design of new immunotherapeutic strategies to test in pre-clinical immunocompetent models. Initially, we will test our approaches in models of paediatric sarcomas, including osteosarcoma and rhabdomyosarcoma. Our hypothesis is that immune-inflamed ‘hot’ tumours will respond well to immune checkpoint inhibitors as monotherapy, while non-inflamed ‘cold’ tumours will require combination therapy with other immunomodulatory drugs to achieve optimal results.
Explaining unexplained drug responses in childhood sarcomas
Contact: Dr Emmy Fleuren, EFleuren@ccia.org.au
Despite aggressive treatments, survival of young, high-risk sarcoma patients is poor, and side-effects are frequent. No targeted treatment is available, underlining the unmet need for better and less toxic treatments. Finding better treatments is, however, challenging.
In this project, we will address a major clinical challenge in the Zero Childhood Cancer Program: explaining why some sarcomas appear to respond to targeted drugs when there is no biomarker of response. When it is unknown why a drug is so effective in the lab, it is difficult to transform these findings into an actual clinical treatment recommendation. The opportunity this study may bring is to identify new markers of response, and so expand the number of patients who may receive the treatment.
We will use a range of molecular methodologies, including mass-spectrometry and targeted phosphoproteomic assays, combined with genomics and transcriptomics patient data. In vitro siRNA and drug assays will be employed for functional validations. Broader kinome-siRNA/CRISPR screens (+/- drug) will be done, plus in vivo drug inhibition studies.
Phosphoproteomic profiling for novel target identification in childhood sarcomas
Contact: Dr Emmy Fleuren, EFleuren@ccia.org.au; Ashleigh Fordham, AFordham@ccia.org.au
Sarcomas are a diverse group of rare, highly aggressive tumours of the connective tissue that disproportionally affect the young. Despite aggressive treatments, survival is limited (~20% in advanced setting) and side-effects frequently occur, stressing the unmet need to identify novel, tumour-specific treatments. Pinpointing clinically actionable targets is, however, extremely challenging in these tumours. Widely used genomics interrogations report very few targetable defects.
Tumour genomics is one piece of the cancer puzzle, but the picture this paints is incomplete. The oncogenic effect of a gene is ultimately mediated by the protein encoded by the gene, and in some instances, these proteins are molecular switches, turned on and off by phosphorylation and dephosphorylation.
This project is an excellent opportunity for a PhD/Honours student to study the complete activation (phosphorylation) patterns (pTyr/pSer/pThr) of key effector molecules (kinases) in a diverse set of sarcoma cell lines, PDX models and unique patient samples, with the ultimate aim of identifying novel, clinically actionable targets for young sarcoma patients. The student will work closely with the Zero Childhood Cancer Program (ZERO), which involves a national clinical trial aimed at identifying targeted treatments for high-risk paediatric cancer patients (including sarcoma). The student will use a variety of molecular methodologies, including mass-spectrometry and targeted phosphoproteomic assays (kinome profiler/western blot/immunohistochemistry). Functional relevance of identified targets will be validated using in vitro (drug screens/siRNA/CRISPR) and in vivo (drug efficacy) sarcoma models.
Exploiting aberrations of DNA damage signalling to identify combination therapies for paediatric cancer treatment
Contact: Dr Emmy Dolman, EDolman@ccia.org.au; Dr Emmy Fleuren, EFleuren@ccia.org.au
DNA damage signalling plays an important role in cancer as impaired DNA repair enables cancer cells to accumulate oncogenic DNA lesions. Molecular profiling of tumour samples from the Zero Childhood Cancer national clinical trial indeed shows frequent aberrations in DNA repair genes such as CHEK1 and -2, ATM, BRCA1, MSH6 and TP53, as well as the presence of mutational signatures indicative for BRCA-deficiency or impaired mismatch repair.
This study aims to unravel the DNA damage signaling landscape of paediatric cancers and to investigate strategies to exploit this knowledge to develop personalised therapies. This will include high-throughput in vitro testing of a DNA damage/repair drug library on unique patient-derived model systems. As treatment with single agents has been proven to be insufficient for complete cure in most cases, most promising drug candidates will be further studied in vitro and in vivo to identify combination strategies overcoming tumour resistance to single agents. Results aim to guide future clinical trials for paediatric cancer treatment.
Dr Emmy Fleuren
Dr Emmy Dolman
Dr Lauren Brown
Post Doctoral Scientist
Dr Rachael Terry
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