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Childrens Cancer Research Group - Research

1. Epigenetic mechanisms in the pathogenesis of cancer in childhood

Dr Tracy Hale, Rachel Purcell and Dr Michael Sullivan.
Child Cancer Foundation Project Grant, 3 years

This project is investigating the role of epigenetic processes in the development of cancer in children. DNA methylation, histone modification and genomic imprinting are epigenetic processes crucial to the control of gene expression, cell division and differentiation. We are investigating how these epigenetic mechanisms are disrupted in the development of neuroblastoma and hepatoblastoma, with a particular interest in identifying potential therapeutic targets and novel markers that may be relevant to the diagnosis and assessment of these tumours (manuscript in preparation).

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2. Developmental biology of hepatoblastoma and related tumours

Dr Dejan Arsic, Dr Michael Sullivan.
Foundation for Science Research and Technology Post Doctoral Fellowship, 3 years

Dr Arsic has a 3-year FRST postdoctoral fellowship to investigate the developmental biology of hepatoblastoma and other foregut-derived tumours (pancreatoblastoma). Dr Arsic has established a model cell line system to study the role of the sonic hedgehog pathway in hepatoblastoma. The effects of several small molecule inhibitors of the SHH pathway are being investigated by microarray gene expression analysis (manuscript in preparation).

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3. An international collaborative study to identify diagnostic and prognostic markers of hepatoblastoma

This study is being conducted under the auspices of the International Paediatric Oncology Society Liver Tumour Strategy Group (SIOPEL). SIOPEL was established in 1990, and has conducted 3 prospective international collaborative clinical trials (SIOPEL 1, 2 and 3) on the diagnosis and management of hepatoblastoma and hepatocellular carcinoma. Two new trials have just opened (SIOEPL 4 and 5), and another new trial is planned to open in 2006 (SIOPEL 6).

While the clinical trials have been very successful and have greatly improved the overall survival for children with these tumours, much less progress has been made in identifying the biological markers that may be incorporated into the risk stratification of patients for treatment. Commencing in 2004, the SIOPEL group has sought to develop a strategy for identifying and validating biological markers for this group of tumours. In collaboration with a group in Paris, we have conducted an initial microarray gene expression analysis of a small number of tumours and have just received approval for a further collaborative microarray gene expression study of a large bank of tumours from the UKCCSG tissue bank. To validate any potential markers, we have, with the support of SIOPEL, collected over 100 tumours from international clinical trial centres of patients entered in the SIOPEL 2 and 3 studies. We have commenced assembling these into a tissue array (this work is being done in our Christchurch laboratory). We have also developed the methods for recovery of RNA and DNA from paraffin-embedded blocks as a means of overcoming the limited access to fresh tumour tissue. Initial data from this work were presented at an International Workshop at the Amsterdam Medical Centre in March 2006, co-chaired by Dr Sullivan.

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4. A clinical study: hepatoblastoma and Beckwith-Wiedemann syndrome

Dr Michael Sullivan, Margaret Childs, Dr Mike Capra (Toronto Children’s Hospital)
for the SIOPEL group, International Paediatric Oncology Society

SIOPEL has requested a review of the clinical and biological features of children with Beckwith-Wiedemann Syndrome (BWS) who develop hepatoblastoma. Little is known about the biological features of this tumour in BWS, or the clinical outcome of these patients. Data have been collected from all patients with BWS entered in SIOPEL trials, and additional data are being sought for the preparation of a manuscript.

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5. An international clinical trial for the diagnosis and treatment of pancreatoblastoma

Dr Michael Sullivan (Chairman) and Dr Patricia D’Aligna (University of Padua, Italy)
for the SIOPEL group, International Paediatric Oncology Society

The SIOPEL group has requested the development of an international clinical trial for the diagnosis and management of pancreatoblastoma. We have previously shown that this tumour is biologically similar to hepatoblastoma, and have now completed the development of a formal collaborative clinical trial. The trial has been approved by ethics committees in NZ, and is currently proceeding through the UK multi-regional ethics committee. Once approved, the study will open for entry of patients in 2006. The study is a worldwide protocol for the management of pancreatoblastoma, a very rare embryonal tumour of childhood. Recruitment is anticipated from Europe, US, Canada, South America and Oceania.

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6. Children’s cancer heart study #1

Novel biological markers of anthracycline-related cardiotoxicity in children with cancer.

Mr Jonathon Panckhurst, Dr Lochie Teague, Professor Christine Winterbourne, Professor Mark Richards, Dr Michael Sullivan (PI).
Kids for Cancer Research Calendar Fund

As the outcome of cancer in children has improved, there is a need to address the issue of treatment-related late effects. Anthracycline-related cardiomyopathy is a common treatment- related complication, with a clinical spectrum ranging from asymptomatic cardiac dysfunction through to frank heart failure. In this clinical trial, we have prospectively recruited patients who are receiving anthracycline-based chemotherapy to evaluate several potential markers of cardiac toxicity, including NT-BNP, TnT, and free radical protein carbonyls. Jonathon Panckhurst has now completed his year of research and is preparing his thesis for submission in the next month.

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7. Children’s cancer heart study #2

A comparative study of cardiac echocardiography and functional MRI imaging for the assessment of potential cardiac dysfunction following anthracycline-based chemotherapy.

Ms Catherine Smart, Jonathon Panckhurst, Dr Ross Keenan, Dr Sharon McDonald, Dr Richard Troughton, Dr Brett Cowan (MRI Research Unit University of Auckland), Dr Michael Sullivan (PI).
Summer Research Project, Cancer Society of New Zealand Scholarship

This is the first study to evaluate the possible role of functional MRI imaging in the assessment of children who have been treated with anthracycline-based chemotherapy. Here we have studied a cohort of 12 patients with functional MRI and echocardiography. The MRI data will be evaluated by the MRI Research Unit, Auckland University, who will develop 3D functional cardiac models for each patient and compare the data to research-quality cardiac echos. This study is ongoing.

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8. Children’s cancer bone study

The CNP as a marker of bone growth in children undergoing chemotherapy.

Mr Tim Prickett, Dr Tim Yandle, Professor Eric Espiner (PI), Dr Michael Sullivan (PI).
Lottery Health, CMRF, and Cure Kids, Project Grants 2 years

Children undergoing chemotherapy are at risk of developing treatment-related bone disease, especially from corticosteroids, chemotherapy and radiotherapy. In a prospective clinical study, children undergoing treatment for cancer that includes corticosteroids are having their growth assessed and serial measurements of CNP determined to evaluate whether this protein may be a biological marker for the bone-related effects of treatment.

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9. Foregut and hindgut malformations in children

The role of the sonic hedgehog pathway in the pathogenesis of developmental abnormalities in children.

Dr Parkash Mandhan (PhD student), Professor Spencer Beasley, Dr Dejan Arsic, Dr Michael Sullivan
MacKenzie Trust Grant

There is a very close relationship between the genetic pathways that control normal embryonic development and the development of cancer in childhood. A candidate for the developmental pathway for child cancer is the sonic hedgehog/Gli signalling pathway, which is known to be involved in the development of several congenital disorders and some specific cancers.

Two studies have investigated the development of foregut and hindgut abnormalities in children.
In an animal model, we have investigated the development of hindgut abnormalities and identified altered expression of sonic hedgehog pathway genes in this spectrum of conditions. (PhD in preparation). In a second study, conducted through the national Paediatric Disease Surveillance Unit, we are conducting a national study of the incidence and prevalence of Foregut and Hindgut developmental disorders. This is an ongoing 2-year study.

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10. Bioinformatics, gene expression and clinical decision support

Dr Liang Goh (PhD student), Professor Nik Kasabov (PI) (Auckland University of Technology) and Dr Michael Sullivan.
NERF Project Grant

We have collaborated with Professor Nik Kasabov in the application of novel neural network algorithms to the evaluation of gene expression data, and its combination with other clinical diagnostic and prognostic features of cancer. Dr Sullivan was medical advisor and co-supervisor for Ms Goh, who has now submitted her PhD in information science (publications and patents previously published).

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11. Gene expression analysis of skin cancer

Dr Sydney Shuat Ch’ng, Dr Swee Tan WSM&HS (PI), Dr Dejan Arsic, Dr Michael Sullivan.
Lottery Health Project Grant

We have provided technical and scientific support for this project, which forms the basis of the PhD research for Dr Sydney Shuat Ch’ng, a trainee in Plastic Surgery at the Wellington School of Medicine. (Dr Sullivan – scientific advisor and co-supervisor for Dr Ch’ng.)

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12. Mutation analysis and clinical features of Rett Syndrome in New Zealand

Dr Tony Raizis, Ms Sarah Abbott, Dr Michael Sullivan (PI).
Deane Endowment Fund

We have received support to develop mutation and apply DNA analysis for patients suspected of having Rett Syndrome. We have now completed a study of over 40 patients, and are currently collecting clinical data on these patients (with ethics approval and informed consent). We have a collaboration and memorandum of understanding with the Telethon Institute for Child Health Research, Perth, to provide data to the Australasian Rett Syndrome database (summer research project).

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