A description of research projects supported by The Children's Cancer Centre Tissue Bank can be found below.
Use of Human Tissues for the Study of Langerhans Cell Histiocytosis (LCH)
Researchers: Prof George Kannourakis and Dr Sharon Olsen from the Fiona Elsey Cancer Research Institute in Ballarat
LCH is a rare and poorly understood disease where dendritic cells abnormally accumulate, resulting in destruction of adjacent tissues. Dendritic cells normally act as antigen-presenting cells where their main function is to process and present antigens to the T cells of the immune system. The research project at the Fiona Elsey Cancer Research Institute in Ballarat aims to characterize the various cells within LCH lesions and blood from LCH patients, with a specific focus on these dendritic cells, T cells and T cells with a regulatory function. This research requires cryopreserved live cells from patients with LCH that can be analysed through our flow cytometer. This research has allowed us to publish the identification of a previously unreported unusual type of T-cell in LCH and we hypothesize that further studies will show that T cells with a regulatory function are altered in LCH. A comprehensive study of the immune response pathways in LCH will provide a valuable insights into the pathogenesis of LCH.
In October 2016 Dr Sharon Olsen from the Fiona Elsey Cancer Research Institute in Ballarat visited the Children’s Cancer Centre Tissue Bank to obtain samples from Dr Louise Ludlow (Tissue Bank Coordinator). The use of LCH tissue samples in this project was approved by the Tissue Bank Access and Oversight Committee.
Understanding the genetic basis of chemotherapy-induced heart disease
Researchers: Rachel Conyers, David Elliot, Paul Ekert, Michael Cheung, Charlotte Burns, Anne Tripaydonis, Lauren Craig, Stephen Leslie and Francoise Mechinaud (MCRI and RCH)
Andre La Gerche and Ben Costello (Baker IDI)
Anthracyclines are valuable chemotherapeutic drugs that are used to treat over 70% of childhood and adolescent malignancies and have significantly improved childhood cancer survival rates. However, a major side effect of this drug class is irreversible and fatal heart damage. Cancer survivors treated with these drugs are nine times more likely, than average to develop heart failure. However, only 20-30% of patients are susceptible to chemotherapy-induced heart failure. The aim of this research is to find out why some patients are resistant and some are sensitive to this toxicity.
The CCC Tissue Bank processed over 300 blood samples from cases and controls toward this project which is led by Dr Rachel Conyers, an oncologist together with Dr David Elliot, a researcher at MCRI. Peripheral blood mononuclear cells were collected for DNA extraction and were also cryopreserved for functional assays. A comprehensive genomic analysis was performed using this cohort. Over 300 childhood cancer survivors were genetically profiled to identify variations in genes. This will improve our understanding of the genetic basis of chemotherapy-induced heart failure. A novel exciting approach called stem cell technology was used to create a functional assay with patient samples. This technology allowed the creation of induced pluripotent stem cell (iPSC) lines. Blood cells were reprogramed to stem cells which were then turned into cardiomyocytes (cardiac muscle cells). The cardiomyocytes were used in functional assays to assess sensitivity to these chemotherapeutic drugs.
The goal is to set up a clinically applicable tool to predict patient sensitivity to chemotherapy. This will enable a more tailored chemotherapy to patients resulting in less cardiac toxicity.
Drs Rachel Conyers and Dave Elliot discuss sample processing with Dr Louise Ludlow (Tissue Bank Coordinator).
Identification of genetic drivers in paediatric subcutaneous panniculitis-like T-cell lymphoma: an integrative clinical and genomic analysis
Researchers: Drs Dong Anh Khuong Quang and Rachel Conyers from the Murdoch Children's Research Institute in collaboration with Prof Nada Jabado from McGill University Health Centre, Montreal, Quebec, Canada
Subcutaneous panniculitis-like T-cell lymphoma is a rare form of T-cell lymphoma. This lymphoma is most common in young adults, and although the age range is broad, it rarely affects children. Patients typically present with multiple subcutaneous lesions, which are sometimes associated with symptoms that affect the entire body and/or laboratory abnormalities such as a reduction in the number of blood cells. It has only been identified as a separate entity since 2005 and officially included in the 2008 World Health Organization classification.
To date, less than 30 paediatric patients have been reported in the literature and mostly as individual case reports or part of a series of mostly adult patients, with limited biological data. These cases differ from their adult counterparts and there is no well-defined treatment strategy. Although cancer is often multifactorial, genetics likely plays a key role in this instance because patients often have a common genetic background (Pacific Islanders).
The research project aims to perform DNA sequencing of tumours using next-generation technologies and to shed light on potential key genetic players in their formation. The CCC Tissue Bank supplied tissue from two patients contributing significantly to this multi-centric study. This will lead to an improved management strategy for these patients for which there is no standard of care.
Dr Dong Anh Khuong Quang (front) from the Murdoch Children's Research Institute with collaborator Prof Nada Jabado from McGill University Health Centre, Montreal, Quebec, Canada.
Characterisation of Diffuse Midline Gliomas
Researchers: Dr Misty Jenkins and Shiqi Stacie Wang from The Walter and Eliza Hall Institute of Medical Research
Diffuse Midline Gliomas, otherwise known until recently as Diffuse Intrinsic Pontine Glioma (DIPG), is a paediatric brain tumour located in the brainstem and affects approximately 20 children per year in Australia with a mean age at diagnosis of 6-7 years. The progression free survival has remained at 9 months for decades and sadly <10% of children are alive at 2 years. Unfortunately, by it’s inherently ‘diffuse and infiltrative nature’ in an essential functional area of the brain, surgical resection of this tumour is impossible, and many different chemotherapeutic approaches for decades have been ineffective. Radiotherapy only extends lifespan and is used as a palliative measure. Immunotherapy, an approach to use the body’s own immune system to identify and eradicate tumours, has recently been used in leukaemia and adult cancers such as melanoma and kidney tumours, with great success.
We aim to identify new targets for immunotherapy treatments, by analysis of the currently stored specimens in the CCC Tissue bank. By analyzing the tissue for proteins expressed in DIPG, we will identify potential targets for immunotherapy treatments for DIPG. This research is essential, given there are no current curative treatments for DIPG.
Dr Misty Jenkins, Dr Shiqi Stacie Wang and team members from The Walter and Eliza Hall Institute of Medical Research.
The identification of a novel prognostic marker in ALL
Researchers: Prof. Susie Nilsson and Dr Ben Cao from Biomedical Manufacturing, CSIRO
Acute lymphoblastic leukaemia (ALL) is the most common childhood cancer and although high remission rates can be achieved with standard chemotherapy, drug-resistance and cancer relapse remains a significant problem. Leukaemic cell survival and drug-resistance is regulated by various receptor-protein interactions that occur in the bone marrow. We have identified a specific receptor called “integrin α9β1” that we show to be expressed on a cohort of ALL samples and our preliminary results suggest the expression of this receptor is associated with drug resistance and poor prognosis. This project seeks to validate integrin α9β1 as a prognostic marker for poor survival in paediatric ALL, which we can use to categorise patients as low or high risk as a means of directing the best course of treatment. If successful, this project will significantly change best clinical practice for treatment of ALL in Australia.
Prof. Susie Nilsson and Dr Ben Cao from Biomedical Manufacturing, CSIRO