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Garron Family Cancer Centre

GFCC Research Fellows

Garron Family Cancer Centre Research Fellows 2017/18

The GFCC fellowships support clinicians, scientists and graduate students on an annual basis who are looking to advance their knowledge of cancer care and research. These fellowship opportunities aim to provide training through direct participation in basic science or clinical investigation under the supervision of world leaders in oncology research and clinical care. Through a competitive selection process the following fellowships were awarded for the 2017/18 academic year:

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Dr. Jack Bartram, GFCC Leukemia Clinician Scientist Fellowship
Supervisor: Dr. Jim Whitlock, Division Head, Haematology/Oncology, Women’s Auxiliary Millennium Chair in Haematology/Oncology, Director, Garron Family Cancer Centre, Senior Associate Scientist, Child Health Evaluative Sciences Program

Development of Clinical Applications for Advanced Diagnostics and Novel Strategies for Risk Stratification in Paediatric Acute Lymphoblastic Leukaemia
Acute lymphoblastic leukaemia (ALL) is the most common type of cancer in children. Although the treatment for ALL has improved, it is an aggressive disease and many children are still refractory to treatment or suffer from disease relapse. The outcome for this group is very poor and it is essential to learn more about the mechanisms of resistance to treatment and about the changes that occur at relapse. Development of more effective therapies for this group based on the underlying molecular pathogenesis is a priority. Advanced diagnostic technologies capable of interrogating these important questions are evolving into use in clinical practice. We will use a combination of these advanced diagnostic technologies; in the form of high throughput sequencing (next generation sequencing), digital PCR and Nanostring along with more conventional technologies to identify specific changes inherent to this group. We hope to identify factors which will provide important information on the treatment of this high risk group of childhood ALL. Previously it was not possible to sensitively analyse the “whole picture” of disease in assessing the risk of relapse throughout treatment (termed minimal residual disease (MRD)). However with the advent of high throughput sequencing technologies this is now possible. Finally the increased sensitivity this affords could replace analysis of bone marrow with the analysis of peripheral blood, reducing the need for general anaesthetic and pain associated with bone marrow testing in children. Improving how MRD is performed by establishing high througtput sequencing with complement current techniques and will put SickKids at the forefront of MRD analysis and research.

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Dr. Julie Bennett, Sears Childhood Cancer Fellowship
Supervisor: Dr. Uri Tabori, Staff Haematologist/Oncologist, Division of Haematology/Oncology, Senior Scientist, Research Institute and The Arthur and Sonia Labatt Brain Tumour Research Centre 

The Clinical and Molecular Characterization of Low Grade Glioma in Adolescents and Young Adults
Low grade glioma is the most common type of brain tumour in children.  Most children with this tumour survive, but may require multiple treatments including surgery, chemotherapy and radiation.  Low grade glioma can also be seen in adults, where we know there is a much higher risk of transformation into a highly aggressive tumour that is incurable despite aggressive treatments.  Recent studies have described different genetic mutations occurring in children versus adults in the tumour cells.  Certain mutations are generally considered to lead to a better prognosis compared to others in both age groups.
Currently, there is limited information on the frequency and behavior of low grade glioma in adolescents and young adults under the age of 40 years.  It is unknown what the long-term outcome is for these patients, whether the mutations in the tumour resembles childhood or adult tumours, and the impact this has on prognosis.  This study aims to correlate molecular and clinical characteristics with long term outcome in a large group of patients from hospitals across Toronto.  We believe the type of mutation in the tumour may be predictive of response to treatment and long-term outcome.  This study will help us offer better care for these people with a deeper understanding of their disease.  Certain groups may benefit from personalized medicine using newer drugs targeted specifically to the tumour cells when the mutation is known.  This information has the potential to transform care of adolescents and young adults with low grade glioma.           

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Dr. Jack Brzezinski, Scotiabank Clinician Scientist Fellowship
Supervisor: Dr. Rosanna Weksberg, Senior Scientist and Staff Geneticist, Department of Clinical and Metabolic Genetics, SickKids Research Institute and Associate Professor, Department of Pediatrics, University of Toronto

Combining Genetic and Epigenetic Data to Define a Biologically and Clinically Relevant Stratification of Wilms Tumors  
Wilms tumour is the most common kidney cancer in children with approximately 50 new cases each year in Canada. Although many children can be cured with a combination of surgery, chemotherapy, and radiotherapy, the long-term side effects of these therapies can be significant and include kidney failure and second cancers. With a more precise system of predicting which children are more likely to have a relapse or second tumour, clinicians could tailor therapy to minimize the risk of these late side effects and also intensify therapy for those more likely to relapse. Dr. Brzezinski’s research is focussed on discovering the genetic and epigenetic determinants of outcomes in Wilms tumours. These factors can then be used to identify biomarkers that will improve our ability to choose the best therapy for each child.

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Dr. Ana Guerreiro Stucklin, Scotiabank Clinician Scientist Fellowship
Supervisor: Dr. Michael Taylor, Neurosurgeon, Division of Neurology, Garron Family Chair in Childhood Cancer Research, Senior Scientist, Development & Stem Cell Biology  

Overcoming Metastases and Chemoresistance in Medulloblastoma
Medulloblastoma is an aggressive brain tumour that affects young children and teenagers. Metastatic disease with tumour spread within the brain and spinal cord ¬— common at diagnosis and present in the overwhelming majority of patients at relapse — is particularly challenging to treat, with poor or no response to treatment. Despite being a major cause of morbidity and mortality, metastatic and relapsed medulloblastoma remain critically understudied.
Dr. Guerreiro Stucklin and colleagues conduct a series of studies using novel functional genomic tools, searching for genes that render tumour cells and metastases resistant to chemotherapy. Understanding how metastatic medulloblastoma ensues and prevails despite intensive chemotherapy holds the key to new treatments, essential to improve outcomes of children with medulloblastoma.

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Dr. Michal Zapotocky, Northbridge Fellowship in Cancer Research
Supervisor:Dr. Uri Tabori, Staff Haematologist/Oncologist, Division of Haematology/Oncology, Senior Scientist, Research Institute and The Arthur and Sonia Labatt Brain Tumour Research Centre 

Liquid Biopsy as a Tool to Precision Medicine in Childhood Cancer 
Brain tumors are the most frequent cancer in childhood. There is increasing evidence that proportion of brain tumors are driven by mutations in one of oncogenes. Tumor biopsy can be very challenging and associated with significant risk of morbidity and mortality. On top of that, no biopsy is performed in centrally located gliomas and these are diagnosed based on MRI findings. As such, no molecular diagnostic can be done from tumor tissue and these patients are disqualified from possible use of targeted therapies. Liquid biopsy is a method of detection of tumor cell-free DNA in patient’s plasma. This method is being tested in various adult cancers and allows to monitor response to therapy or to detect targetable mutations (i.e. RAS, BRAF, etc.). 
Dr. Zapotocky and team aimed to establish tool for detection tumor specific alterations in plasma in pediatric population. As a part of validation, they have proven that BRAFV600E mutation can be detected in plasma of Langerhans cell histiocytosis patients using digital droplet PCR and can be used as a target for monitoring during therapy. Unfortunately, this was not replicated in plasma of brain tumor patients in plasma. Therefore, we focused on detection of BRAFV600E in cerebrospinal fluid (CSF). Indeed, CSF was found to be feasible for circulating DNA detection. Dr. Zapotocky continue to collect CSF samples from brain tumor patients to optimize this technique for non-invasive diagnostics of bain tumour using various point mutations.
One clinically validated, such a tool will serve for diagnosis of tumor specific mutations from patients’ blood and CSF. Moreover it will be used for monitoring of response to anticancer therapy and eventually early prediction of emerging relapse.