imagine15-16cell biology and electrophysiology, dr. huang’s group studies ion channel-regulated...

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

Peter Gilgan Centre for Research and Learning (PGCRL)

WHAT IS NEW IN THE BTRC

I am pleased and proud to provide you with this year’s introduction to the Annual Scientific Report of the Labatt Brain Tumour Research Centre (BTRC). We have had, once again, a highly productive and memorable 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, China, Switzerland, Japan, Ukraine, and the United States, continue to join us for advanced training in the lab. We continue to be recognized as an Institute of the Pediatric Brain Tumor Foundation (PBTF) along with Duke University and the University of California, San Francisco. We celebrated the third annual Mike and Dianne Traynor Lectureship in brain tumour research, and our lecturer was Dr. Linda Liau from the University of California, Los Angeles. Dr. Liau also serves as Editor-in-Chief of the Journal of Neuro-Oncology. Our annual Labatt BTRC Academic Lecturer was Dr. Jeremy Rich from the Department of Molecular Medicine at the Cleveland Clinic.

This past year, Michael Taylor and colleagues published a seminal report in Nature on how divergent clonal selection dominates medulloblastoma at recurrence; Vijay Ramaswamy published in the Journal of Clinical Oncology the therapeutic impact of cytoreductive surgery and irradiation for posterior fossa ependymoma; Uri Tabori and colleagues published their work in the Journal of Clinical Oncology on BRAF mutation and CDKN2A deletion in a distinct subgroup of children with high-grade glioma; Cynthia Hawkins and colleagues published on the potential of poly-ADP ribose as a therapeutic target in diffuse intrinsic pontine glioma in Cancer Research; Peter Dirks and colleagues published in Cancer Cell on the role of SOX2 in defining the renewable stem cell population in gliomas; and the Rutka lab published on the role of PINK1 as a regulator of the Warburg effect in Cancer Research.

One of the highlights this year was the celebration of Peter Dirks’ “Dream Team” capture of an $11.7 million Stand Up To Cancer Canada grant along with his colleagues across the country.

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.

Since our move to the new Peter Gilgan Centre for Research and Learning (PGCRL) on September 17th, 2013, we have quickly expanded to fill the space that has been allocated to us on the 17th floor. We now have a record 110 personnel working within the Labatt BTRC at this site. This includes all Masters and PhD students, post-doctoral fellows, research assistants and associates, and Principal Investigators. Our space on the 17th floor of PGCRL is comprised of a balance of office and wet lab bench spaces for the conduction of scientific studies. We are also enjoying the friendly “neighborhood” space, which enables individuals from the 16th –18th floors to come together to discuss ongoing science and research projects. The Labatt BTRC played host to numerous invited scholars and scientists last year. Our academic lectureship program is becoming the envy of brain tumour centres around the world.

Stand Up To Cancer Canada in collaboration with the Canadian Institutes of Health Research, the Ontario Institute for Cancer Research and Genome Canada recently awarded funding to the Cancer Stem Cell Dream Team. Pictured are Dream Team members Dr. Peter Dirks (Co-Team Lead) and Dr. Michael Taylor, both from the BTRC at SickKids.

ON THE COVER

3The Annual Scientific Report of The Arthur and Sonia Labatt Brain Tumour Research Centre at The Hospital for Sick Children

PROFILE OF DR. XI HUANG

5 QUESTIONS FOR DR. XI HUANG:

1) What does working at the Labatt BTRC mean to you?

The Labatt BTRC is my dream place to do brain tumour research. The BTRC is the home for many preeminent leaders in basic science and clinical research of brain tumours, and it provides a highly collegial and collaborative environment. As a new investigator I have received invaluable mentorship and resources at the BTRC, which will undoubtedly solidify my research program. I look forward to contributing to the BTRC with my expertise in animal modelling of human brain tumours and identifying ion channel proteins as novel drug targets to effectively treat brain tumour in patients.

2) What do you like most about living in Toronto?

For my work, Toronto provides an unparalleled environment to do science and the opportunity to interact with many of the best players in brain tumour research. For my family, we love Toronto because it is such a beautiful city with endless possibilities. My two young kids always look forward to weekends since that’s when I will take them out to some places in Toronto to have fun!

3) What do you like the most about doing research on brain tumours?

I am always fascinated by everything about the brain since a very young age. That’s why I chose to study early brain development for my PhD studies and brain tumours for my postdoctoral training. Brain tumours are the leading cause of cancer death in children, and I would like to do some “untraditional” research to help develop novel and effective ways to treat brain tumour patients. My current brain tumour research program focuses on ion channels, a class of drug targets that have historical success to treat many human diseases. I am passionate about uncovering the unrealized potential to target ion channels to treat brain tumours.

4) Tell us about where you were educated?

I was born and raised in Changsha, the capital city of Hunan in Southern China, where I received my earlier education. I received my B.S. in Biological Sciences at Xiamen University 2004, after which I joined the lab of Dr. Chin Chiang at Vanderbilt University for my PhD studies. In 2010 I started my postdoctoral training in Dr. Lily Jan’s lab at the University of California, San Francisco to study how ion channels control malignant growth and metastasis of brain tumours.

5) What would you like to accomplish in your research program in the next 5 years?

I would like to define an ion channel network that cooperatively regulates brain tumour initiation, progression, metastasis and therapy resistance. The identification of this network will provide ample opportunities for us to develop cancer therapies. Currently we have identified several unique ion channels specifically expressed in various cell types of the brain tumour hierarchy. We are using our multi-species platform to define how these ion channels regulate brain tumour malignancy. We are currently collaborating with Drs. James Rutka, Peter Dirks and Michael Taylor on several projects that have led to multiple publications.

Dr. Xi Huang

Recording the electrical activity in a dividing brain tumour cell.

Dr. Xi Huang in the lab.

Dr. Xi Huang completed his PhD study in Developmental Biology at Dr. Chin Chiang’s lab at Vanderbilt University in 2010. He then completed a Damon Runyon Cancer Research Foundation postdoctoral fellowship at Dr. Lily Jan’s lab at the University of California, San Francisco. In 2015 Dr. Huang joined as an Investigator at the Labatt BTRC, a Scientist at the Developmental & Stem Cell Biology Program at SickKids, and an Assistant Professor at the Department of Molecular Genetics at the University of Toronto. Using multi-disciplinary approaches including Drosophila and mouse genetics, xenograft modelling, cell biology and electrophysiology, Dr. Huang’s group studies ion channel-regulated bioelectrical and biomechanical mechanisms in brain development and tumourigenesis. Since ion channels comprise a large class of drug targets, Dr. Huang’s goal is to develop mechanism-based novel brain tumour therapy using ion channel-targeting drugs. Since starting the lab in 2015, Dr. Huang has received funding support from the Labatt BTRC, Garron Family Cancer Centre, SickKids Foundation, American Brain Tumor Association, Cancer Research Society, Natural Sciences and Engineering Research Council, The Concern Foundation, Rare Diseases Models and Mechanisms Network, b.r.a.i.n.child, and anonymous Donors.

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DR. PETER DIRKSSenior Scientist, Principal Investigator

The Dirks lab applies stem cell concepts and experimental methodologies to the study of brain cancer, with focus on glioblastoma, medulloblastoma, and ependymoma. We have found that glioblastomas and medulloblastomas, both in human tumours and in experimental mouse models, contain subpopulations of cells that have stem cell properties that drive tumour growth. Most of the cells in these tumours, contributing to the tumour bulk, are more differentiated progeny of the tumour cells with stem cell properties, and do not ultimately sustain long term tumour growth. Essentially, our view is that brain cancers represent aberrant organogenesis or development, at the root are cells resembling stem cells that act to continually regenerate the tumour. It follows that, in addition to therapies that kill bulk cells, we need therapies to kill the brain tumour stem cells, and we predict that identification of these therapies will have an important impact on brain tumour treatment. With this latter goal in mind, our current work focuses on the genetic and epigenetic mechanisms that drive brain tumour stem cell growth, understanding the cell to cell intratumoural heterogeneity of these tumours from a functional perspective, and developing novel treatments that kill brain tumour stem cells.

LABORATORY PERSONNELLilian Lee, Research Project CoordinatorRenee Head, Research Project CoordinatorMichelle Kushida, Research Project CoordinatorHeather Whetstone, Research Project CoordinatorClare Che, Research TechnologistNaghmeh Rastegar, Research TechnologistKinjal Desai, Postdoctoral FellowSonam Dolma, Postdoctoral FellowMarco Gallo, Postdoctoral FellowMona Meyer, Postdoctoral Fellow Katherine Rowland, Postdoctoral FellowPatty Sachamitr, Postdoctoral FellowHayden Selvadurai, Postdoctoral FellowNataliia Svergun, Postdoctoral FellowHelen Yu, Postdoctoral FellowFiona Coutinho, Graduate StudentKevin Lan, Graduate StudentErika Luis, Graduate StudentRochelle McAdam, Graduate StudentNicole Park, Graduate Student

RESEARCH SUPPORT: Canadian Institutes of Health Research, Canadian Cancer Society Research Institute, Ontario Institute for Cancer Research, Terry Fox Research Institute, Genome Canada, Stand Up To Cancer, American Association for Cancer Research

Dr. Das studied literature at the University of Michigan and philosophy 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 returned to Northwestern for neurosurgical residency, during which he undertook a postdoctoral fellowship in the lab of Jack Kessler. His research work focused on the mechanisms controlling adult neurogenesis. He also developed a program in cancer stem cell biology. On completion of his residency in 2010, Dr. Das was recruited to the Division of Neurosurgery at St. Michael’s Hospital, the University of Toronto. He has received numerous honours and awards locally and internationally, and has published his research findings in journals including the Journal of Biological Chemistry, Molecular Cell, JAMA, the New England Journal of Medicine, and JAMA Neurology. His research is focused on understanding the epigenetic mechanisms that control cell identity and cell fate in glioblastoma.

LABORATORY PERSONNELMegan Wu, Research Project ManagerRohit Sachdeva, Postdoctoral FellowSandra Smiljanic, Research TechnologistAngela Celebre, Graduate StudentFrederick Zhang, Undergraduate Student

DR. SUNIT DASSenior Scientist, Principal Investigator

RESEARCH SUPPORT: Early Research Award, Canadian Institutes of Health Research, J.P. Bickell Foundation, St. Michael’s Hospital Foundation

PRINCIPAL INVESTIGATORS OF THE BTRC


LABORATORY PERSONNELSanja Pajovic, Research AssociateRobert Siddaway, Postdoctoral FellowMan Yu, Postdoctoral FellowTaylor Bridge, TechnicianStephie Leung, Graduate StudentPatricia Rakopoulos, Graduate StudentScott Ryall, Graduate StudentJaval Sheth, Undergraduate Student

RESEARCH SUPPORT: Canadian Institutes of Health Research, Genome Canada, Canadian Cancer Society Research Institute, The Cure Starts Now Foundation

DR. CYNTHIA HAWKINSSenior Scientist, Principal Investigator

Dr. Hawkins’ laboratory focuses on genetic and proteomic markers for prognostication and therapy guidance in paediatric brain tumours including diffuse intrinsic pontine glioma (DIPG) and high-grade glioma. Dr. Hawkins’ laboratory developed a clinical-biological model to predict the survival of DIPG and is now working on acquiring a more detailed knowledge of the biology of DIPG in order to tailor therapy to the particular biology and predict behaviour of an individual patient’s tumour. Recent efforts by Dr. Hawkins’ laboratory has led to findings related to the clinical relevance of histone H3-K27M mutations in DIPG, molecular subgroups of DIPG (MYCN, Silent and H3-K27M), as well as mutations in a novel cancer gene, ACVR1. Current projects aim to model the interaction between these genetic alterations in DIPG to determine which combination of changes is necessary for tumour formation. In this way, we can better understand which genetic alterations are driving tumour formation and growth and thus represent the best candidates for drug targeting. The development of new subgroup-specific models will help us understand why current radiation and chemotherapeutic strategies are failing. They will also serve as useful preclinical models for testing promising, new therapies and set the stage for stratified, subgroup-tailored clinical trials.

LABORATORY PERSONNELMei Lu, Lab ManagerJoseph Norman, Postdoctoral FellowNatalia Ruiz, TechnicianPatrick Sin-Chan, Graduate StudentJonathon Torchia, Graduate StudentAlex Vasiljevic, Visiting Research FellowNeil Chang, Lab AssistantAdil Abdullahi, Bioinformatic AssistantMarcus Kwok, Lab VolunteerValerie Yau, Summer StudentAlice Ma, Summer Student

RESEARCH SUPPORT: Canadian Institutes of Health Research, Canadian Cancer Society Research Institute, Genome Canada, Brain Canada, Brain Tumour Foundation of Canada, b.r.a.i.n.child

DR. ANNIE HUANGSenior Scientist, Principal Investigator

Dr. Huang’s research focuses on rare embryonal brain tumours of childhood and understanding mechanisms of tumour spread. Embryonal brain tumours which represent the largest category of malignant childhood brain tumours span a large spectrum of diseases, many of which are rare diseases that are poorly characterized and for which best therapy remains unknown. The Huang lab established a rare brain tumour network and consortium to study large number of rare tumours using advanced genomic tools. Their work has led to the discovery of new genetic markers that can now be used to accurately diagnose categories of rare brain tumours and accelerated research into specific treatments for these rare diseases. Specifically recent work from the Huang lab has established that rhabdoid brain tumours comprise three different genetic categories that respond differently to various drugs; this research will allow tailoring of treatment for rhabdoid tumour patients in the near future. Many embryonal brain tumours, like rhabdoid tumours and medulloblastoma, have a tendency to spread to other parts of the brain making it challenging to treat children without use of whole brain and spine radiation. Recent work from the Huang lab has shown that the Myc oncoprotein and a critical protein partner, JPO2 regulates a critical signalling pathway, the PI3K pathway, to silence a potent tumour suppressor and promote embryonal brain tumour metastases. Through this work they have identified a potential new drug to inhibit tumour metastases, which may ultimately help to spare radiation treatment in children with embryonal brain tumours.

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RESEARCH SUPPORT: Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, The Leukemia & Lymphoma Society of Canada, b.r.a.i.n.child, Cancer Research Society, SickKids Garron Family Cancer Centre

DR. JANE MCGLADESenior Scientist, Principal Investigator

Dr. McGlade’s research program is directed towards understanding the specificity and dynamics of protein-protein interactions involved in cell signalling events that contribute to the development of cancer. With Canadian Foundation for Innovation support, Dr. McGlade’s group also helped establish a systems biology facility now known as SPARC BioCentre, a core facility supporting drug discovery at SickKids. Work in her laboratory focuses on the molecular structure, cellular functions and interaction networks of modular adaptor proteins that regulate critical oncogenic signalling pathways. Together with clinical collaborators they work towards translating discovery of specific molecular signalling events into strategies for drug discovery. Ongoing projects in the laboratory focus on how cell type specific expression of modular adaptors and isoforms promotes the activation of unique oncogenic signalling and protein modifications, creating distinct molecular signatures in cancer subtypes, and investigation of the developmental and oncogenic signalling pathways that control alternative splicing giving rise to specific protein isoform expression in tumour cells. As well, Dr. McGlade’s lab has used analysis of protein structures to determine the mechanisms that regulate signalling molecules and develop approaches to control oncogenic signalling. The long-term goal of her research is to advance knowledge of the molecular mechanisms that regulate signal transduction and determine the specific molecular events that can be translated into targets for therapeutic intervention.

LABORATORY PERSONNELDonna Berry, Research AssociateSascha Dho, Research AssociateEmilie Ernoult, Postdoctoral FellowNamit Sharma, Postdoctoral FellowLeanne Wybenga-Groot, Project ManagerAndrew Bondoc, Research TechnologistAmanda Luck, Research TechnologistTracy Smith, Graduate StudentYangjing (Alice) Zhang, Graduate Student

LABORATORY PERSONNELChristian Smith, Operations ManagerSaira Alli, Postdoctoral FellowDaniel Coluccia, Postdoctoral FellowSemra Isik, Postdoctoral FellowIsabelle Ferry, Postdoctoral FellowHidehiro Okura, Postdoctoral FellowJames Loukides, Project ManagerJenny Wang, Project ManagerAndrew Bondoc, Research TechnologistAmanda Luck, Research TechnologistCarlyn Figueiredo, Graduate StudentBrian Golbourn, Graduate StudentAlexandra Riemenschneider, Graduate StudentUswa Shahzad, Graduate StudentStacey Krumholtz, Medical Illustrator

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. Dr. Rutka’s lab is actively exploring the application of novel technologies for tumour therapies including delivery of therapeutics to the tumour using gold nanoparticles and temporary disruption of the blood-brain barrier with focused ultrasound to facilitate drug entry to tumour tissue while avoiding damage to normal brain tissues.

Dr. Rutka’s laboratory also focuses on childhood brain tumours. His laboratory personnel are studying the genetic changes in Atypical Teratoid Rhabdoid Tumours (ATRTs) and leveraging this information to identify drug candidates for preclinical testing. Additionally, Dr. Rutka’s lab is interested in developing new strategies of drug delivery to metastatic medulloblastoma and patients with diffuse intrinsic pontine glioma (DIPG). Specifically the Rutka lab is adapting ultrasound technology to precisely target the tumours, open the blood-brain barrier to permit drug access and deliver novel drug compounds attached to gold nanoparticles in these tumour types.

RESEARCH SUPPORT: Canadian Institutes of Health Research, Pediatric Brain Tumor Foundation of the United States, Curing Kids Cancer, b.r.a.i.n.child, Meagan’s Walk


LABORATORY PERSONNELCindy Hiu Zhang, Lab Research Project ManagerMelissa Edwards, Clinical Research Project CoordinatorAbolfazl Heidari, Postdoctoral FellowNuno Miguel Nunes, Postdoctoral FellowNataliya Zhukova, Postdoctoral FellowRicardo Leao, Clinical Research FellowMartin Komosa, Research TechnologistTatiana Lipman, Research TechnologistMatthew Mistry, Research TechnologistBrittany Campbell, Graduate StudentJiil (Brian) Chung, Graduate StudentMelissa Galati, Graduate StudentDave Lee, Graduate Student

LABORATORY PERSONNELXiaochong Wu, Research AssociateFlorence Cavalli, Post-Doc-Bioinformatics AnalystSorana Morrissy, Senior Project ManagerCraig Daniels, Project Manager/Scientific WriterLaura Donovan, Postdoctoral FellowLivia Garzia, Postdoctoral FellowClaudia Kuzan-Fischer, Postdoctoral FellowBorja Lopez, Postdoctoral FellowAntony Michealraj, Postdoctoral FellowCarolina Nör, Postdoctoral FellowHiromichi Suzuki, Postdoctoral FellowAna Guerreiro Stucklin, Postdoctoral Clinical FellowJessica Liu, Research TechnologistBetty Luu, Research TechnologistLei Qin, Research TechnologistAlex Manno, Research TechnicianHamza Farooq, Graduate StudentJohn Lee, Graduate StudentStuart Matan-Lithwick, Graduate StudentJohn Peacock, Graduate StudentDavid Przelicki, Graduate StudentPatryk Skowron, Graduate StudentYuan Thompson, Graduate StudentMaria Vladoiu, Graduate Student

DR. URI TABORISenior Scientist, Principal Investigator

Dr. Tabori’s lab investigates the genetic mechanisms that control tumour progression and survival. Although his lab studies several cancers, the main focus is on childhood gliomas. To achieve this goal Dr. Tabori’s program has three areas of research: 1) Telomere maintenance in cancer. Since telomeres and telomerase control the ability of cancers to recur, Dr. Tabori’s laboratory has been studying how inhibiting this pathway can exhaust the ability of cancer cells and cancer stem cells to regrow causing cancer relapse. 2) Dr. Tabori is studying replicative and oncogene-induced senescence factors in paediatric low-grade astrocytomas that may be used for prognosis in these tumours. These cancers have the tendency to stop growing spontaneously or transform to malignant glioma. Together with Dr. Hawkins and other members of the BTRC we constructed a large database of >1000 patients and tumours and utilize genomic tools and techniques to study these mechanisms. 3) In order to uncover mechanisms that cause tumour initiation in childhood gliomas, Dr. Tabori established the International Biallelic Mismatch Repair Deficiency Consortium. This genetic syndrome is associated with high risk of glioma formation during childhood. Using genomic and genetic tools, Dr. Tabori’s group is studying which early genetic events could be traced and treated to prevent glioma initiation and progression in these children.

RESEARCH SUPPORT: BioCanRx Enabling Studies Program, Canadian Institutes of Health Research, Canadian Cancer Research Society, PLGA Foundation, Making Headway Foundation, McLaughlin Centre for Molecular Medicine

DR. MICHAEL D. TAYLORSenior Scientist, Principal Investigator

Dr. Taylor’s laboratory uses genetic tools to investigate how normal cells are turned into brain tumours. Genomic analyses and genetic tools allow us to create new animal models of medulloblastoma and ependymoma so that novel targeted therapies can be developed. This multi-layered approach using laboratory-driven scientific discovery and bioinformatics allows for rapid clinically-important changes to brain tumour therapy, such that the quality of life of patients can be drastically improved.

The lab continues to analyse tumour genomic data while using the previous findings to develop new animal and cell culture models. Dr. Taylor’s laboratory currently have numerous highly impactful projects which use these newly developed models, including, using functional genomics to investigate metastases and recurrence, immunotherapy using chimeric antigen receptors and ‘synthetic vital’ high-throughput drug screening. Improving the therapy for children with brain tumours is a major goal of our research. Dr. Taylor’s group have published extensively on medulloblastoma (and to a lesser extent on ependymoma), and their findings have had some impact on the care of children with these diseases.

RESEARCH SUPPORT: Pediatric Brain Tumor Foundation of the United States, Canadian Institutes of Health Research, Terry Fox Research Institute, Genome Canada, Ontario Institute for Cancer Research, SickKids Garron Family Cancer Centre, National Institutes of Health (USA), CureSearch, Stand Up To Cancer, Cancer Research Society, Brain Tumour Foundation of Canada, b.r.a.i.n.child, Swifty Foundation, NeuroDevNet/Brain Canada Foundation, Worldwide Cancer Research, McLaughlin Centre for Molecular Medicine, Meagan’s Walk

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LABORATORY PERSONNELSameer Agnihotri, Research AssociateJulie Metcalf, Postdoctoral AssociateKelly Burrell, Lab ManagerTakyee Tung, Clinical Research ManagerMira Li, Research TechnicianSuganth Suppiah, Graduate StudentTansy Zhao, Graduate StudentRomina Nejad, Undergraduate Student

RESEARCH SUPPORT: Canadian Institutes of Health Research, b.r.a.i.n.child, Canadian Cancer Society Research Institute, Ontario Cancer Institute, Mitacs-Accelerate Graduate Research Internship Program, Triphase

DR. GELAREH ZADEHSenior Scientist, Principal Investigator

Dr. Gelareh Zadeh is a neurosurgeon-scientist and Chief of the Department of Surgical Oncology at University Health Network and Princess Margaret Cancer Centre. She is the Chair of Wilkins Family Brain Tumour Research and the director of the Brain Tumour Biobank at Toronto Western Hospital. She is secretary treasurer of Society of Neuro-Oncology and Chair of the Neuro-Oncology Committee at World Federation of Neurological Surgeons. Her research interests include genomic and basic science investigations of brain tumours, most recently she has published a landmark paper in Nature Genetics establishing the genomic landscape of schwannomas and is working on understanding the genomic and molecular regulators of aggressive meningiomas.

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.

DR. PAUL KONGKHAMScientist, Principal Investigator

RESEARCH SUPPORT: Canadian Institutes of Health Research

DR. TODD MAINPRIZESenior Scientist, 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 agentsto 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.

LABORATORY PERSONNELWioletta Glowacka, Research AssociateHarshika Jain, Research AssociateMakiko Okura, Postdoctoral Fellow

RESEARCH SUPPORT: b.r.a.i.n.child, Canadian Cancer Society Research Institute


AFFILIATED SCIENTISTS

Cameron Ackerley, PhDKenneth Aldape, MD, PhDMark Bernstein, MDEric Bouffet, MDXi Huang, PhDNormand Laperrière, MDDonald Mabbott, PhDWarren Mason, MDJames Perry, MD

ADVISORY BOARD OF THE LABATT BTRC

Sonia and Arthur LabattDr. Michael ApkonDr. David BermanDr. Chris CaldaroneMr. Ted GarrardDr. Christopher PaigeDr. Peter PistersDr. Michael SalterDr. Jim WhitlockDr. Trevor Young

SPECIAL AWARDS

DR. RUTKA HONOURED WITH TWO NEW AWARDS

In 1967, Queen Elizabeth II established the Order of Canada as the cornerstone of Canadian honours. The Order of Canada recognizes outstanding achievement, dedication and service to the nation. It is the highest honour to be bestowed upon a Canadian citizen. This year, we are proud to announce that Dr. Rutka received the distinction of Officer of the Order of Canada – recognizing national achievement for his contributions to advancing treatment for paediatric brain tumours and for his international leadership in neurosurgery.

Dr. Rutka was also recognized by the University of British Columbia (UBC) and awarded the 2015 Margolese National Brain Disorders Prize. The Margolese prizes were created by an estate gift to UBC by Leonard Herbert Margolese to recognize Canadians who have made outstanding contributions to the treatment, amelioration or cure of brain or heart disorders.

DR. TAYLOR RECEIVES PRESTIGIOUS K-J. ZÜLCH AWARD

The K-J. Zülch Prize of the Gertrud Reemtsma Foundation has been awarded for outstanding achievements in basic neurological research every year since 1990. This year, Dr. Michael Taylor received the award for the achievement of crucial improvements in the diagnosis and treatment of brain tumours.

DR. TABORI RECEIVES THE BERNARD AND FRANCINE DORVAL AWARD

This year, the Canadian Cancer Society recognized Dr. Tabori with the Bernard

and Francine Dorval Prize for outstanding contributions to foundational cancer research in paediatric oncology, which has significantly advanced the scientific community’s understanding of childhood brain tumours. The Bernard and Francine Dorval Prize is given to a young investigator whose outstanding contributions to basic biomedical research have the potential to lead, or have already led to improved understanding of cancer treatments and/or cures.

Michael Taylor

Uri Tabori

Dr. Rutka with His Excellency the Right Honourable David Johnston receiving the distinction of Officer of the Order of Canada.

Dr. Rutka with family receiving the 2015 Margolese National Brain Disorders Prize.

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Wednesday, January 6, 2016

Dr. Bodour SalhiaTowards Prediction, Prevention and Curative Therapies for Metastatic Breast Cancer

Thursday, March 31, 2016

Dr. Charles RobertsSWI/SNF (BAF) complex mutations in cancer: mechanisms and vulnerabilities

Thursday, September 8, 2016

Dr. Yoon-Jae ChoTranscriptional and translational regulation in Medulloblastoma

Thursday, September 22, 2016

Dr. David EisenstatLinking the Biology of Childhood Brain Tumours to the Transcriptional Regulation of Central Nervous System Development

18TH ANNUAL LABATT BTRC ACADEMIC LECTURESHIP

Dr. Jeremy Rich is a renowned researcher who investigates cancer stem cells in brain tumours and novel treatments aimed at slowing brain tumour growth. Currently, Dr. Rich is the Chair of the Cleveland Clinic Lerner Research Institute’s Department of Stem Cell Biology and Regenerative Medicine. Dr. Rich was recruited from Duke University Medical Center in Durham, North Carolina, where he was Associate Professor in the Department of Medicine’s Division of Neurology, Associate Professor in the Department of Pharmacology and Cancer Biology, and Associate Professor in the Department of Surgery. Dr. Rich received his medical degree from the Duke University School of Medicine, and had clinical training in neurology at Johns Hopkins University.

Dr. Linda M. Liau

Left to right: Dr. Michael Taylor, Dr. James Rutka, Dr. Annie Huang, Dr. Jeremy Rich, Dr. Sunit Das, Dr. Ken Aldape

3RD ANNUAL MIKE AND DIANNE TRAYNOR ANNUAL LECTURESHIP HELD AT THE LABATT BTRC

Dr. Linda M. Liau is Professor and Vice Chair of Research in the Department of Neurosurgery at the David Geffen School of Medicine at UCLA, and Director of the UCLA Brain Tumor Program in the Department of Neurosurgery. She has been voted by her peers as one of the Best Doctors in America and ranked as one of the top neurosurgeons in the country by U.S. News Top Doctors. Dr. Liau has been the Principal Investigator on several NIH research grants over the past 15 years. She is the lead investigator on various novel clinical trials for brain cancer patients, and developed one of the first human applications of a personalized brain tumour vaccine (DCVax-L), which is currently

being tested in multi-center clinical trials in the United States and Europe. Dr. Liau is currently the Editor-in-Chief of the Journal of Neuro-Oncology.

2016 BTRC GUEST LECTURERS

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.


On World Cancer Day, SickKids hosted the announcement of $11.7 million in cancer research funding for the Stand Up To Cancer (SU2C) Stem Cell Dream Team led by Dr. Peter Dirks (Brain Tumour Research Centre, SickKids) and Samuel Weiss (Hotchkiss Brain Institute, University of Calgary). The SU2C Canada Dream Team will focus on brain cancer stem cells, in both adults and children, which can be resistant to treatment and drive tumour regrowth.

“Our team will conduct multiple analyses of brain cancer stem cells, profiling their biological makeup to identify drugs that are likely to block the uncontrolled growth of the tumours, and carry out clinical trials across Canada to find the safest and most effective drugs to treat these cancers,” says Dr. Dirks.

The team of researchers will focus on two types of brain tumours: glioblastoma in both adults and children, and posterior fossa ependymoma that affects young infants. Both tumour types have limited treatment options and are associated with very poor survival. Most adults diagnosed with malignant glioblastoma succumb to the disease within 2 years. Malignant brain tumours in children are the number one cause of cancer related death in children under 18.

Co-team member Dr. Michael Taylor, neurosurgeon and BTRC scientist, specializes in cancer genomics. “It’s like a Peter Pan syndrome, in which the immature cell, the stem cell, never grows up,” says Dr. Taylor. “Our objective is to take those cancer stem cells and convince them to quit multiplying and leave the rest of the brain alone.”

The Dream Team will take a three-pronged approach to understanding and targeting brain cancer stem cells that resist treatment and fuel tumour regrowth. Initially they will perform detailed analysis of stem cells taken from 70 different glioblastomas or ependymomas to understand the full biological profile of these cells – from changes in the cells’ genetic codes to epigenetic programs that control when genes are turned on or off and alterations in the way the cells metabolize nutrients.

The Dream Team’s second approach will be to screen a collection of chemicals on the same cells for potential new drugs and drug combinations that are effective against these cells. Finally, while they are learning about the biology of brain tumour stem cells and screening for new compounds, the Dream Team will test five new potential drugs that they have already identified as very promising by tests performed in laboratory mice to find out which drugs or drug combinations might kill glioblastomas or ependymomas. The Dream Team hopes to bring new drugs for brain cancer rapidly into clinical trials.

1999 Dr. Robert Martuza Georgetown University2000 Dr. Gregory Cairncross University of Western Ontario2001 Dr. David Kaplan Montreal Neurological Institute2002 Dr. Charles Stiles 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 Hospital

2008 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 Center2012 Dr. Inder Verma Salk Institute2013 Dr. Fred Lang University of Texas2014 Dr. William Weiss University of California, San Francisco2015 Dr. Robert Wechsler-Reya Sanford Burnham Institute

VISITING LECTURESHIP

PREVIOUS LABATT BTRC ACADEMIC GUEST LECTURERS

STAND UP TO CANCER GRANT AWARD EVENT

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MEAGAN’S WALK: CREATING A CIRCLE OF HOPE – 15 YEARS OF INSPIRATION

This past year, Meagan’s Walk achieved a significant milestone in brain tumour education and awareness with the 15th annual Meagan’s Walk that took place on Mother’s Day weekend. The annual 5K fundraising walk culminates with a human hug that encircles SickKids. To date, more than $4.55 million has been raised for brain tumour research at the BTRC. Specifically the donations fund seed project grants and the purchase of costly research equipment used by every lab in the BTRC.

For the first time, Meagan’s Walk also held their annual Soiree at the BTRC and invited the community to visit the labs and see first hand where their fundraising dollars are spent. Throughout the evening, guests were able to tour the labs and learn about the different research projects that graduate students and Postdoctoral Fellows are working on.

Meagan Bebenek was only four years old when she was diagnosed with brain stem glioma. Meagan died in 2001, just months after learning of the diagnosis. Upon leaving the hospital, Meagan’s mother Denise knew something had to be done and the mission that would become Meagan’s Walk began.

“Fifteen years ago we knew a great thing to do for these children is simply to love them,” says Denise. “The hug shows the power of the spirit, that they are not facing difficulties alone. Let’s thank Meagan for the gift of living in the moment. Her wish was to give each person a gift to thank them for their kindness, and this hug continues to be her gift focused on every single child who needs us.”


On May 7th, 2016 many scientists and researchers from the BTRC participated in the 15th Annual 5K Meagan’s Walk.

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THE YEAR IN REVIEW – CURRENTLY HELD GRANTS

Dr. James Rutka

Epigenetic alterations define lethal CIMP positive ependymomas of infancy. Pediatric Brain Tumor Foundation of the United States

Targeted therapy for diffuse intrinsic pontine glioma in childhood. Canadian Institutes of Health Research

Targeted therapeutic disruption of the blood-brain-barrier in childhood brain stem cancers. Curing Kids Cancer

The role of RNA stress granules in GBM treatment resistance. Meagan’s Walk National Collaboration Seed Grant

Cancer’s sweet tooth: PINK1 negatively regulates glycolysis in GBM. b.r.a.i.n.child

Dr. Jane McGlade

Ubiquitin System regulation of epithelial polarity. Natural Sciences and Engineering Research Council of Canada (NSERC)

Gads adaptor function in BCR-ABL B-ALL. Leukemia & Lymphoma Society of Canada

Activation of CBL tumour suppressor function in leukemia. SickKids Garron Family Cancer Centre Pitblado Discovery Grant

SLAP adaptor regulation of Cbl and tyrosine kinase signaling in leukemia. Cancer Research Society

Alternative splicing of the numb tumor suppressor in medulloblastoma. b.r.a.i.n.child

Function and regulation of numb isoform expression in cancer. Canadian Institutes of Health Research

Dr. Peter Dirks

Defining and targeting medulloblastoma intratumoral diversity. Canadian Institutes of Health Research

Pharmacologic and optogenetic dopamine-directed therapy of glioblastoma stem cells. Canadian Cancer Society Research Institute

Functional and genomic clonal analysis of human glioblastoma. Canadian Institutes of Health Research

Functional genomic screen to identify drivers of human GBM. Terry Fox Research Institute

Linking clonal heterogeneity and stemness. Ontario Institute for Cancer Research

Targeting brain tumour stem cell epigenetic and molecular networks. Stand Up To Cancer, American Association for Cancer Research, Canadian Institutes of Health Research, Genome Canada, Ontario Institute for Cancer Research

Dr. Annie Huang

Delineating transforming pathways in primitive neuro-ectodermal brain tumours. Canadian Institutes of Health Research

Investigating the role of the CpG island methylator phenotype (CIMP) to EZH2 remodeling and for cancer epigenetic therapy. Canadian Cancer Society Research Institute

A high resolution analysis of the functional epigenome of primitive neuroectodermal tumours [PNETs] Canadian Institutes of Health Research

Translating next-generation sequencing technologies into improved therapies for high-risk childhood cancer. Genome Canada/Canadian Institutes of Health Research Advancing Technology Through Innovation Grant: The Canadian Pediatric Cancer Genome Consortium

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

The ICHANGE (International Childhood Astrocytomas iNtegrated Genomics and Epigenomics) Consortium. Genome Canada

Utilization of a global systems and informatics approach to define the role of ncRNAs in determining molecular phenotypes of embroyonal brain tumours. Brain Canada

Myc-mediated cell extrinsic signaling in brain tumor progression. Brain Tumour Foundation of Canada

Epigenetic analysis of pineoblastomas. b.r.a.i.n.child



Dr. Gelareh Zadeh

Molecular characterization of radiation induced meningiomas. Canadian Institutes of Health Research

Exploring the role of R/S-2HG as a biomarker for optimizing glioma resection and understanding glioma microenvironment heterogeneity. Canadian Cancer Society Research Institute

Does exercise improve progression-free survival in glioblastoma? A prospective single-arm intervention trial. Canadian Cancer Society Research Institute

Discovery of molecular targets for treatment of clinically malignant meningioma. Canadian Institutes of Health Research

Intraoperative RS-2HG as a biomarker of IDH mutation in personalized glioma surgery. Ontario Cancer Institute

Investigating the therapeutic benefits of azoles in preclinical models of pediatric gliomas. b.r.a.i.n.child

Clinical investigation of Frameless, Adaptive, Image-guided Gamma Knife Radiosurgery. Canadian Institutes of Health Research

Investigation of biomarkers of response to treatment with marizomib in GBM patients. Mathematics of Information Technology and Complex Systems (MITACS) Mitacs-Accelerate Graduate Research Internship Program

To identify potential biomarkers of response to Marizomib treatment in GBM patients. Triphase

Dr. Michael D. Taylor

A novel oncogene restricted to group 4 medulloblastoma. National Institutes of Health

Ependymomas of infancy. Pediatric Brain Tumor Foundation of the United States

Overcoming resistance in high risk medulloblastoma. University of California, San Francisco, CureSearch

Epigenetic landscape of medulloblastoma. Cancer Research Society of Canada

Metastatic medulloblastoma. Swifty Foundation

Cellular and genetic basis of anaplastic medulloblastoma. National Institutes of Health

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

Immunogenomics to create new therapies for high risk childhood cancers. Stand Up To Cancer Pediatric Dream Team

Killing the Hydra: Genetic dissection of actionable targets required for maintenance of metastatic disease. Terry Fox New Frontiers Program

Defining the subgroup specific epigenetic landscape of medulloblastoma. Cancer Research Society

Discovery of novel chemotherapeutic agents active metastatic medulloblastoma. b.r.a.i.n.child

Disruptive innovations, functional genomics in human cells for drivers of lethal metastatic human cancers. Genome Canada

Identification of mediators of chemoresistance in recurrent paediatric medulloblastoma using functional genomics. Worldwide Cancer Research

Targeting brain tumor cell epigenetics and molecular networks. Stand Up To Cancer Cell Dream Team

Validation of structural variants in medulloblastoma using long read sequencing technology. McLaughlin Centre at University of Toronto

Medulloblastoma metastases are hematogenous, and driven by expression of CCL2. Canadian Institutes of Health Research

Broad deletions of chromosome 17p constitute a therapeutically targetable driver event in medulloblastoma, Canadian Institutes of Health Research

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Dr. Cynthia Hawkins

Clinical development and translation of genomics-driven pediatric cancer diagnostics using NanoString Technology. Genome Canada

Prediction and prevention of glioma recurrence by targeting telomere dependent self-renewal capacity of tumour initiating cells. Co-Investigator, Canadian Institutes of Health Research

Role of HK2 in regulating brain tumor metabolism and angiogenesis and response to therapeutics. Co-Applicant, Canadian Institutes of Health Research

The role of histones in the development of pediatric diffuse intrinsic pontine glioma. Canadian Cancer Society Research Institute

Development of subgroup-specific models of paediatric DIPG. The Cure Starts Now Foundation

Mitochondrial DNA alterations and their potential as a novel therapeutic target in DIPG. The Cure Starts Now Foundation

Exploring the interactome of H3K27M to find therapeutic targets for DIPG. The Cure Starts Now Foundation

Dr. Uri Tabori

Development of predictive companion biomarkers and therapeutic monitoring for hypermutant cancers to immune checkpoint inhibition. BioCanRx Enabling Studies Program

Novel implications of THOR hypermethylation in telomere maintenance and gliomagenesis. Canadian Institutes of Health Research

Utilization of THOR hypermethylation for stratification and noninvasive detection of cancer. Canadian Cancer Research Society

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

Long term clinical implication of pediatric low grade glioma molecular subgroups. PLGA Foundation

Long term clinical implication of pediatric low grade glioma molecular subgroups (part 2). Making Headway Foundation

Translating genomic discoveries to cure ultra-hyper mutant mismatch repair deficient brain tumors. Israel-Canada Joint Research Program, Canadian Institutes of Health Research

Targeting the telomere maintenance pathway for cancer diagnostics and therapeutics. Canadian Cancer Research Society

Genetic signatures of pediatric cancer predisposition syndromes. McLaughlin Centre at the University of Toronto, Accelerator Grant in Genomic Medicine

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

Dr. Sunit Das

Targeting treatment resistance by modifying cancer cell identity in malignant brain tumours. Early Research Award

Targeting bevacizumab resistance via live-mediated vascular mimicry in glioblastoma. Canadian Institutes of Health Research

Defining the role of vascular mimicry in bevacizumab resistance in glioblastoma. J.P. Bickell Foundation

Vascular mimicry in human brain tumours: The role of the non-coding transcriptome. St. Michael’s Hospital Foundation


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.

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

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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. 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 a great corporate citizen supporting the important research of b.r.a.i.n.child at the Labatt 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 $4.5 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.

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. 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 plays 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.


PUBLICATIONS

2015

Au K, Singh SK, Burrell K, Sabha N, Hawkins C, Huang A, Zadeh G. A preclinical study demonstrating the efficacy of nilotinib in inhibiting the growth of pediatric high-grade glioma. Journal of Neuro-Oncology. 2015 May; 122(3):471-80.

Bharadwaj S, Venkatraghavan L, Mariappan R, Ebinu J, Meng Y, Khan O, Tung T, Reyhani S, Bernstein M, Zadeh G. Serum lactate as a potential biomarker of non-glial brain tumors. Journal of Clinical Neuroscience. 2015 Jun; S0967-5868(15):00239-8.

Buczkowicz P, Hawkins C. Pathology, Molecular Genetics, and Epigenetics of Diffuse Intrinsic Pontine Glioma. Frontiers in Oncology. 2015; 5:147.

Chornenkyy Y, Agnihotri S, Yu M, Buczkowicz P, Rakopoulos P, Golbourn B, Garzia L, Siddaway R, Leung S, Rutka JT, Taylor MD, Dirks PB, Hawkins C Poly-ADP-Ribose-Polymerase as a therapeutic target in pediatric diffuse intrinsic pontine glioma and pediatric high grade astrocytoma. Molecular Cancer Therapeutics. 2015; 14(11):2560-8.

Diaz RJ, Dios RR, Hattab EM, Rakopoulos P, Sabha N, Hawkins C, Zadeh G, Rutka JT, Cohen-Gadol AA. Study of the biodistribution of fluorescein in glioma-infiltrated mouse brain and histopathological correlation of intraoperative findings in high grade gliomas resected under fluorescein fluorescence guidance. Journal of Neurosurgery. 2015; 122(6):1360-9.

Diaz RJ, Golbourn B, Faria C, Picard D, Shih D, Raynaud D, Leadly M, MacKenzie D, Bryant M, Bebenek M, Smith CA, Taylor MD, Huang A, Rutka JT. Mechanism of action and therapeutic efficacy of Aurora kinase B inhibition in MYC overexpressing medulloblastoma. Oncotarget. 2015; 6(5):3359-74.

Durno CA, Sherman PM, Aronson M, Malkin D, Hawkins C, Bakry D, Bouffet E, Gallinger S, Pollett A, Campbell B, Tabori U; International BMMRD Consortium. Phenotypic and genotypic characterisation of biallelic mismatch repair deficiency (BMMR-D) syndrome. European Journal of Cancer. 2015 May; 51(8):977-83.

Elhasid R, Dvir R, Rosenfeld Keidar H, Ben Shachar S, Bitan M, Solar I, Durno C, Aronson M, Malkin D, Hawkins C, Bouffet E, Tabori U; BMMRD Consortium. Management of acute myeloblastic leukemia in a child with biallelic mismatch repair deficiency. Journal of Pediatric Hematology/Oncology. 2015 Nov; 37(8):e490-3.

Faria CC, Agnihotri S, Mack SC, Golbourn BJ, Diaz RJ, Olsen S, Bryant M, Bebenek M, Wang X, Bertrand KC, Kushida M, Head R, Clark I, Dirks P, Smith CA, Taylor MD, Rutka JT. Identification of alsterpaullone as a novel small molecule inhibitor to target group 3 medulloblastoma. Oncotarget. 2015 Aug 28; 6(25):21718-29.

Faria CC, Golbourn BJ, Dubuc AM, Remke M, Diaz RJ, Agnihotri S, Luck A, Sabha N, Olsen S, Wu X, Garzia L, Ramaswamy V, Mack SC, Wang X, Leadley M, Reynaud D, Ermini L, Post M, Northcott PA, Pfister SM, Croul SE, Kool M, Korshunov A, Smith CA, Taylor MD, Rutka JT. Foretinib is effective therapy for metastatic sonic hedgehog medulloblastoma. Cancer Research. 2015; 75(1):134-46.

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PUBLICATIONS

Gallo M, Coutinho FJ, Vanner RJ, Gayden T, Mack SC, Murison A, Remke M, Li R, Takayama N, Desai K, Lee L, Lan X, Park NI, Barsyte-Lovejoy D, Smil D, Sturm D, Kushida MM, Head R, Cusimano MD, Bernstein M, Clarke ID, Dick JE, Pfister SM, Rich JN, Arrowsmith CH, Taylor MD, Jabado N, Bazett-Jones DP, Lupien M, Dirks PB. MLL5 orchestrates a cancer self-renewal state by repressing the histone variant H3.3 and globally reorganizing chromatin. Cancer Cell. 2015 14; 28(6):715-29.

Jalali S, Singh S, Agnihotri S, Wataya T, Salehi F, Alkins R, Burrell K, Navab R, Croul S, Aldape K, Zadeh G. A role for matrix remodelling proteins in invasive and malignant meningiomas. Neuropathology and Applied Neurobiology. 2015 Feb; 41(2):e16-28.

Krieger JR, Taylor P, Moran MF, McGlade CJ. Comprehensive Phosphorylation site analysis of the endocytic adaptor protein numb. Proteomics. 2015; 15(2-3):434-446.

Mack SC, Agnihotri S, Bertrand KC, Wang X, Shih DJ, Witt H, Hill N, Zayne K, Barszczyk M, Ramaswamy V, Remke M, Thompson Y, Ryzhova M, Massimi L, Grajkowska W, Lach B, Gupta N, Weiss WA, Guha A, Hawkins C, Croul S, Rutka JT, Pfister SM, Korshunov A, Pekmezci M, Tihan T, Philips JJ, Jabado N, Zadeh G, Taylor MD. Spinal myxopapillary ependymomas demonstrate a warburg phenotype. Clinical Cancer Research. 2015; 21(16):3750-8.

Mansouri S, Zadeh G. Neddylation in glioblastomas. Neuro-Oncology. 2015 Oct; 17(10):1305-6.

Mariappan R, Venkatraghavan L, Vertanian A, Agnihotri S, Cynthia S, Reyhani S, Tung T, Khan OH, Zadeh G. Serum lactate as a potential biomarker of malignancy in primary adult brain tumours. Journal of Clinical Neuroscience. 2015 Jan; 22(1):144-8.

Meyer M, Reimand J, Lan X, Head R, Zhu X, Kushida M, Bayani J, Pressey JC, Lionel AC, Clarke ID, Cusimano M, Squire JA, Scherer SW, Bernstein M, Woodin MA, Bader GD, Dirks PB. Single cell-derived clonal analysis of human glioblastoma links functional and genomic heterogeneity. Proceedings of the National Academy of Sciences USA. 2015; 112(3):851-6.

Mistry M, Zhukova N, Merico D, Rakopoulos P, Krishnatry R, Shago M, Stavropoulos J, Alon N, Pole JD, Ray PN, Navickiene V, Mangerel J, Remke M, Buczkowicz P, Ramaswamy V, Guerreiro Stucklin A, Li M, Young EJ, Zhang C, Castelo-Branco P, Bakry D, Laughlin S, Shlien A, Chan J, Ligon KL, Rutka JT, Dirks PB, Taylor MD, Greenberg M, Malkin D, Huang A, Bouffet E, Hawkins CE, Tabori U. BRAF mutation and CDKN2A deletion define a clinically distinct subgroup of childhood secondary high-grade glioma. Journal of Clinical Oncology. 2015 Mar 20; 33(9):1015-22.

Ramaswamy V, Nör C, Taylor MD. p53 and Meduloblastoma. Cold Spring Harbor Perspectives in Medicine. 2015; 6(2):a026278.

Ramaswamy V, Taylor MD. The Amazing and Deadly Glioma Race. Cancer Cell. 2015; 28(3):275-7.

Ramaswamy V, Taylor MD. Pediatric cancer genomics, a play rather than a portrait. Nature Genetics. 2015; 47(8):851-2.

Shlien A, Campbell BB, de Borja R, Alexandrov LB, Merico D, Wedge D, Van Loo P, Tarpey PS, Coupland P, Behjati S, Pollett A, Lipman T, Heidari A, Deshmukh S, Avitzur N, Meier B, Gerstung M, Hong Y, Merino DM, Ramakrishna M, Remke M, Arnold R, Panigrahi GB, Thakkar NP, Hodel KP, Henninger EE, Göksenin AY, Bakry D, Charames GS, Druker H,


PUBLICATIONS

Lerner-Ellis J, Mistry M, Dvir R, Grant R, Elhasid R, Farah R, Taylor GP, Nathan PC, Alexander S, Ben-Shachar S, Ling SC, Gallinger S, Constantini S, Dirks P, Huang A, Scherer SW, Grundy RG, Durno C, Aronson M, Gartner A, Meyn MS, Taylor MD, Pursell ZF, Pearson CE, Malkin D, Futreal PA, Stratton MR, Bouffet E, Hawkins C, Campbell PJ, Tabori U; Biallelic Mismatch Repair Deficiency Consortium. Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers. Nature Genetics. 2015 Mar; 47(3):257-62.

Skowron P, Ramaswamy V, Taylor MD. Genetic and molecular alterations across medulloblastoma subgroups. Journal of Molecular Medicine. 2015; 93(10):1075-84.

Thompson YY, Ramaswamy V, Diamandis P, Daniels C, Taylor MD. Posterior fossa ependymoma: current insights. Child’s Nervous System. 2015; 31(10):1699-706.

Torchia J, Picard D, Lafay-Cousin L, Hawkins CE, Kim SK, Letourneau L, Ra YS, Ho KC, Chan TS, Sin-Chan P, Dunham CP, Yip S, Ng HK, Lu JQ, Albrecht S, Pimentel J, Chan JA, Somers GR, Zielenska M, Faria CC, Roque L, Baskin B, Birks D, Foreman N, Strother D, Klekner A, Garami M, Hauser P, Hortobágyi T, Bognár L, Wilson B, Hukin J, Carret AS, Van Meter TE, Nakamura H, Toledano H, Fried I, Fults D, Wataya T, Fryer C, Eisenstat DD, Scheineman K, Johnston D, Michaud J, Zelcer S, Hammond R, Ramsay DA, Fleming AJ, Lulla RR, Fangusaro JR, Sirachainan N, Larbcharoensub N, Hongeng S, Barakzai MA, Montpetit A, Stephens D, Grundy RG, Schüller U, Nicolaides T, Tihan T, Phillips J, Taylor MD, Rutka JT, Dirks P, Bader GD, Warmuth-Metz M, Rutkowski S, Pietsch T, Judkins AR, Jabado N, Bouffet E, Huang A. Lancet Oncology. 2015 May; 16(5):569-82.

Wang X, Dubuc AM, Ramaswamy V, Mack S, Gendoo DM, Remke M, Wu X, Garzia L, Luu B, Cavalli F, Peacock J, López B, Skowron P, Zagzag D, Lyden D, Hoffman C, Cho YJ, Eberhart C, MacDonald T, Li XN, Van Meter T, Northcott PA, Haibe-Kains B, Hawkins C, Rutka JT, Bouffet E, Pfister SM, Korshunov A, Taylor MD. Medulloblastoma subgroups remain stable across primary and metastatic compartments. Acta neuropathologica. 2015; 129(3):449-57.

Wybenga-Groot LE, McGlade CJ. The SLAP adaptor proteins and regulation of receptor tyrosine kinase signaling. Cellular Signalling. 2015; 27(2):267-274.

2016

Agnihotri S, Golbourn B, Huang X, Remke M, Younger S, Cairns RA, Chalil A, Smith CA, Krumholtz SL, Mackenzie D, Rakopoulos P, Ramaswamy V, Taccone MS, Mischel PS, Fuller GN, Hawkins C, Stanford WL, Taylor MD, Zadeh G, Rutka JT. PINK1 Is a negative regulator of growth and the warburg effect in glioblastoma. Cancer Research. 2016 Aug 15; 76(16):4708-19.

Agnihotri S, Jalali S, Wilson MR, Danesh A, Li M, Klironomos G, Krieger JR, Mansouri A, Khan O, Mamatjan Y, Landon-Brace N, Tung T, Dowar M, Li T, Bruce JP, Burrell KE, Tonge PD, Alamsahebpour A, Krischek B, Agarwalla PK, Bi WL, Dunn IF, Beroukhim R, Fehlings MG, Bril V, Pagnotta SM, Iavarone A, Pugh TJ, Aldape KD, Zadeh G. The genomic landscape of schwannoma. Nature Genetics. 2016 Oct; doi: 10.1038/ng.3688.

Agnihotri S, Zadeh G. Metabolic reprogramming in glioblastoma: The influence of cancer metabolism on epigenetics and unanswered questions. Neuro-Oncology. 2016 Feb; 18(2):160-72.

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PUBLICATIONS

Aldape K, Nejad R, Louis DN, Zadeh G. Integrating molecular markers into the World Health Organization classification of CNS tumors: a survey of the neuro-oncology community. Neuro-Oncology. 2016 Sep. In press.

Bouffet E, Larouche V, Campbell BB, Merico D, de Borja R, Aronson M, Durno C, Krueger J, Cabric V, Ramaswamy V, Zhukova N, Mason G, Farah R, Afzal S, Yalon M, Rechavi G, Magimairajan V, Walsh MF, Constantini S, Dvir R, Elhasid R, Reddy A, Osborn M, Sullivan M, Hansford J, Dodgshun A, Klauber-Demore N, Peterson L, Patel S, Lindhorst S, Atkinson J, Cohen Z, Laframboise R, Dirks P, Taylor M, Malkin D, Albrecht S, Dudley RW, Jabado N, Hawkins CE, Shlien A, Tabori U. Immune Checkpoint inhibition for hypermutant glioblastoma multiforme resulting from germline biallelic mismatch repair deficiency. Journal of Clinical Oncology. 2016 Jul 1; 34(19):2206-11.

Castelo-Branco P, Leão R, Lipman T, Campbell B, Lee D, Price A, Zhang C, Heidari A, Stephens D, Boerno S, Coelho H, Gomes A, Domingos C, Apolonio JD, Schäfer G, Bristow RG, Schweiger MR, Hamilton R, Zlotta A, Figueiredo A, Klocker H, Sültmann H, Tabori U. A cancer specific hypermethylation signature of the TERT promoter predicts biochemical relapse in prostate cancer: A retrospective cohort study. Oncotarget. 2016 Jul 16; doi: 10.18632/oncotarget.10639.

Chan SY T, Hawkins CE, Krieger J, McGlade J, Huang A. JPO2/CDCA7L and LEDGF/p75 are novel mediators of PI3K/AKT signalling and aggressive phenotypes in medulloblastoma. Cancer Research. 2016 May 1; 76(9):2802-12.

Coluccia D, Figuereido C, Isik S, Smith C, Rutka JT. Medulloblastoma: Tumor biology and relevance to treatment and prognosis paradigm. Current Neurology and Neuroscience Reports. 2016 May; 16(5):43.

Dolma S, Selvadurai HJ, Lan X, Lee L, Kushida M, Voisin V, Whetstone H, So M, Aviv T, Park N, Zhu X, Xu C, Head R, Rowland KJ, Bernstein M, Clarke ID, Bader G, Harrington L, Brumell JH, Tyers M, Dirks PB. Inhibition of dopamine receptor D4 impedes autophagic flux, proliferation, and survival of glioblastoma stem cells. Cancer Cell. 2016 Jun 13; 29(6):859-73.

Dorfer C, Tonn J, Rutka JT. Ependymoma: a heterogeneous tumor of uncertain origin and limited therapeutic options. Handbook of Clinical Neurology. 2016; 134:417-31.

Gallo M, Dirks PB. Global chromatin architecture defines functional cancer hierarchies. Cell Cycle. 2016 Aug 17; 15(16):2093-2094.

Jalali S, Monsalves E, Tateno T, Zadeh G. Role of mTOR Inhibitors in growth hormone-producing pituitary adenomas harboring different FGFR4 genotypes. Endocrinology. 2016 Sep; 157(9):3577-87.

Krishnatry R, Zhukova N, Guerreiro Stucklin AS, Pole JD, Mistry M, Fried I, Ramaswamy V, Bartels U, Huang A, Laperriere N, Dirks P, Nathan PC, Greenberg M, Malkin D, Hawkins C, Bandopadhayay P, Kieran MW, Manley PE, Bouffet E, Tabori U. Clinical and treatment factors determining long-term outcomes for adult survivors of childhood low-grade glioma: A population-based study. Cancer. 2016 Apr 15; 122(8):1261-9.

Lassaletta A, Guerreiro Stucklin A, Ramaswamy V, Zapotocky M, McKeown T, Hawkins C, Bouffet E, Tabori U. Profound clinical and radiological response to BRAF inhibition in a 2-month-old diencephalic child with hypothalamic/chiasmatic glioma. Pediatric Blood Cancer. 2016 Jul 11; 63(11):2038-41.


PUBLICATIONS

Lassaletta A, Zapotocky M, Bouffet E, Hawkins C, Tabori U. An integrative molecular and genomic analysis of pediatric hemispheric low-grade gliomas: an update. Child’s Nervous System. 2016 Oct; 32(10):1789-97.

Mansouri A, Mansouri S, Hachem LD, Klironomos G, Vogelbaum MA, Bernstein M, Zadeh G. The role of 5-aminolevulinic acid in enhancing surgery for high-grade glioma, its current boundaries, and future perspectives: A systematic review. Cancer. 2016 Aug; 122(16):2469-78.

Mansouri S, Nejad R, Karabork M, Ekinci C, Solaroglu I, Aldape KD, Zadeh G. Sox2: regulation of expression and contribution to brain tumors. CNS Oncology. 2016 Jul; 5(3):159-73.

Mansouri S, Singh S, Alamsahebpour A, Burrell K, Li M, Karabork M, Ekinci C, Koch E, Solaroglu I, Chang JT, Wouters B, Aldape K, Zadeh G. DICER governs characteristics of glioma stem cells and the resulting tumors in xenograft mouse models of glioblastoma. Oncotarget. 2016 Jul; doi: 10.18632/oncotarget.10570.

Morrissy AS, Garzia L, Shih DJ, …(134 additional authors)… Taylor MD. Divergent clonal selection dominates medulloblastoma at recurrence. Nature. 2016; 529(7586):351-7.

Okura H, Golbourn BJ, Shahzad U, Agnihotri S, Sabha N, Krieger JR, Figueiredo CA, Chalil A, Landon-Brace N, Riemenschneider A, Arai H, Smith CA, Xu S, Kaluz S, Marcus AI, Van Meir EG, Rutka JT. A role for activated Cdc42 in glioblastoma multiforme invasion. Oncotarget. 2016 Jul 29; doi: 10.18632/oncotarget.10925.

Rajendran D, Zhang-Y, Berry DM, McGlade CJ. Oncogenic signaling through ERK regulates alternative splicing of Numb. Oncogene. 2016; 35(39):5202-5213.

Ramaswamy V, Taylor MD. Fall of the Optical Wall: Freedom from the Tyranny of the Microscope Improves Glioma Risk Stratification. Cancer Cell. 2016; 29(2):137-8.

Sarras H, Wu M, Celebre A, Merico D, Karamchandani J, Das S. A novel amplification-based approach to enable gene expression profiling from small clinical tumor speciment. Journal of Neuro-Oncology. 2016 Jan; 126(1):69-75.

Thompson EM, Hielscher T, Bouffet E, …(103 additional authors)… Taylor MD. Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: a retrospective integrated clinical and molecular analysis. The Lancet Oncology. 2016; 17(4):484-95.

Torchia J, Golbourn B, Feng S, …(112 additional authors)… Huang, A. Integrated (epi)-genomic analyses identify subgroup specific therapeutic targets in CNS rhabdoid tumours. Cancer Cell. 2016. In Press.

Weeks A, Agnihotri S, Lymer J, Chalil A, Diaz R, Isik S, Smith C, Rutka JT. Epithelial Cell Transforming 2 and Aurora Kinase B Modulate Formation of Stress Granule-Containing Transcripts from Diverse Cellular Pathways in Astrocytoma Cells. American Journal of Pathology. 2016 Jun; 186(6):1674-87.

Zadeh G, Karimi S, Aldape KD. PIK3CA mutations in meningioma. Neuro-Oncology. 2016 May; 18(5):603-4.

We 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 and Meagan’s Walk: Creating a Circle of Hope for generously supporting ongoing research projects.

The BTRC would like to thank and acknowledge the volunteer and professional photographers who have contributed to this year’s Report including: Meagan’s Walk Gala and Walk photographers; and SickKids Creative Services for on-site photography and publication of the report.

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: [email protected]

Acknowledgement

imagine15-16cell biology and electrophysiology, dr. huang’s group studies ion channel-regulated...

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