The Annual Scientific Report of The Arthur and Sonia Labatt Brain Tumour Research Centre at The Hospital for Sick Children

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MESSAGE FROM DR. JAMES RUTKA

Dr. James Rutka, Director

ABOUT THE BTRC LOGOThe Arthur and Sonia Labatt Brain Tumour Research Centre logo was created at the time of the grand opening of the centre in January 1999. The logo depicts a dove, symbolizing hope, carrying a twig in its beak. The twig is actually a piece of double-stranded DNA representing molecular medicine. The logo symbolizes the mandate of the BTRC: Hope through molecular medicine.

WHAT IS NEW IN THE BTRC

I am pleased and proud to provide you with this introduction to this year’s Annual Scientific Report of the Labatt Brain Tumour Research Centre (BTRC). We have had, once again, an incredible year characterized by numerous successes, honours and awards. All principal investigators have garnered numerous multi-year grant awards and have published their work in the best scientific journals. Students and researchers, from all corners of the world including Italy, Portugal, Korea, Japan, India, and the United States, continue to join us for advanced training in the laboratory. We continue to be recognized as an institute of the Pediatric Brain Tumor Foundation along with Duke University and the University of California San Francisco. We were incredibly honoured last year to host the International Brain Tumour Research and Therapy Conference in Niagara Falls June 21-24, 2012. From all accounts, this was a highly successful and informative meeting for all those who attended from around the world.

This past year, Michael Taylor published his major research findings on subgroup-specific structural alterations in over 1000 medulloblastoma genomes in Nature. His work and classification system for medulloblastoma is being referenced in the literature and at all neuro-oncology meetings around the world. Since 1998, the investigators within the Labatt BTRC have been dedicated to determining the molecular underpinnings of the genetically most complex and devastating brain tumours in hopes at arriving at new treatment options. Our group has made progress not only with the genetic origins of medulloblastoma, but also more recently with ependymoma, diffuse intrinsic pontine glioma, and atypical teratoid rhabdoid tumours.

We look forward to sharing future issues of Imagine with you as we strive to translate our research observations into tangible clinical benefits for patients, both adults and children, with brain tumours.

On September 17th, 2013, The Hospital for Sick Children celebrated the official opening of the Peter Gilgan Centre for Research and Learning. The Centre is located at the corner of Bay and Elm streets, and is now the home to over 2,000 researchers, trainees, and staff. The tower cost approximately $400 Million to construct, and has 21 stories of research space making it one of the largest research towers of its kind in the world. The building was designed to enhance collaborations through the creation of research neighbourhoods where scientists and trainees can work side by side, generating new ideas and discussing future research plans. The Labatt BTRC is located on the 17th floor of the Peter Gilgan Centre, and is comprised of a balance of office and wet lab bench spaces for research. While we truly enjoyed the opportunity to work at the MaRS Discovery Site for the past 6 years, our relocation to the new research tower at SickKids has sparked new enthusiasm and desire to advance our projects as quickly as possible.

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PROFILE OF DR. JANE MCGLADE

POSTDOCTORAL RESEARCH, SAMUEL LUNENFELD, ANTHONY PAWSON SUPERVISOREDUCATION PhD, McMASTER UNIVERSITY, VIROLOGY, PHILLIP E. BRANTON SUPERVISOR

ASSOCIATE CHIEF OF RESEARCH, FACULTY DEVELOPMENT, SICKKIDS RESEARCH INSTITUTECO-DIRECTOR, SIDNET

Dr. McGlade obtained her B.Sc in Biology at the University of Guelph and after a very short stop in Pharmacy at University of Toronto, moved on to do graduate work with Dr. Phil Branton in the Cancer Research Group at McMaster University. After receiving her PhD, Dr. McGlade did post-doctoral research with Dr. Tony Pawson at Mount Sinai Hospital in Toronto and then landed her first independent research position next door at former Amgen Institute and Ontario Cancer Institute. She moved to SickKids and joined the BTRC as a scientist in 1999.

Dr. McGlade’s area of expertise includes signal transduction – that is, the transmission of regulatory messages within cells – and the discovery and characterization of new genes/proteins that control cell communication. Her interest in studying how proteins function in cells to transmit signals started as a graduate student studying how viruses can highjack the cell machinery to control cell division and survival. Her work now focuses on how intercellular signals that modify the behavior of cells are transmitted at the molecular level, and how theses signals become defective in cancer cells. A detailed understanding of the pathways used by cancer cells can provide the basis for new strategies and a rationale for drug design in the development of new cancer therapies.

One of her proudest moments as a scientist was when she was recruited to SickKids and the BTRC. “Having spent many hours, days and weeks at SickKids as a worried mom, it felt great years later to become part of the team.”

Outside of work Dr. McGlade is married to Jim Dolson and they have two daughters Kate and Sarah, both currently students at the University of Guelph. She is an avid fan and participant in endurance cycling and running events, but enjoys many other outdoor activities such as skiing or just walking the dogs.

Dr. Jane McGlade

The McGlade laboratory

The McGlade laboratory and families With Dr. Rutka and the late Dr. Guha at a lecture

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DR. PETER DIRKSScientist, Principal Investigator

Dr. Dirks’ research program’s long-term goal is to determine if a normal neural stem cell or progenitor cell is transformed into a brain tumour. Two approaches are being used to study this question. One approach involves a study of primary human brain tumours to determine if stem cell populations exist in brain tumours. The Dirks laboratory is answering the question: is there a small population of cancer cells in a brain tumour that uniquely has the ability to maintain the tumour? Dr. Dirks’ laboratory has recently isolated and characterized a repopulating cell from human brain tumours of different phenotypes that expresses neural stem cell markers and has stem cell-like behaviour in vitro. This subpopulation of tumour cells could be considered as cancer stem cells, because the cells share properties with normal stem cells and because they are necessary for maintaining tumour growth in vitro.

The second approach involves a study of the key determinants of proliferation and self-renewal in normal neural stem cells. The focus is on the sonic hedgehog signalling pathway, as it is perturbed in primary human brain tumours (medulloblastomas), and because it has been shown to be critically important for normal brain development. Preliminary studies suggest that different Shh pathway members play important and distinct roles in neural stem cell proliferation and self-renewal. A better understanding of how this pathway functions in normal neural stem cells may help us to better understand brain tumour proliferation and self-renewal.

LABORATORY PERSONNELIan Clarke, AssociateTzvi Aviv, Postdoctoral FellowFiona Coutinho, Graduate StudentSonam Dolma, Graduate StudentMarco Gallo, Postdoctoral FellowJeremy Graham, TechnicianRenee Head, TechnicianMichelle Kushida, TechnicianKevin Lan, Graduate StudentLilian Lee, TechnicianKathleen Nethery-Brokx, TechnicianNicole Park, Graduate StudentKatherine Rowland, Postdoctoral FellowHayden Selvadurai, Postdoctoral FellowMilly So, TechnicianRob Vanner, Graduate StudentXueming Zhu, Technician

RESEARCH SUPPORT: Canadian Institutes of Health Research, Canadian Cancer Society Research Institute, Ontario Institute of Cancer Research

Dr. Das was educated at the University of Michigan and at Harvard University before attending medical school at Northwestern University in Chicago. During medical school, he performed studies at the NINDS/NIH leading to his PhD in Neurobiology. Dr. Das completed neurosurgical training at Northwestern University in 2010. He was recruited to the Division of Neurosurgery at St. Michael’s Hospital, the University of Toronto in 2010. Over the years, he has received numerous honours and awards. He has published his research findings in excellent scientific journals including J Biol Chem, Mol Cell, JAMA, and PLoS One. His main areas of research interest are in glioblastoma stem cells and epithelial-mesenchymal transitions in these cells.

LABORATORY PERSONNELMegan Wu, Research Project ManagerLoury Janbazian, Observer

DR. SUNIT DASScientist, Principal Investigator

RESEARCH SUPPORT: b.r.a.i.n.child

PRINCIPAL INVESTIGATORS OF THE BTRC

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LABORATORY PERSONNELSanja Pajovic, AssociateMark Barszczyk, Graduate StudentPawel Buczkowicz, Graduate StudentYevgen Chornenkyy, Graduate Student Andrew Morrison, TechnicianPatricia Rakopoulos, Graduate Student

RESEARCH SUPPORT: National Brain Tumor Society, Canadian Institutes of Health Research, b.r.a.i.n.child

DR. CYNTHIA HAWKINSScientist, Principal Investigator

Dr. Hawkins’ laboratory focuses on genetic and proteomic markers for prognostication and therapy guidance in paediatric brain tumours including medulloblastoma, astrocytoma and ependymoma. Traditionally, medulloblastomas have been classified on the basis of their appearance into different pathological types, but with poor correlation between these categories and outcome.

Dr. Hawkins’ laboratory developed a clinical-biologic model to predict survival in medulloblastoma. Although this goes beyond previous studies in differentiating those children with a good versus a poor prognosis, Dr. Hawkins’ laboratory aims to acquire more detailed knowledge of the biology of medulloblastomas in order to tailor therapy to the particular biology and predicted behaviour of an individual patient’s tumour. Genome-wide approaches are being used to better understand the genes important for development of paediatric astrocytoma. Potential targets are then verified at the RNA and then protein level using tissue microarrays. In ependymoma, Dr. Hawkins’ laboratory has found that expression of telomerase, a protein important for continued cell division, can predict outcome in paediatric ependymoma more effectively than clinical prognostic factors and is investigating its potential as a therapeutic target for these tumours.

LABORATORY PERSONNELMei Lu, AssociateTiffany Chan, Graduate StudentKing Ching Ho, TechnicianDeena Gendo, Postdoctoral FellowDaniel Picard, Graduate StudentPatrick Sin-Chan, Graduate StudentTara Spence, Graduate StudentJonathon Torchia, Graduate Student

RESEARCH SUPPORT: Canadian Institutes of Health Research, Canadian Cancer Society Research Institute, Childhood Cancer and Blood Disorders Research Network, Genome Canada/National Brain Tumor Society

DR. ANNIE HUANGScientist, Principal Investigator

Brain tumours, the most common solid malignancies of childhood, differ from other solid malignancies in that brain tumours rarely metastasize outside of the central nervous system. Despite this relatively “restricted” pattern of progression, metastatic brain tumours are therapy resistant. Due to the devastating growth and neurocognitive consequences of the best current treatment, which includes radiation, there is much interest in identifying molecular pathways that specify metastatic behaviour in malignant paediatric brain tumours, in order to ultimately develop more effective and less toxic tumour therapy. Dr. Huang’s laboratory is interested in cellular and molecular mechanisms that underlie tumour progression in central nervous system primitive neuro-ectodermal tumours (PNET), the most frequent group of paediatric malignant brain tumours. Current projects involve use of high-resolution genomic tools such as SNP microarrays and ChiP-on-chip technology to define novel genes and pathways associated with aggressive PNET phenotypes. A major interest in the laboratory is to determine how c-Myc, a potent oncoprotein, specifies aggressive phenotypes in cerebellar PNET/medulloblastoma. To investigate the molecular basis of this association the laboratory has focused on identifying Myc protein interactors and target genes with key contributions to Myc-mediated transformation in medulloblastoma cells. Recently, Dr. Huang and her team discovered that a novel family of Myc-interacting and co-transforming proteins, the JPO proteins that are overexpressed in metastatic medulloblastoma. Characterization of the role of JPO proteins and other novel Myc partners/targets in medulloblastoma/PNET pathogenesis is the focus of ongoing work.

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RESEARCH SUPPORT: Canadian Institutes of Health Research, Canadian Cancer Society Research Institute, The Leukemia and Lymphoma Society of Canada, The Foundation Fighting Blindness – Canada, b.r.a.i.n.child

DR. JANE MCGLADEScientist, Principal Investigator

Dr. McGlade’s research is directed towards understanding the molecular changes that occur during the process of malignant cell transformation. Work in the laboratory involves several aspects of signal transduction and the identification and characterization of novel signalling molecules.

Recently, Dr. McGlade has focused specifically on one class of cytoplasmic adapter molecules and the role they play in the localization, integration and co-ordination of signalling cascade components within two distinct signalling paradigms. It is anticipated that the research results will have broad implications in terms of understanding the temporal and spatial organiza tion of mitogenic signal transduction pathways, as well as the process of asymmetric cell division and epithelial cell polarity in mammals.

The long-term goal of this work is to define the molecular processes that regulate the formation and activation of signalling complexes and how disruption of this regulation can lead to cell dysfunction and malignant disease.

LABORATORY PERSONNELDonna Berry, AssociateSascha Dho, AssociateSarah DeClemente, Graduate StudentEmily Griffiths, Postdoctoral FellowJonathan Krieger, Graduate StudentFabio Morgese, Postdoctoral FellowZhongda Pan, Graduate StudentBrittany Prevost, Graduate StudentDushyandi Rajendran, StudentNancy Silva, AssociateChristopher J. Smith, Graduate StudentLeanne Wybenga-Groot, Postdoctoral Fellow

LABORATORY PERSONNELChristian Smith, Operations ManagerSameer Agnihotri, Postdoctoral FellowAlenoush Albertvartania, Graduate StudentRoberto Diaz, Graduate StudentClaudia Faria, Postdoctoral FellowBrian Golbourn, Graduate StudentJames Loukides, Project CoordinatorAmanda Luck, TechnicianMustafa Nadi, Postdoctoral FellowHidehiro Okura, Postdoctoral FellowNesrin Sabha, Laboratory ManagerYuzo Terakawa, Postdoctoral Fellow

DR. JAMES T. RUTKADirector, The Arthur and Sonia Labatt Brain Tumour Research Centre,

Principal Investigator

Dr. Rutka’s laboratory has been studying the cytoskeleton as a means to increase our understanding of the mechanisms by which astrocytoma cells grow, adhere to surrounding substrates and invade normal brain tissue. Current studies are aimed at investigating how cytoskeletal matrix interactions lead to the profound cellular changes that we have observed through a detailed analysis of cell cycle gene alterations, metalloproteinase and inhibitor secretion and ultrastructural cytoskeletal relationships. Recent emphasis has been placed on the small Rho-GTPases as potential targets for inhibiting astrocytoma invasiveness.

In a second project, Dr. Rutka’s laboratory has focused on the childhood brain tumour known as medulloblastoma. His laboratory personnel are studying the contributions of the hepatocyte growth factor (HGF)/cMET pathway in the pathogenesis of this malignant brain tumour. The laboratory has recently shown that HGF/cMET elements are epigenetically regulated in medulloblastoma leading to increased tumour cell growth and invasion. In addition, through a comprehensive mutational analysis, the laboratory has now shown that members of the HGF/cMET pathway are mutated suggesting a possible mechanism underlying tumour cell proliferation. More importantly, the laboratory has found that inhibition of the HGF/cMET pathway with well characterized small molecules leads to inhibition of medulloblastoma growth both in vitro and in vivo.

RESEARCH SUPPORT: Canadian Institutes of Health Research, Canadian Cancer Society Research Institute, Pediatric Brain Tumor Foundation of the United States, Brain Tumour Foundation of Canada, b.r.a.i.n.child

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LABORATORY PERSONNELCindy Zhang, AssociatePedro Castelo-Branco, Postdoctoral FellowCynthia Elizabeth, TechnicianTatiana Lipman, Graduate StudentJoshua Mangeral, Postdoctoral FellowMatthew Mistry, Graduate StudentNataliya Zhukova, Graduate Student

LABORATORY PERSONNELXiaochong Wu, AssociateFlorence Cavalli, Postdoctoral FellowAdrian Dubuc, Graduate StudentLivia Garzia, Postdoctoral FellowNoriyuki Kijima, Postdoctoral FellowBorja Lopez, Postdoctoral FellowJessica Lui, TechnicianBetty Luu, TechnicianStephen Mack, Graduate StudentSorana Morrissy, StatisticianJohn Peacock, Graduate StudentLei Qin, TechnicianVijay Ramaswamy, Postdoctoral FellowMarc Remke, Postdoctoral FellowAdi Rolider, Postdoctoral FellowDavid Shih, Graduate StudentYuan Thompson, Graduate StudentKevin Xin Wang, Graduate StudentKory Zayne, Technician

DR. URI TABORIScientist, Principal Investigator

Dr. Tabori studies mechanisms that control brain tumour progression and survival. One of his main research interests is paediatric low-grade astrocytoma, a tumour that has unique growth characteristics when compared to other paediatric or adult brain tumours. Dr. Tabori is studying replicative and oncogene-induced senescence factors in paediatric low-grade astrocytomas that then may be used for prognosis in these tumours.

In addition, Dr. Tabori will extend his studies to develop novel therapies for high-grade paediatric gliomas such as ependymomas and glioblastomas. Finally, the laboratory will investigate the genetic alterations that determine the clinical course of patients with neurofibromatosis type 1, the most common cancer predisposition syndrome, in which low-grade and high-grade neuroglial tumours predominate.

RESEARCH SUPPORT: Canadian Institutes of Health Research, Terry Fox Foundation, Comprehensive Cancer Centre, Ontario Institute of Cancer Research, Pediatric Brain Tumor Foundation of the United States, b.r.a.i.n.child

DR. MICHAEL D. TAYLORScientist, Principal Investigator

Dr. Taylor’s laboratory uses the tools of forward and reverse genetics to better understand the underlying biology of medulloblastoma and ependymoma, two of the most common malignant paediatric brain tumours.

In forward genetic approaches, the normal cells that are thought to give rise to cancer are perturbed in a systemic fashion in an attempt to determine which genes or signalling pathways promote malignant transformation. By randomly over-expressing genes in the cellular precursor of medulloblastoma, the laboratory hopes to determine which genes are important to the initiation, maintenance and progression of medulloblastoma. This sort of functional genomic approach has recently been made feasible by the completion of the mouse genome project.

In reverse genetic approaches, primary human tumours are studied in an attempt to determine the genetic events that lead to transformation. The laboratory is using a number of genome-wide techniques to identify novel tumour suppressor genes and oncogenes important in the pathogenesis of medulloblastoma and ependymoma.

Through an understanding of the genetic basis of brain tumours, it is anticipated that novel, rational therapeutics may be developed that are more effective and less toxic than existing therapies. In addition, synergism between forward and reverse genetic approaches promises to accelerate the discovery of key genes important in brain tumour biology.

RESEARCH SUPPORT: Canadian Institutes of Health Research, Canadian Cancer Society Research Institute, Genome Canada, National Institutes of Health, McLaughlin Centre for Molecular Medicine, b.r.a.i.n.child

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LABORATORY PERSONNELSanjay Singh, Research AssociateSameer Agnihotri, Postdoctoral FellowKelly Burrell, TechnicianFelipe Carvalho, Postdoctoral FellowShahrzad Jalali, Postdoctoral FellowGeorge Klironomos, Postdoctoral FellowBoris Krischek, Postdoctoral FellowEric Monsalves, Graduate StudentKrisanne Rego, TechnicianTakyee Tung, Technician

RESEARCH SUPPORT: Canadian Institutes of Health Research, b.r.a.i.n.child

DR. GELAREH ZADEHScientist, Principal Investigator

Dr. Zadeh’s overall research goal is to gain a better understanding of the molecular regulators of tumour angiogenesis in response to ionizing radiation (IR) in order to improve the therapeutic benefit of radiation therapy (RT) for brain tumours. She has two inter-related research aims. Her first aim focuses on understanding the molecular mechanisms that regulate bone marrow progenitor cells (BMPCs) and specifically the contribution of endothelial progenitor cells (EPCs) in response to IR in both normal and tumour-related vasculature. Her second aim is to identify the mechanisms and sequence of therapeutics targeting tumour angiogenesis concurrent with IR in order to identify the most efficacious therapeutic combination for treatment of malignant astrocytomas. She employs three principal anti-angiogenic strategies: VEGF-TRAP, pharmaceutical inhibitors of angiogenesis and, lastly, a novel strategy using radiation-activated angiogenic and anti-angiogenic genes of interest in collaboration with Dr. Susan Scott, UK. In order to carry out these experiments, she takes advantage of a wide range of molecular biology, molecular imaging, molecular physics and angiogenesis techniques in collaboration with other groups.

Dr. Paul Kongkham began his faculty appointment in the Division of Neurosurgery in the Department of Surgery at the University of Toronto in September of 2012. He completed the neurosurgery residency program at the University of Toronto in June of 2011. Midway through his residency, he embarked on his PhD in the laboratory of Dr. Rutka in the graduate school program of Laboratory Medicine and Pathobiology. His PhD thesis was on the role of epigenetic alterations in human brain tumours, and in particular, medulloblastoma. For his PhD, Paul published a number of key papers in Cancer Research, Oncogene, and Translational Oncology. Following his residency, Paul travelled to MD Anderson Cancer Center and did a clinical fellowship in neurosurgical oncology. He has now returned to Toronto and will be starting his research efforts on the genetics and biology of human glioblastoma multiforme. Paul is married to Dini, an assistant professor in Obstetrics and Gynecology at the University of Toronto, and they have two daughters, Natalie (age 6) and Naomi (age 3½). We welcome Paul as the latest Principal Investigator of the Labatt BTRC.

DR. PAUL KONGKHAMScientist, Principal Investigator

LABORATORY PERSONNELDonya Aref, Graduate StudentConner Moffat, Technician

LABORATORY PERSONNELWioletta Glowacka, Research Associate

DR. SIDNEY E. CROULScientist, Principal Investigator

Dr. Croul’s primary research interest is the role that cell surface adhesive molecules play in the tendency of certain central nervous system tumours, particularly medulloblastoma, to undergo leptomeningeal dissemination. This process in which cancer cells spread across the surface of the brain and spinal cord is associated with significant morbidity and mortality. The identification of these molecules may help to predict which patients are at risk for leptomeningeal dissemination at an earlier and more treatable stage than is presently possible. Recognition of cellular pathways that are activated by this spread may also help in the design of more effective and less toxic therapies than those that are currently available.

RESEARCH SUPPORT: The Grant Miller Foundation, b.r.a.i.n.child

RESEARCH SUPPORT: b.r.a.i.n.child

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AFFILIATED SCIENTISTS

Cameron Ackerley, PhDMark Bernstein, MDEric Bouffet, MDDavid Kaplan, PhDJason Karamchandani, MDNormand Laperrière, MDDonald Mabbott, PhDWarren Mason, MDJames Perry, MD

ADVISORY BOARD OF THE LABATT BTRC

Sonia and Arthur LabattDr. Robert S. BellDr. David BermanHelen BermanTed GarrardMary Jo HaddadDr. Ben NeelDr. Christopher PaigeDr. Janet RossantDr. Catharine WhitesideDr. Jim Wright

BTRC WELCOMES DR. JASON KARAMCHANDANI AS A NEW AFFILIATED SCIENTIST

Following his graduation from Harvard College, Dr. Karamchandani attended medical school at Stanford University School of Medicine, where he remained for residency training in anatomic pathology followed by fellowship training in surgical pathology and neuropathology. He currently practices neuropathology at St. Michael’s Hospital in Toronto, where he is the director of the immunopathology laboratory. Dr. Karamchandani’s research is focused on tumors of the central nervous system and peripheral nerves with a focus on molecular pathology, bioinformatics, and the identification and characterization of diagnostic and prognostic biomarkers.

RESEARCH SUPPORT: Canadian Institutes of Health Research

DR. TODD MAINPRIZEScientist, Principal Investigator

Dr. Mainprize has two main areas of research interest. Firstly, he is collaborating with scientists at Sunnybrook Health Science Centre to investigate the utility of MR-guided focused ultrasound in the treatment of primary and metastatic brain tumours. This novel modality can be used to safely and reversibly disrupt the blood-brain barrier allowing for better delivery of chemotherapeutic agents to a tumour. Focused ultrasound can target and destroy tumour cells with millimetre accuracy and may be a radiation-free alternative to radiosurgery. Secondly, he is investigating the various pathway dysregulations in meningiomas with the hopes of developing more effective treatments for recurrent and higher-grade tumours.

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2012-13 BTRC GUEST LECTURERS

Thursday, March 28, 2013

Signaling by the ELMO/DOCK180 complex in breast cancer metastasis and muscle development Dr. Jean-François Côté

Thursday, May 30, 2013

Preclinical testing of experimental therapeutics for treating brain tumors: raising the bar for clinical trial evaluationDr. David James

15TH ANNUAL LABATT BTRC ACADEMIC LECTURESHIP

The 15th annual Arthur and Sonia Labatt Brain Tumour Research Centre academic lecture took place on Thursday, February 7, 2013. Our guest speaker was Dr. Fred Lang, MD, The University of Texas MD Anderson Cancer Center, Houston, Texas, Director of Clinical Research. The topic of his lecture was Mesenchymal Stem Cells in the Therapy and Biology of Gliomas.

1999 Dr. Robert Martuza Georgetown University2000 Dr. Gregory Cairncross University of Western Ontario2001 Dr. David Kaplan Montreal Neurological Institute2002 Dr. Charles Stiles The Dana-Farber Cancer Institute2003 Dr. Luis Parada University of Texas2004 Dr. Eric Holland Sloan-Kettering Cancer Center2005 Dr. Darell Bigner Duke Comprehensive Cancer Center2006 Dr. Webster Cavenee Ludwig Institute for Cancer Research2007 Dr. David H. Gutmann St. Louis Children’s Hospital2008 Dr. Henry Brem Johns Hopkins University2009 Dr. Joe Costello University of California – San Francisco2010 Dr. Waldemar Debinski Wake Forest University2011 Dr. Kenneth Aldape MD Anderson Cancer Centre2012 Dr. Inder Verma The Salk Institute

VISITING LECTURESHIP

PREVIOUS BTRC ACADEMIC GUEST LECTURERS

Dr. Fred Lang

Left to right: Dr. Cynthia Hawkins, Dr. Sidney Croul, Dr. Jane McGlade, Dr. Uri Tabori, Dr. James Rutka, Dr. Fred Lang, Dr. Michael D. Taylor, Dr. Annie Huang and Dr. Paul Kongkham

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ESTABLISHMENT OF THE MIKE AND DIANNE TRAYNOR LECTURESHIP AT THE LABATT BTRC

The Labatt BTRC at SickKids has been associated with the Pediatric Brain Tumor Foundation (PBTF) of the United States for several years. Initially, we had several research projects funded through the PBTF; however, more recently, we were given “Institute” status within the PBTF along with Duke University and the University of California San Francisco. Each year, as Institutes of the PBTF, we meet to discuss our present and future collaborations. This has spawned new areas of research study within pediatric neuro-oncology between these groups. The success of the PBTF Institute model has been incalculable. It was the vision of Mike and Dianne Traynor to apply the Institute model for pediatric neuro-oncology. Since the passing of Mike and Dianne, we have been pleased to be working with Robin Boettcher, CEO, and Joanne Salcido, VP Research and Family Support, of the PBTF. The Labatt BTRC at SickKids is pleased to announce the establishment of the Mike and Dianne Traynor Lectureship this year. The inaugural lecture was given by Dr. Rolf Bjerkvig, Professor of Anatomy and Cell Biology at the University of Bergen, on November 19, 2013.

LABATT BTRC SIGNS HISTORIC COLLABORATIVE RESEARCH DOCUMENT WITH CRP-SANTÉ LUXEMBOURG

Dr. James Rutka travelled to Luxembourg on March 7, 2013, to visit the Norlux Neuro-Oncology Research Laboratory in Luxembourg City. There, he signed a collaborative document celebrating the research collaboration agreement between the Labatt BTRC and CRP-Santé. Dr. Rutka gave an overview of the BTRC to those in Luxembourg, and was asked to speak before the Minister of the Economy and Foreign Trade, The Honourable Etienne Schneider. Other members of the Norlux Neuro-Oncology Research Laboratory with whom the Labatt BTRC will be collaborating include Dr. Simone Niclou, and Dr. Rolf Bjerkvig. Shown in the photograph below following the signing of the document.

Robin Boettcher and Joanne Salcido

The late Mike and Dianne Traynor

The Traynor’s with Dr. Rutka

Back row, left to right: the Hon. Etienne Schneider; Dr. Ralf Bjerkvig, Research Scientist, Norlux LaboratoryFront row, left to right: Mr. Frank Gansen, President CRP-Santé; Dr. James Rutka; and Dr. Jean-Claude Schmit, CEO, CRP-Santé

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Lunch alfresco

A MOVE TO HIGHER GROUND

On September 19, 2013, the Labatt BTRC moved from the 11th floor of the MaRS Discovery site, where it had held residence over the past 6 years, to the 17th floor of the new Peter Gilgan Centre for Research and Learning at SickKids. The move occurred in two waves. At first, the offices were moved, and this was followed by the move of the wet bench space the following week. As with any move of this magnitude, there were some challenges to overcome including information technology upgrades, freezer space and electrical power shortages, and identification badge recognition issues, but all in all, the move went very well. We are extremely pleased with the new space that the Peter Gilgan Centre affords for the Labatt BTRC, and look forward to our many future discoveries and communications that will take place from this new site. A special thanks are given to Christian Smith and Donna Berry for their dedication to and assistance with all aspects of the move.

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Left to right: Wioletta Glowacka, Megan Wu, Amanda Luck

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NEWS AT THE BTRC

LABATT BTRC SPONSORS THE 6th ANNUAL INTERNATIONAL MUTANT p53 WORKSHOP IN TORONTO

ALAN AND SUSAN HUDSON CHAIR IN NEURO-ONCOLOGY AT THE PRINCESS MARGARET HOSPITAL

DR. RUTKA DELIVERS FIRST ANNUAL AB GUHA LECTURE AT THE SOCIETY FOR NEURO-ONCOLOGY ANNUAL MEETING

The Labatt BTRC was pleased to help sponsor the 6th Annual International Mutant p53 Workshop in Toronto that was organized by Dr. David Malkin, Senior Scientist at SickKids, on June 15-18, 2013. The workshop was a huge success, as new collaborations were formed, and new data regarding the role of p53 in cancer was presented.

Several years ago, the Foundation of the Princess Margaret Hospital at the University Health Network (UHN) established the Alan and Susan Hudson Chair in Neuro-Oncology. Dr. Alan Hudson was the former Chair of the Division of Neurosurgery at the University of Toronto, Surgeon-In-Chief at the Toronto Hospital (UHN), Chief Executive Officer at UHN, and Lead of the Wait Times Strategy for the Ministry of Health and Long-Term Care. The first chair holder was Dr. Ab Guha. Following Dr. Guha’s passing in 2011, plans are in place to search for a new chair holder to continue with research efforts in adult experimental neuro-oncology. In the 1980’s it was Dr. Hudson who realized the importance of establishing a research community in neuro-oncology research, and who sent several neurosurgical trainees away for advanced research studies in the field. These trainees, including Mark Bernstein, Jim Rutka, Paul Muller, and Ab Guha, returned to Toronto and were pivotal in helping to establish the Labatt BTRC many years later.

On October 16, 2012, Jim Rutka was honored by the Society for Neuro-Oncology to give the first Annual Ab Guha Lecture. Dr. Rutka spoke about his lab’s work on astrocytoma invasion and the use of focused ultrasound to help deliver gold nanoparticles across the blood brain barrier. In the audience were Dr. Guha’s family members, Soma, his wife, and his children, Deep, a neurosurgery resident in the University of Toronto training program, and Tia, a masters student in the Institute of Medical Sciences at the University of Toronto. Soma Guha, Deep Guha and Tia Guha

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THE YEAR IN REVIEW – CURRENTLY HELD GRANTS

Dr. James Rutka

Translational targeting of Group D medulloblastomas. Pediatric Brain Tumor Foundation of the United States (PBTFUS)

Molecular targeting of the Rho-GTPase pathway in human astrocytomas. Canadian Institutes of Health Research (CIHR)

Blockade of aberrant HGF/cMET signaling in medulloblastoma. Canadian Cancer Society Research Institute (CCSRI)

Dr. Jane McGlade

Role of the SLAP adaptor proteins in ubiquitin dependent regulation of receptor tyrosine kinases. Canadian Institutes of Health Research (CIHR)

Role of the CRB1-EPB41L5 complex in retinal degeneration. Foundation Fighting Blindness – Canada

Function and regulation of Numb isoform expression in cancer. Canadian Institutes of Health Research (CIHR)

Role of LNX family E3 ubiquitin ligases in polarity, Wnt signaling and cancer. Canadian Cancer Society Research Institute

Dr. Peter Dirks

Therapeutic opportunities to target tumor initiating cells in solid tumors. Canadian Institutes of Health Research (CIHR)

Defining cancer stem cell and clonal heterogeneity in mouse brain tumors. National Cancer Institute of Canada

Asymmetrical self renewal in normal and cancer stem cells of the human brain. Canadian Institutes of Health Research (CIHR)

Characterization of brain cancer stem cells. Ontario Institute for Cancer Research (OICR)

Screening brain cancer stem cells. Ontario Institute for Cancer Research (OICR)

Dr. Annie Huang

Discovery and characterization of C19MC a novel oncogenic miRNA locus in malignant brain tumors. Canadian Institutes of Health Research (CIHR)

Identification of prognostic factors and therapeutic targets in childhood CNS atypical teratoid rhabdoid tumours (ATRT). (co-PI). C17 Childhood Cancer and Blood Disorders Research Network

The Canadian Pediatric Cancer Genome Consortium: Translating next-generation sequencing technologies into improved therapies for high-risk childhood cancer. (co-PI). Canada/CIHR Advancing Technology Through Innovation Grant

Targeting thrombospondin-1 in medulloblastoma. Canadian Institutes of Health Research (CIHR)

TRAINEE AWARDS

Fiona CoutinhoRestracomp

Roberto DiazFirst place PhD Poster Presentation, Graduate Student Research Day, Laboratory Medicine & Pathobiology

Claudia FariaRestracompGarron Family Cancer Centre

Deena GendooCIBC-Brain Canada Brain Cancer Training Award

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TRAINEE AWARDS

Dr. Michael D. Taylor

Role of histone lysine methylation in medulloblastoma and cerebellar development. Canadian Institutes of Health Research (CIHR)

Medulloblastoma and metastases. National Institute of Health, United States

The Canadian Pediatric Cancer Genome Consortium: Translating next-generation sequencing technologies into improved therapies for high-risk childhood cancer. Genome Canada/Canadian Institutes of Health Research (CIHR)

Stratifying and targeting medulloblastoma through genomics. Genome Canada

Cellular and genetic basis of anaplastic medulloblastoma. National Institutes of Health (NIH) – United States

Co-operating events and drug response in sonic hedgehog driven medulloblastoma. Accelerator Grant in Genomic Medicine Competition 2011 McLaughlin Centre for Molecular Medicine – Toronto

Creation of a tractable preclinical model of metastatic medulloblastoma in zebrafish. b.r.a.i.n.child

Identification and validation of the first Group D medulloblastoma oncogene. b.r.a.i.n.child

Addressing tumor heterogeneity through targeting of subgroup specific shared maintenance genes – the correct target for each cancer. CIHR Team Grant – Terry Fox Frontiers Program

Translational targeting of Group D medulloblastoma. Pediatric Brain Tumor Foundation Institute Award

Medulloblastoma metastases arise from the cancer stem cell compartment. Ontario Institute of Cancer Research Cancer Stem Cell Program

Dr. Cynthia Hawkins

Targeting paediatric brainstem glioma using integrated whole genome analysis. Canadian Institutes of Health Research (CIHR)

Prediction and prevention of glioma recurrence by targeting telomere dependent self-renewal capacity of tumor initiating cells. Canadian Institutes of Health Research (CIHR)

The Canadian Pediatric Cancer Genomic Consortium: Unravelling the genetic basis of childhood cancer through next-generation sequencing. Canadian Institutes of Health Research (CIHR)/Genome Canada

GATA4 and GATA6 transcription factors in gliomagenesis. Canadian Institutes of Health Research (CIHR)

Dr. Uri Tabori

An international network to determine the origins and improve survival for children with mismatch repair genes mutations affected by malignant brain tumors. b.r.a.i.n.child

Prediction and prevention of glioma recurrence by targeting telomere dependent self-renewal capacity of tumor initiating cells. Canadian Institutes of Health Research (CIHR)

Exhaustion of tumor initiating cells by targeting their self-renewal capacity with telomerase inhibition. The Terry Fox Foundation

Examining the relationship between white matter integrity and the speed of neural processing in healthy children and children with brain tumours. ‘New Ideas’ Cancer Research Funds, Garron Family Comprehensive Cancer Centre

The neuro-protective effects of exercise in children treated with cranial radiation for brain tumors. Canadian Institutes of Health Research (CIHR)

hTERT methylation as a diagnostic and predictive tool for various tumors. MARs innovation POP grant

Biological and clinical impact of chromothripsis and early TP53 mutations on carcinogenesis in Li-Fraumeni syndrome. Canadian Cancer Research Society

THE YEAR IN REVIEW

Shahrzad JalaliGallie Bateman and McMurrich Resident Research Award

Vijay Ramaswamy2013 AACR Millennium Scholar-in-Training Award

2013 Canadian Association of Child Neurology President’s Prize

CIHR Fellowship and an Alberta Innovates Health Solutions Clinical Fellowship

Marc RemkePostdoctoral fellowship from the German Cancer Aid/Mildred-Scheel foundation

Katherine RowlandBrain Canada – Canadian Imperial Bank of Commerce Brain Cancer Fellowship

17The Annual Scientific Report of The Arthur and Sonia Labatt Brain Tumour Research Centre at The Hospital for Sick Children

STUDENT AWARDS

Examining the relationship between white matter integrity and the speed of neuronal processing in children with brain tumours. Canadian Institutes of Health Research (CIHR)

Clinical and biological implications of monoallelic gene expression in pediatric malignant brain tumors. Canadian Institutes of Health Research (CIHR)

Combined telomerase inhibition and drug screen as novel therapies for tumor initiating cells in pediatric nervous system tumors. Canadian Institutes of Health Research (CIHR) – New Investigator Award

Dr. Sidney Croul

Signaling from IGF1 to Beta 1 integrin in medulloblastoma. b.r.a.i.n.child

Metastatic medulloblastoma: whole genome expression. b.r.a.i.n.child

The role of Beta 1 and Beta 8 integrins in medulloblastoma metastasis. Grant Miller Foundation

Beta integrins as adhesive molecules in leptomeningeal medulloblastoma. b.r.a.i.n.child

Dr. Gelareh Zadeh

Role of HK2 in regulating brain tumor neovascularization and response to therapy. Canadian Institutes of Health Research (CIHR)

Role of bone marrow derived progenitor cells in brain tumor neovascularization. Canadian Institutes of Health Research (CIHR)

Phase II clinical trial of Nilotinib in treatment of growing vestibular schwannomas. Ontario Institute of Cancer Research

Discovery of biomarkers to guide individualized therapy of patients with brain metastases. Brain Tumour Foundation of Canada

Nilotinib in growing Vestibular Schwannomas: Phase I Clinical Trial. Canadian Institutes of Health Research (CIHR)

Nilotinib in growing Vestibular Schwannomas: Phase I Clinical Trial. Novartis Canada Ltd

Dr. Sunit Das

The role of the epithelial-mesenchymal transition in the maintenance of stem-cell identity in glioblastoma brain tumor stem cells. b.r.a.i.n.child

The role of prostacyclins in the survival of glioblastoma brain tumor stem cells. b.r.a.i.n.child

Targeting vascular mimicry in glioblastoma. b.r.a.i.n.child

Improved functional magnetic resonance imaging for pre-surgical planning of brain tumours.Canadian Cancer Society Research Institute Innovation Award

Dr. Todd Mainprize

Molecular targeting of the Rho-GTPase pathway in human astrocytomas. Canadian Institutes of Health Research (CIHR) Co-applicant

THE YEAR IN REVIEW

Yuan ThompsonOntario Graduate ScholarshipRestracomp

Xin (Kevin) WangVanier Canada Graduate Scholarship - CIHR

Mr. Robert and Ms. Francine Ruggles MD/PhD Innovation Award

Nataliya ZhukovaGFCC Fellowship

Young Investigator. Education Award, SIOP

Clinician Scholar Award, Paediatric Oncology Group of Ontario Research Unit

18 imagine 12-13

JACK MICHAEL BAKER FUNDBrian and Erin Baker have established a fund to further research on cancer stem cells in brain tumours. This donation is in honour of their son, Jack Michael Baker.

LAURIE BERMAN FUND FOR BRAIN TUMOUR RESEARCHEstablished in 2002 by Helen and Joe Berman in memory of their son, Laurie, this fund provides ongoing support for graduate students, postdoctoral research fellows, lab equipment and supplies. The fund also enables neurosurgical nurses to attend the annual Canadian Neurological Sciences Federation meeting.

NATHALIE CROSBIE ENDOWMENT FUND The Nathalie Crosbie Endowment Fund was created in 1998 by Jolie Lin and Ian Crosbie to support paediatric brain tumour research at SickKids. The fund is now fully endowed and enables scientists at the BTRC to perform research on medulloblastoma, the most common malignant brain tumour in children.

JONATHAN HILL FUNDIn 1997, Jonathan Hill, a vivacious, charismatic boy with an infectious smile, an irresistible charm, a beloved son and nephew, lost his courageous battle to a brain tumour at the age of eight. At the same time, two of his cousins were fighting their own battles and both are survivors. Why? Mostly because of the tireless efforts of doctors and researchers who were able to develop life-saving treatments for their particular cancers. Paediatric cancer research has come a long way, and has resulted in treatments that improve the quality of life for children with cancer, and even produced higher cure rates. The Jonathan Hill Fund will specifically assist research in the areas of brain tumours and leukemia, two of the most common childhood cancers. This fund will help future children afflicted with cancer beat the odds and help keep Jonathan’s memory alive.

ROCHELLE SHERWOOD FUND FOR BRAIN TUMOUR RESEARCHJudy Stein-Korte and Carl Korte have given generously to establish a fund to support research in the BTRC in honour of Judy’s sister, Rochelle, who was diagnosed with a brain tumour. This endowment fund will be used to support ongoing research projects on esthesioneuroblastoma, medulloblastoma and primitive neuro-ectodermal tumours.

THE WILEY FUND IN BRAIN TUMOUR RESEARCHEstablished in 2001 by Averil and Joe Wiley in honour of their son, Andrew, who was cared for by Dr. Rutka. This fund supports the ongoing research projects of two PhD students and two postdoctoral research fellows.

BEQUEST FROM THE ESTATE OF ERIC YOLLESA bequest has been received from the estate of Eric Yolles to be used for furthering research in the BTRC.

CHARITABLE DONATION FROM SOLMON ROTHBART GOODMAN LLPFor the past several years the Labatt BTRC has received an annual donation from Solmon Rothbart Goodman LLP. Randall Rothbart and Dr. Rutka have been friends since elementary school.

MAJOR DONORS

19The Annual Scientific Report of The Arthur and Sonia Labatt Brain Tumour Research Centre at The Hospital for Sick Children

ANNUAL FUNDRAISING EVENTS

Amy’s Shining Star is an event that continues to occur bi-annually and engages family and friends to attend a lovely gala while continuing to make a difference in tribute to Amy Beacock.

Bunzl Canada is deeply committed to their support of b.r.a.i.n.child, Dr. Rutka and his researchers. These corporate citizens take great pride and joy in giving back to their community and making an impact on the lives of children and their families affected by brain tumours.

Care for Kids celebrated 25 years of support of SickKids Foundation. These dedicated event organizers and their community of supporters are motivated by cutting-edge brain tumour research and the brilliant researchers at SickKids.

Entertainment One has a meaningful relationship with SickKids, as one of their own staff has a son who was successfully treated at SickKids. Entertainment One is great corporate citizen supporting the important research of b.r.a.i.n.child at Labatt Family Brain Tumour Research Centre.

Jessica’s Footprint has created a philanthropic legacy to help other families not endure what the Durigon family faced.

Laughing with the Ladybugs is a much anticipated event bringing together the greater community of Peterborough and surrounding areas in support of b.r.a.i.n.child and SickKids Foundation in honour of Kathryn Peeters. The event organizer Elizabeth Peeters and her family have been very involved with SickKids in a variety of roles as President of b.r.a.i.n.child and SickKids ambassadors. We are grateful for their outstanding commitment and volunteerism.

Meagan’s Walk: Creating a Circle of Hope continue to host community-based events in support of brain tumour research at SickKids. This walk is a unique, signature event for participants, and it continues to increase in numbers. This special event provides a forum for bereaved donors to honour the lives of their loved ones. It has raised over $3 million to date, providing valuable financial resources for brain tumour research.

Skate With Daniel continues to honour Daniel’s spirit and engage the community to change the future for patients affected by brain tumours by fundraising for brain tumour research. This year, Daniel’s mom, Marisa Bertoia, became one of the top eight finalists of Walmart Mom of the Year, securing a $10,000 award for Skate With Daniel.

Suri’s Smile was created in tribute of little Suri, who suffered from a brain tumour and lost her battle with cancer at a very young age. An inspiring gala was created in her honour as a way for her parents to give back to other families by supporting brain tumour research at SickKids.

Tali’s Fund is an organization that raises funds for paediatric brain tumour research. This fund was created following the tragic passing of the Doron family’s daughter, Tal, at the age of 4. Tali’s Fund raises money by collecting donations, hosting fundraising events, and selling items such as cards with paintings on the front made by Tali herself. Through the help of Tali’s Fund, research projects at the Arthur and Sonia Labatt Brain Tumour Research Centre have been funded, leading to large collaborative projects with many Canadian and international paediatric cancer centres around the world.

Team Brother Bear is celebrating five years of support for SickKids Foundation. This group funds brain tumour research through b.r.a.i.n.child and also provides funding for the b.r.a.i.n.child family fund dedicated to helping families in exceptional financial need. This dynamic group also play Santa during the holidays by providing gifts for brain tumour families in financial need at SickKids to help make their holidays special during very difficult days.

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ESTABLISHMENT OF THE UNIVERSITY OF TORONTO BRAIN TUMOUR BANK

The Department of Surgery has received an unprecedented $2 million gift to establish a Brain Tumour Bank!

Thanks to the generosity and leadership of Michael and Amira Dan, longtime U of T supporters, the University of Toronto Brain Tumour Bank network will enable researchers in our health sciences community to make more rapid progress towards effective treatment for people with brain cancer – progress that will prolong and save tens of thousands of lives in Canada and around the world.

The Department of Surgery shares the Dan’s commitment to addressing the urgent need for progress in the fight against brain cancer. With the establishment of a Brain Tumour Bank – a permanent resource for researchers and clinicians – we will speed discovery and improve treatment, saving lives.The number of cases of brain cancer treated at U of T-affiliated hospitals represents an unparalleled opportunity to collect and study tissue samples. The volume of tumour specimens available to Toronto researchers through a single medical school and university exceeds that in other large cities where samples are divided among several schools and institutions.

As you know, we are in an era of advances in genomics, proteomics, diagnostic technologies, surgical techniques and pharmacology, leading toward personalized therapies. The rapid and precise characterization of patient tumour tissue samples and individual patient tumour cells will soon be the new standard of diagnosis. Treatment plans based on this characterization will define the standard of care. With a vision of personalized molecular diagnosis and drug screening of every patient’s tumour based on systematic banking and analysis, the U of T Brain Tumour Bank network will be a momentous step in the development of these personalized therapies for brain cancer.

A philanthropist and active supporter of initiatives in global and aboriginal health, as well as neurosurgery, Michael holds a medical degree from U of T, a PhD in experimental medicine from McGill and an MBA from Louisiana’s Tulane University. After five years as an assistant professor of neurosurgery at Louisiana State University, he became the CEO of Novopharm Biotech Inc., a publicly-traded drug discovery company. Today, Michael is president of Gemini Power Corporation, a private hydroelectric power generating business focused on Canada’s First Nations. Amira holds an MA from OISE at U of T, a PhD in social and political thought from York University, and is a supporter of the faculty of humanities at the University of Haifa, Israel.

Darina Landa, Senior Development Officer, Department of SurgeryUniversity of Toronto

Amira and Michael Dan

21The Annual Scientific Report of The Arthur and Sonia Labatt Brain Tumour Research Centre at The Hospital for Sick Children

PUBLICATIONS

2012

Agnihotri, S., Gajadhar, A. S., Ternamian, C., Gorlia, T., Diefes, K. L., Mischel, P. S., Kelly, J., McGown, G., Thorncroft, M., Carlson, B. L., et al. (2012). Alkylpurine-DNA-N-glycosylase confers resistance to temozolomide in xenograft models of glioblastoma multiforme and is associated with poor survival in patients. Journal of Clinical Investigation 122, 253-266.

Castelo-Branco, P., and Tabori, U. (2012). Promises and challenges of exhausting pediatric neural cancer stem cells. Pediatric Research 71, 523-528.

Diaz, R. J., Golbourn, B., Shekarforoush, M., Smith, C. A., and Rutka, J. T. (2012a). Aurora kinase B/C inhibition impairs malignant glioma growth in vivo. Journal of Neuro-Oncology 108, 349-360.

Diaz, R. J., Guduk, M., Romagnuolo, R., Smith, C. A., Northcott, P., Shih, D., Berisha, F., Flanagan, A., Munoz, D. G., Cusimano, M. D., et al. (2012b). High-resolution whole-genome analysis of skull base chordomas implicates FHIT loss in chordoma pathogenesis. Neoplasia 14, 788-798.

Dubuc, A. M., Mack, S., Unterberger, A., Northcott, P. A., and Taylor, M. D. (2012a). The epigenetics of brain tumors. Methods in Molecular Biology 863, 139-153.

Dubuc, A. M., Morrissy, A. S., Kloosterhof, N. K., Northcott, P. A., Yu, E. P., Shih, D., Peacock, J., Grajkowska, W., van Meter, T., Eberhart, C. G., et al. (2012b). Subgroup-specific alternative splicing in medulloblastoma. Acta Neuropathology 123, 485-499.

Etame, A. B., Diaz, R. J., O’Reilly, M. A., Smith, C. A., Mainprize, T. G., Hynynen, K., and Rutka, J. T. (2012a). Enhanced delivery of gold nanoparticles with therapeutic potential into the brain using MRI-guided focused ultrasound. Nanomedicine 8, 1133-1142.

Etame, A. B., Diaz, R. J., Smith, C. A., Mainprize, T. G., Hynynen, K., and Rutka, J. T. (2012b). Focused ultrasound disruption of the blood-brain barrier: a new frontier for therapeutic delivery in molecular neurooncology. Neurosurgery Focus 32, E3.

Gajadhar, A. S., Bogdanovic, E., Munoz, D. M., and Guha, A. (2012). In situ analysis of mutant EGFRs prevalent in glioblastoma multiforme reveals aberrant dimerization, activation, and differential response to anti-EGFR targeted therapy. Molecular Cancer Research 10, 428-440.

Khuong-Quang, D. A., Buczkowicz, P., Rakopoulos, P., Liu, X. Y., Fontebasso, A. M., Bouffet, E., Bartels, U., Albrecht, S., Schwartzentruber, J., Letourneau, L., et al. (2012). K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Neuropathology 124, 439-447.

Li, M., Lockwood, W., Zielenska, M., Northcott, P., Ra, Y. S., Bouffet, E., Yoshimoto, M., Rutka, J. T., Yan, H., Taylor, M. D., et al. (2012). Multiple CDK/CYCLIND genes are amplified in medulloblastoma and supratentorial primitive neuroectodermal brain tumor. Cancer Genetics 205, 220-231.

Northcott, P. A., Dubuc, A. M., Pfister, S., and Taylor, M. D. (2012a). Molecular subgroups of medulloblastoma. Expert Review of Neurotherapeutics 12, 871-884.

Northcott, P. A., Korshunov, A., Pfister, S. M., and Taylor, M. D. (2012b). The clinical implications of medulloblastoma subgroups. Nature Reviews Neurology 8, 340-351.

Northcott, P. A., Shih, D. J., Peacock, J., Garzia, L., Morrissy, A. S., Zichner, T., Stutz, A. M., Korshunov, A., Reimand, J., Schumacher, S. E., et al. (2012c). Subgroup-specific structural variation across 1,000 medulloblastoma genomes. Nature 488, 49-56.

Northcott, P. A., Shih, D. J., Remke, M., Cho, Y. J., Kool, M., Hawkins, C., Eberhart, C. G., Dubuc, A., Guettouche, T., Cardentey, Y., et al. (2012d). Rapid, reliable, and reproducible molecular sub-grouping of clinical medulloblastoma samples. Acta Neuropathology 123, 615-626

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PUBLICATIONS

Onvani, S., Terakawa, Y., Smith, C., Northcott, P., Taylor, M., and Rutka, J. (2012). Molecular genetic analysis of the hepatocyte growth factor/MET signaling pathway in pediatric medulloblastoma. Genes Chromosomes Cancer 51, 675-688.

Picard, D., Miller, S., Hawkins, C. E., Bouffet, E., Rogers, H. A., Chan, T. S., Kim, S. K., Ra, Y. S., Fangusaro, J., Korshunov, A., et al. (2012). Markers of survival and metastatic potential in childhood CNS primitive neuro-ectodermal brain tumours: an integrative genomic analysis. The Lancet Oncology 13, 838-848.

Sabha, N., Au, K., Agnihotri, S., Singh, S., Mangat, R., Guha, A., and Zadeh, G. (2012). Investigation of the in vitro therapeutic efficacy of nilotinib in immortalized human NF2-null vestibular schwannoma cells. PLoS One 7, e39412.

Seol, H. J., Chang, J. H., Yamamoto, J., Romagnuolo, R., Suh, Y., Weeks, A., Agnihotri, S., Smith, C. A., and Rutka, J. T. (2012). Overexpression of CD99 increases the migration and invasiveness of human malignant glioma cells. Genes Cancer 3, 535-549.

Taylor, M. D., Northcott, P. A., Korshunov, A., Remke, M., Cho, Y. J., Clifford, S. C., Eberhart, C. G., Parsons, D. W., Rutkowski, S., Gajjar, A., et al. (2012). Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathology 123, 465-472.

Unterberger, A., Dubuc, A. M., and Taylor, M. D. (2012). Genome-wide methylation analysis. Methods Molecular Biology 863, 303-317.

Walker, E. J., Zhang, C., Castelo-Branco, P., Hawkins, C., Wilson, W., Zhukova, N., Alon, N., Novokmet, A., Baskin, B., Ray, P., et al. (2012). Monoallelic expression determines oncogenic progression and outcome in benign and malignant brain tumors. Cancer Research 72, 636-644.

Weeks, A., Okolowsky, N., Golbourn, B., Ivanchuk, S., Smith, C., and Rutka, J. T. (2012). ECT2 and RASAL2 mediate mesenchymal-amoeboid transition in human astrocytoma cells. American Journal of Pathology 181, 662-674.

Wu, X., Northcott, P. A., Dubuc, A., Dupuy, A. J., Shih, D. J., Witt, H., Croul, S., Bouffet, E., Fults, D. W., Eberhart, C. G., et al. (2012). Clonal selection drives genetic divergence of metastatic medulloblastoma. Nature 482, 529-533.

2013

Agnihotri, S., Burrell, K. E., Wolf, A., Jalali, S., Hawkins, C., Rutka, J. T., and Zadeh, G. (2013). Glioblastoma, a brief review of history, molecular genetics, animal models and novel therapeutic strategies. Archivum Immunologiae et Therapiae Experimentalis 61, 25-41.

Aref, D., Moffatt, C. J., Agnihotri, S., Ramaswamy, V., Dubuc, A. M., Northcott, P. A., Taylor, M. D., Perry, A., Olson, J. M., Eberhart, C. G., and Croul, S. E. (2013). Canonical TGF-beta pathway activity is a predictor of SHH-driven medulloblastoma survival and delineates putative precursors in cerebellar development. Brain Pathology 23, 178-191.

Buczkowicz, P., Zarghooni, M., Bartels, U., Morrison, A., Misuraca, K. L., Chan, T., Bouffet, E., Huang, A., Becher, O., and Hawkins, C. (2013). Aurora kinase B is a potential therapeutic target in pediatric diffuse intrinsic pontine glioma. Brain Pathology 23, 244-253.

Castelo-Branco, P., Choufani, S., Mack, S., Gallagher, D., Zhang, C., Lipman, T., Zhukova, N., Walker, E. J., Martin, D., Merino, D., et al. (2013). Methylation of the TERT promoter and risk stratification of childhood brain tumours: an integrative genomic and molecular study. The Lancet Oncology 14, 534-542.

23The Annual Scientific Report of The Arthur and Sonia Labatt Brain Tumour Research Centre at The Hospital for Sick Children

PUBLICATIONS

The BTRC would like to thank and acknowledge the volunteer and professional photographers who have contributed to the year’s Report.

Meagan’s Gala and Walk Photographers: Gordon Cheong, Patrick Moher, Kathy Taylor

SickKids Creative Services has been involved in all the BTRC personnel and on-site photographs.

Dubuc, A. M., Remke, M., Korshunov, A., Northcott, P. A., Zhan, S. H., Mendez-Lago, M., Kool, M., Jones, D. T., Unterberger, A., Morrissy, A. S., et al. (2013). Aberrant patterns of H3K4 and H3K27 histone lysine methylation occur across subgroups in medulloblastoma. Acta Neuropathology 125, 373-384.

Gallo, M., Ho, J., Coutinho, F. J., Vanner, R., Lee, L., Head, R., Ling, E. K., Clarke, I. D., and Dirks, P. B. (2013). A tumorigenic MLL-homeobox network in human glioblastoma stem cells. Cancer Research 73, 417-427.

Krieger, J. R., Taylor, P., Gajadhar, A. S., Guha, A., Moran, M. F., and McGlade, C. J. (2013). Identification and selected reaction monitoring (SRM) quantification of endocytosis factors associated with Numb. Molecular Cell Proteomics 12, 499-514.

Mack, S. C., Witt, H., Wang, X., Milde, T., Yao, Y., Bertrand, K. C., Korshunov, A., Pfister, S. M., and Taylor, M. D. (2013). Emerging insights into the ependymoma epigenome. Brain Pathology 23, 206-209.

Muñoz, D. M., Singh, S., Tung, T., Agnihotri, S., Nagy, A., Guha, A., Zadeh, G., and Hawkins, C. (2013a). Differential transformation capacity of neuro-glial progenitors during development. PNAS, Proceedings of the National Academy of Sciences 110, 14378-14383.

Muñoz, D. M., Tung, T., Agnihotri, S., Singh, S., Guha, A., Zadeh, G., and Hawkins, C. (2013b). Loss of p53 cooperates with K-ras activation to induce glioma formation in a region-independent manner. Glia 61, 1862-1872.

Ramaswamy, V., Remke, M., Bouffet, E., Faria, C. C., Perreault, S., Cho, Y. J., Shih, D. J., Luu, B., Dubuc, A. M., Northcott, P. A., et al. (2013). Recurrence patterns across medulloblastoma subgroups: an integrated clinical and molecular analysis. The Lancet Oncology 14, 1200-1207.

Remke, M., Ramaswamy, V., Peacock, J., Shih, D. J., Koelsche, C., Northcott, P. A., Hill, N., Cavalli, F. M., Kool, M., Wang, X., et al. (2013). TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma. Acta Neuropathologica Epub.

Remke, M., Ramaswamy, V., and Taylor, M. D. (2013). Medulloblastoma molecular dissection: the way toward targeted therapy. Current Opinion in Oncology 25, 674-681.

Smith, C. J., Berry, D. M., and McGlade, C. J. (2013). The E3 ubiquitin ligases RNF126 and RabRING7 regulate endosomal sorting of the epidermal growth factor receptor. Journal Cell Science 126, 1366-1380.

Terakawa, Y., Agnihotri, S., Golbourn, B., Nadi, M., Sabha, N., Smith, C. A., Croul, S. E., and Rutka, J. T. (2013). The role of drebrin in glioma migration and invasion. Experimental Cell Research 319, 517-528.

Wybenga-Groot, L. E., and McGlade, C. J. (2013). Crystal structure of Src-like adaptor protein 2 reveals close association of SH3 and SH2 domains through beta-sheet formation. Cellular Signalling 25, 2702-2708.

Zhukova, N., Ramaswamy, V., Remke, M., Pfaff, E., Shih, D. J., Martin, D. C., Castelo-Branco, P., Baskin, B., Ray, P. N., Bouffet, E., et al. (2013). Subgroup-specific prognostic implications of TP53 mutation in medulloblastoma. Journal of Clinical Oncology 31, 2927-2935.

AcknowledgementWe would like to acknowledge the generous support of the research institutes and foundations of The Hospital for Sick Children and the University Health Network in the establishment of The Arthur and Sonia Labatt Brain Tumour Research Centre. Special thanks to b.r.a.i.n.child for generously supporting ongoing research projects.

To learn more about The Arthur and Sonia Labatt Brain Tumour Research Centre, visit www.sickkids.ca/research/BTRC.

The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick ChildrenPeter Gilgan Centre for Research and Learning, 686 Bay Street, 17th Floor, Toronto, ON M5G 0A4

Phone: 416-813-8811 Fax: 416-813-8456 Email: labatt@sickkids.ca