Research
Research Funded 2011 to 2021
Flagship
FLAGSHIP 1: IMPROVING MODELS OF CHILD CARE
Fertility preservation in children, adolescents and young adults facing a fertility threatening treatment plan
While fertility preservation is standard practice in adult patients it is still not incorporated into standard practice for paediatric and AYA patients. The objective of this study is to develop an international multidisciplinary oncofertility medical and psychosocial competency framework. This will enable the development and implementation of a paediatric and AYA fertility preservation model of care and referral pathways, as well as leading the development and implementation of patient reported experience of care measures (PREM) for oncofertility services.
Started: 1 December 2016
Ending: 30 November 2018
Principal Investigator:
Dr Antoinette Anazodo
The impact of electronic clinical systems on medication safety and workload in oncology
The current project is to empirically assess some of the core anticipated benefits of the electronic medication management system on the inpatient wards at The Children’s Hospital Westmead. Rigorous evidence demonstrating the effects of eMM/eMR systems on safety is limited, especially in paediatric oncology settings. This project is the first of its kind – it will provide invaluable practical evidence to inform future implementations of eMM/eMR for Oncology Patients (and other patients by comparison), both in Australia and internationally, while also generating new evidence regarding medication safety and workload in oncology inpatients.
The project has three aims:- to quantify the safety and effectiveness of an eMM/eMR system to reduce prescribing errors, including adverse drug events, in oncology; to identify eMM system-related problems and areas where system redesign is necessary; and to quantify investigation/surveillance test, supportive care test and medication-ordering workload for Oncology patients and compare this with workloads for patients in other hospital areas.
Started: 1 July 2017
Ending: 30 June 2019
Principal Investigator:
Dr Luciano Dalla Pozza
Lifestyle interventions to prevent abnormal body composition, including obesity, and associated comorbidities in childhood cancer survivors.
Survivors of childhood cancer (CCS) are a vulnerable population. Compared to age matched peers they have an increased risk of second malignancies, cardiovascular disease (including stroke) and osteoporosis. In part, this may be a result of poor dietary habits, low levels of physical activity and excess adiposity. A healthy body weight has been associated with a decrease in morbidity and mortality from cancer, as well as preventing recurrence, improving survival for people diagnosed with cancer and improving quality of life. Our research shows that poor dietary and physical activity habits may manifest early after cancer therapy. There is a paucity of studies assessing lifestyle interventions in young CCS.
The overall aim of these projects is to develop interventions with patients and their carers early on to encourage healthy eating habits, participation in physical activity and establish a healthy body weight to prevent or decrease morbidity and mortality in CCS. The lifestyle interventions are designed to be feasible and acceptable to the CCS and their families. The studies will extend our previous work, translate our findings into real changes to survivor care as well as develop new lifestyle interventions.
Started: 1 July 2018
Ending: 30 June 2020
Principal Investigator:
Professor Claire Wakefield
Febrile child with cancer in rural areas
Queensland Children’s Hospital, Sydney Children's Hospital Randwick, and the Children’s Hospital Westmead are undertaking a collaborative study of optimal fever management in the paediatric oncology population. Neutropenic fevers are the most common emergency presentation in children with cancer, with a risk for rapid deterioration to septic shock. There are established guidelines which direct the management of the child presenting with fever, requiring a time to antibiotics of <60 minutes from presentation. The primary study objective is to identify those factors which impede optimal fever management in children with cancer.
Started: 1 July 2013
Ending: 30 June 2020
Principal Investigators:
Dr Luciano Dalla-Pozza & Assoc Prof Julia Clark
FLAGSHIP 2: TREATMENT OF HIGH RISK CHILD CANCER
Molecular profiling for factors predicting sensitivity or resistance therapy in relapsed child cancer
KCA has funded research to establish molecular profiling of tumours from patients who have failed standard therapy with a view to identifying alternate effective therapies using personalized treatment with currently available targeted pharmaceuticals. Molecular profiling of individual patient tumours provides additional treatment options for relapsed patients and leads to improved outcomes. We plan to use molecular profiling to undertake a multi-centre prospective clinical trial in paediatric patients with recurrent or refractory solid tumours or leukemia, and to further investigate uncharacterised molecular anomalies identified in patient samples that are hypothesized to be clinically important.
Started: 1 July 2016
Ending: 30 June 2018
Professor Michelle Haber
Principal Investigator:
Professor Jennifer Byrne
FLAGSHIP 3: MONITORING AND PREVENTING TREATMENT SIDE-EFFECTS
Telomeres
The KCA program has enhanced capacity in patient care through the development of the telomere length assay which will enable patients with short telomere syndromes to more safely receive their treatment. Pioneering work of KCA researchers in the field of telomere maintenance has led to the clinical development of a short telomere diagnostic which is now being used to identify children whose DNA damaging therapy should be reduced. The telomere length assay has been available for clinical patients at risk of short telomere syndromes have been tested. Bone marrow transplant has been standard of care for children with the telomere deficient cancer predisposition syndrome, dyskeratosis congenita.
KCA researchers have also completed a large-scale study of telomere length in children having bone marrow transplant and correlated this with their side-effect profile. This work has progressed from basic to applied research and now is poised to have an impact across all children having a bone marrow transplant.
Started: 1 July 2016
Ending: 30 June 2017
Principal Investigator:
Professor Roger Reddell
Predictive clinical and genetic factors for the side-effects of chemotherapy in children treated with acute lymphoblastic leukaemia
KCA has funded a study to identify clinical and genetic markers which could be used to identify ALL patients at high-risk of treatment related toxicity. The overall goal is to facilitate future development of risk-adapted therapy for children with ALL, to reduce incidence of severe toxicities without reducing treatment efficacy; and improve quality of life for children and their families. A retrospective analysis of a large, homogenously treated Australian ALL cohort was used to identify both clinical and genetic markers for 3 severe treatment related toxicities (thrombosis, neurologic and bone toxicity).
Started: 1 July 2016
Ending: 30 June 2018
Principal Investigator:
Dr Toby Trahair
FLAGSHIP 4: PREVENTION OF CHILD CANCER
Germline DNA
The Germline DNA project will draw on the combined patient resources of the Sydney Children’s Hospitals Network to conduct next-generation sequencing of germline DNA from both retrospectively- and prospectively-identified cancer patients, and in the latter case, from their immediate family members. We anticipate that this approach will identify known cancer-predisposing mutations showing expected and unexpected associations with cancer diagnoses within the cohort, as well as new genetic variants that could be associated with cancer risk. This is a unique project in Australia that will represent the first analysis of tumour predisposition in child cancer patients using whole genome sequencing. The project will also help us to better understand the unique experiences of families who face not only the challenges of navigating a cancer diagnosis in a child, but also need to cope with the additional complexities of potential genetic implications for the whole family.
Started: 1 July 2017
Ending: 31 December 2018
Professor Jennifer Byrne
Principal Investigator:
Professor Claire Wakefield
Down Syndrome
Children with Down Syndrome have a high risk of developing a pre-leukaemia, called transient myeloproliferative disorder (TMD), during the newborn period. One in four of these children with TMD will go on to develop acute myeloid leukaemia. The project objectives are to establish an early detection strategy by assessing the level of GATA1s in the peripheral blood of down syndrome children at risk of myeloid leukaemia down syndrome, and, thus a molecularly defined population of infants in whom a preventative drug could be trialed in the future and to identify novel driver mutations as the “3rd hit” that predicts progression from TMD to myeloid leukaemia down syndrome/acute megakaryocytic leukaemia in children with down syndrome.
Started: 1 January 2018
Ending: 30 June 2019
Principal Investigator:
Dr Belamy Cheung
Innovative Research Directions
Identifying novel synthetic lethal targets in mTOR dysregulated cancers
The mammalian target of rapamycin (mTOR) pathway is frequently dysregulated in several paediatric hematologic and solid tumour malignancies. First generation mTOR inhibitors were poorly tolerated, and therefore had limited clinical utility. While the second-generation mTOR inhibitors demonstrated important clinical benefits the success of single-agent therapy was limited and primarily resulted in disease stabilization rather than regression.
mTOR signalling impacts many cellular processes. The aim of this project is to identify specific mTOR functions required for malignancy and to facilitate selective synthetic lethal targeting while sparing other mTOR functions required for healthy cell survival. Specifically, we identified a novel mTOR-regulated pathway that is activated when DNA replication is hindered in cancer cells. This pathway is essential for nuclear structure and DNA integrity in mTOR-driven cancers and thus, presents an opportunistic synthetic lethal target.
Started: 1 January 2020
Ending: 31 December 2021
Principal Investigator:
Dr Noa Lamm-Shalem
Whole genome sequencing for minimal residual disease markers
The assessment of Minimal Residual Disease (MRD) in children with leukaemia has been transformative, allowing patients at high-risk of relapse to be identified early and have their treatment rapidly altered. But since each patient’s tumour is unique, the identification of genetic MRD markers is currently labour intensive, and for many patients an MRD marker cannot be identified. In this KCA funded project, we propose to use Whole Genome Sequencing data and develop new methods to streamline the identification of patient-specific genetic MRD markers, applicable to all types of leukaemia’s. Furthermore, we propose that each patient’s genomic profile can be used to stage patients into different risk categories and identify new treatment options. This funding, combined with a team of MRD, leukaemia and genomics experts will allow us to retrospectively, and prospectively determine whether WGS provides a new paradigm for MRD.
Started: 1 January 2020
Ending: 31 December 2021
Principal Investigator:
Dr Mark Cowley
Liquid biopsies for molecular monitoring of paediatric solid tumours
This is pilot study which is utilising established KCA expertise in minimal residual disease (MRD), genomics and solid tumours modelling for the preclinical and translational development of liquid biopsies for the molecular monitoring of treatment response in paediatric solid tumours. Specifically, ctDNA, miRNA, CTC and tumour specific epitopes will be monitored.
Started: 1 May 2017
Ending: 30 April 2019
Principal Investigator:
Dr Jonathan Karpelowsky
Inducing DNA lethality in DIPG
The study involves a comprehensive analysis of PLK1 inhibition on our panel of DIPG cultures to identify the most promising combinatorial strategies, and test the most effective combinations in our two robust animal models of DIPG. These experiments can then be rapidly translated to clinical trial through the KCA trials centre. The specific aims of the project are to determine the most potent combination therapies which target PLK1 and other key therapeutic pathways (including the RTK/PI3K signalling pathway) in vitro; and to evaluate the efficacy of PLK1 inhibitors in combination with clinically relevant chemotherapeutic drugs using in vivo models of DIPG.
Started: 1 January 2017
Ending: 30 June 2019
Principal Investigator:
Dr Laura Franshaw
Structure guided development of telomerase inhibitors as cancer therapeutics
The aim of this research program is to develop highly-specific small-molecule telomerase inhibitors through structure-guided design, wherein an atomic-level molecular structure provides a template for the custom-design of small molecules to block enzymatic activity in a predicted manner. Structure-guided design has led to the development of highly successful cancer therapeutics, such as Gleevec, targeting the bcr-Abl fusion, and Venetoclax, targeting Bcl2 and developed at the WEHI.
Started: 1 January 2018
Ending: 31 December 2019
Principal Investigator:
Dr Scott Cohen
Development of CAR T cell immunotherapy for targeting solid tumours in children
The overall goal of the project is to develop CAR T cell therapy for treating children with brain tumours and recurrent, refractory, or metastatic bone tumours. The efficacy of EphA2 CAR T cells will be tested by in vitro cytotoxicity assays, 3D tumour culture models and tumour bearing mouse models for osteosarcoma, ewing’s sarcoma and brain tumours, including orthotopic mouse xenografts of patient derived DIPGs and other tumour types. The project also aims to design novel CAR constructs to address the specific challenges facing solid tumour targeted CAR T cell therapy as a basis for improving efficacy, safety and by broadening potential targets in the context of paediatric cancers
Started: 1 January 2018
Ending: 31 December 2019
Principal Investigator:
Dr Ken Hsu
Molecular characterisation of relapse-initiating ALL cells for targeted therapy
The 5-year survival rate of paediatric acute lymphoblastic leukaemia (ALL) currently exceeds 90%. Based on clinical, morphological and genetic characteristics patients are stratified at diagnosis to receive risk-adapted combination chemotherapy to maximise the likelihood of cure while minimising the toxic side-effects of their treatment. However, several high-risk ALL subtypes require novel approaches to improve treatment outcomes. One high-risk subtype of ALL, known as Ph-like (or BCR-ABL1-like) ALL, is associated with increased risk of relapse and poor outcome, highlighting the need for improved treatment strategies. We aim, through rationally designed combination therapy, to re-sensitise these relapse-initiating cells to targeted therapy by altering their gene expression or epigenomic profiles.
Started: 1 April 2019
Ending: 31 March 2021
Principal Investigator:
Dr Vincent Jing
Pre-clinical testing of MCL1 inhibitor S63845 in infant leukaemia PDX models
Survival rates of infants suffering from acute lymphoblastic leukaemia (ALL) characterised by a rearrangement of the MLL/KMT2A gene (MLL-r ALL) remain below 50% and many survivors suffer from detrimental long-term health issues due to side-effects of conventional chemotherapeutic treatment. New targeted therapeutics with a higher level of cancer-specificity are thus urgently needed to develop more effective and safer treatment schemes.
One of the recent success stories for targeted therapies has been the development and progression of BCL-2 inhibitors (e.g. Venetoclax) into the clinic for haematological malignancies. Based on its success in a range of adult haematopoietic cancers, Venetoclax is currently in clinical trial for refractory/relapsed paediatric malignancies. However, despite its success, inherent or acquired resistance to Venetoclax occurs due to dependency of the cancer cells on other prosurvival BCL-2 family proteins MCL1 and BCL-XL, which has resulted in a push towards the development of specific inhibitors for these molecules. Decades of intense research have recently led to the generation of the first specific small molecule inhibitors of MCL1 which are now being advanced into clinical trials for adult haematological malignancies.
In view of the particularly dismal outcome for infants with MLL-r ALL, our research is focused on identifying novel targeted agents for this disease through the testing of candidate compounds in our state-of-the-art, fully molecularly annotated patient-derived xenograft (PDX) models for infant ALL that are internationally unique and recognised as the gold standard preclinical models for this disease. Based on the hypothesis that MCL1 is a major contributing factor in the survival and therapy resistance of infant MLL-r ALL, the aim of this project is to elucidate the clinical potential of targeted MCL1 inhibition for infant MLL-r leukaemia by investigating the preclinical efficacy of a novel, specific MCL1 inhibitor, S63845 in our in vitro and in vivo models of the disease.
Started: 1 April 2019
Ending: 31 March 2021
Principal Investigator:
Dr Klaartje Somers
Infrastructure
Pharmacokinetic assessment aimed at reducing toxicity and enhancing efficiency in child cancer patients undergoing therapy
Many anti-cancer drugs have a narrow therapeutic window and are associated with significant toxicity. Current dosing methods are generally inadequate and may result in either life-threatening toxicity or impaired disease control. This is particularly evident in babies and young children. Correct dosing is also a challenge for the adolescent and young adult population due to pubertal changes. Through studying the pharmacokinetics (PK, dose vs. concentration relationship) and pharmacodynamics (PD, concentration vs. effect relationship) of these drugs it is possible to identify optimal exposure targets that are associated with reduced toxicity and enhanced efficacy (PK/PD research) and to adjust the dose accordingly. Further research is required to test whether the dose adjustments do actually lead to reduced toxicity and improved efficacy.
Principal Investigator:
Dr Christa Nath
Clinical Trial Centres
Clinical trials centres have been established at Randwick and Westmead to support activities required to set up and monitor early phase clinical trials which have arisen from local pre-clinical research at KCA medical research institutes.
Randwick: Professor David Ziegler
Westmead: Dr Geoff McCowage
Principal Investigator:
Associate Professor David Ziegler / Dr Geoff McCowage
Biobanking
KCA Biobanking initiatives have led to the two large existing biobanks at Sydney Children’s Hospital with Children’s Cancer Institute and Children’s Hospital Westmead with Kids Research merging into a single governance structure and the banks adopting a new common IT system. The banks have harmonised the terminology used to code samples and increased the proportion of new diagnoses for whom samples have been collected. This has increased the total number of samples available to researchers, improved their access and paved the way for the future collection of matching germline DNA and serum samples on all patients. Moreover, analyses of our own banking techniques and international best practice has led to guidelines of benefit other initiatives in NSW. Under the leadership of Prof Jennifer Byrne, and more recently Associate Professor Dan Catchpoole, these developments are now applied to a national child health biobanking.
Childhood Cancer Survivor Bank
In Australia today almost 20,000 young adults are survivors of child cancer and one in three are expected to suffer a severe health problem as a consequence of their anticancer therapy. KCA is seeking to increase research opportunities for future NSW researchers analysing candidate clinical, therapeutic and germline genetic factors for a causal role in the late-effects of successful anticancer therapy. KCA is funding the harmonising of information into a single database with minimal clinical information such as the anticancer treatment received and tissue diagnosis, combined with banked germline DNA (gDNA) from peripheral blood leucocytes, for patients treated at either Sydney Children’s Hospital Randwick or Children’s Hospital Westmead.
The database and gDNA bank is managed by the existing collaborative Tumour Banks at Children’s Hospital Westmead/Kids Research and Sydney Children’s Hospital/Children’s Cancer Institute. This management includes maintaining the database and tissue bank, and assessing, then complying with any requests for access to the gDNA samples and/or clinical information, in accordance with institutional ethical guidelines. The first step is creation of a minimal clinical dataset and archiving of past patient clinical data and gDNA samples, followed by the creation of a prospective collection process, and a system of regular auditing which ensures the integrity of the data and samples, and assesses the ongoing usefulness of the data and samples.
Professor Richard Cohn
Principal Investigator:
Associate Professor Dan Catchpoole
Bioinformatics and Biostatistics
Bioinformaticians and biostatisticians are essential to the translational research capacity of the Kids Cancer Alliance. Many cancer research projects generate enormous volumes of data. This requires expert bioinformatics analysis and interpretation to extract meaningful discoveries from the large datasets and prepare the results for publication in the highest quality journals. Apart from providing valuable input into research programs directly, KCA bioinformaticians have been engaging biological research staff in training and mentoring in order to help them build data analysis skills.
Principal Investigator:
Ms Chelsea Mayoh
KCA encompasses a hospital research division, two medical research institutes and three clinical care centres in the state of New South Wales with the support of two major universities. Refer to Our partners and affiliates for further details.