Team Leader
What we do
Sarcoma is the name of a diverse group of cancers that grow in the connective tissues of the body, such as bones, muscles and fat. These aggressive cancers disproportionally affect children, adolescents and young adults, and often require intensive treatment with toxic therapies. These therapies, which are essentially the same as they were decades ago, are not only ineffective in many cases, but often lead to serious side-effects. New, targeted treatments for sarcoma are urgently needed. Our Group is investigating the biology of sarcoma with the aim of identifying new therapeutic targets, and developing safer and more effective therapies to treat sarcoma in children.
To date, gene-focused approaches such as whole genome sequencing have led to the discovery of very few actionable drug targets in sarcoma, and this is particularly true for subtypes affecting the young. We are therefore taking a different approach. Known as phosphoproteomics, our approach centres on identifying activated (‘switched on’) proteins in sarcoma cells that are driving their growth. We in turn develop targeted treatments that can effectively ‘switch off’ these proteins.
We work closely with the Zero Childhood Cancer Program (ZERO), which is providing a unique opportunity to study phosphoproteomics in a wide range of sarcoma patients, and build a more complete understanding of what drives these cancers and how they can be targeted. Our close connection to ZERO also facilitates clinical translation of our findings in a clinically relevant timeframe. For example, as a direct result of our Group’s research, eligible rhabdomyosarcoma patients enrolled in ZERO now receive a recommendation of a targeted drug that was previously unconsidered for this patient group. Building on this clinical impact, we are on a mission to see more therapies developed in our lab help children enrolled in ZERO and beyond in the future.
We are also working closely with other groups at the Institute to find alternative ways to treat sarcoma, such as immunotherapy and metabolomics.
Research projects
Developing phosphoproteomic pipelines for sarcoma
Contact: Dr Emmy Fleuren, EFleuren@ccia.org.au
Genomic sequencing (‘reading the genome’) of cancer has become the most important way to investigate how cancer cells differ from normal cells. For sarcomas, however, reading the genome is often not enough to identify a suitable treatment. We need to understand how the sarcoma genome causes the many changes characterizing this cancer, how the building blocks of cancer cells (proteins) are made from instructions encoded in their genome, and how these proteins are ‘switched on’ to drive cancer. An emerging technique called phosphoproteomics allows us to do that, showing us which proteins are switched on, so we know which ones we need to switch off.
Phosphoproteomic investigations are at the heart of the studies in our Group. Key questions we aim to answer are:
- Can we utilize a phosphoproteomics approach to identify actionable drug targets for young, high-risk (<30% survival) sarcoma patients that would be missed using other methods?
- Can phosphoproteomics analyses help explain why certain targeted drugs work extraordinarily well in some sarcoma patient cell cultures grown in our laboratory, despite the fact that none of these patients harbour a known genomic biomarker of response? (see Research Project 2)
The advancement of the Zero Childhood Cancer Program − originally exclusively focussed on children with high-risk cancer, but now moving towards including all children and young people with cancer − opens up a whole range of novel and exciting prospects. We now have a unique opportunity to study the so called ‘actionable biology’ of sarcoma across different disease stages.
Key questions we aim to answer in this research include:
- How do phosphoproteomic profiles change during the course of sarcoma progression?
- How might these novel insights help us guide clinical treatment directions?
For example:- Can we use targeted treatments earlier in the disease to spare patients toxic chemotherapy and invasive surgery?
- Do patients at diagnosis need different targeted therapies compared to those at metastasis?
Key collaborator: Prof Roger Daly, Monash University, Melbourne
Transforming unexplained drug sensitivities to personalised clinical treatments
Contact: Dr Emmy Fleuren, EFleuren@ccia.org.au
The Zero Childhood Cancer Program aims to identify tailored targeted treatments for children and young people with cancer using a comprehensive precision medicine platform, including whole genomic and whole transcriptomic molecular profiling. When possible, this program also tests the efficacy of 150 drugs against the patient’s own tumour cells grown in a dish in the lab, using a high-throughput drug screening (HTS) platform.
A substantial number of sarcoma cells have now been exposed to this platform, with more screens expected in the coming years. Excitingly, our analysis of the sarcoma cohort shows that over 60% of patient cells have a drug response. This includes extraordinary sensitivity to a variety of targeted drugs. In most cases, however, we have no idea why these patients’ tumour cells stop growing when exposed to that drug. These patients do not harbour a known genomic biomarker of response, and without the drug screen we would never have expected those drugs to work so well.
These unexplained drug responses have turned out to be a major clinical-translational bottleneck: when we do not know why a patient’s tumour cells respond so well to a targeted drug in our lab, there is no firm basis on which to confidently recommend that drug to the patient’s oncologist. This means that these patients are missing out on a drug that could be of benefit. This project aims to tackle this major challenge and facilitate the clinical translation of HTS findings in more sarcoma patients.
To do this, we will build an experimental framework to maximize our understanding of the molecular basis of extraordinary drug responders, utilizing novel and emerging techniques such as phosphoproteomics and CRISPR screens.
We aim to generate the evidence to:
- transform these unexplained drug responses into a treatment reality for young sarcoma patients who are currently missing out
- recognize drug responders prospectively - a critical step towards faster implementation of precision medicine recommendations for future patients.
Key collaborator: ZERO’s Preclinical Drug Testing Core team.
Developing novel functional models of sarcoma
Contact: Dr Emmy Fleuren, EFleuren@ccia.org.au
Sarcomas are an incredibly heterogenous and difficult-to-treat group of tumours, with over 150 subtypes recognised. The field of precision medicine has made this group even more complex. The more we learn about the molecular profiles of sarcomas, the more we realise that just as every patient is different, so too is every patient’s tumour. Even within the same sarcoma subtype, many different molecular variations can exist.
When performing preclinical research on sarcomas, it is critical that we take this diversity into account and that the models we work with accurately reflect the patient population. Having the right models is essential to facilitate translation of research findings to the clinic. Unfortunately, globally there are not enough models capturing the broad spectrum of sarcoma subtypes, disease stages and specific molecular profiles, and this is particularly true for subtypes affecting the young. This is a major limiting factor in the clinical translation of sarcoma research findings.
In this project, we aim to tackle this problem by establishing the world’s most diverse and comprehensive living biobank of paediatric, adolescent and young adult sarcoma, which is representative of the full spectrum of subtypes, disease stages and specific molecular profiles. We are working with sarcoma patient-derived xenograft models from the Zero Childhood Cancer Program and are establishing new patient-derived sarcoma cell cultures. These new models will help generate the preclinical data needed to drive the translation of new discoveries into clinical practice.
Key collaborator: ZERO’s Preclinical Drug Testing Core team.
Exploring the unexplored biology of paediatric sarcoma
Contact: Dr Emmy Fleuren, EFleuren@ccia.org.au
The Zero Childhood Cancer Program (ZERO) is one of the world’s most comprehensive precision medicine platforms, generating whole genomics, whole transcriptomics and methylation data coupled to functional drug testing profiles of childhood cancer patients across Australia. Sarcoma patients represent the second largest patient group in the ZERO program, providing a unique opportunity to study paediatric sarcoma biology in greater depth than ever before.
We have developed a range of exciting new research projects based on the wealth of sarcoma data generated by ZERO. Our current focus includes but is not limited to:
- exploiting the DNA damage response in childhood sarcoma
- exploring the utility of gene overexpression signatures as actionable targets in sarcoma
- exploring the unexplored actionable biology of childhood sarcoma.
Key collaborators: Chelsea Mayoh, Emmy Dolman, Paul Ekert, Jie Mao.
Team
Group Leader
Postdoctoral Researcher
Alice Salib
PhD Students
Callum Perkins
Larissa Volken
Research Assistants
Zara Barger
Kate Gunter (part time)
News & blogs
Cooper Rice-Brading Foundation funding to benefit sarcoma re...
Surviving sarcoma: Ashleigh’s story
Immunotherapy for children with sarcoma
Join us this Childhood Cancer Awareness Month
Get in touch
Do you have a question about our work? For any enquiries please don’t hesitate to contact us.
