cns cancer - e. van meir (humana, 2009)

Cancer Drug Discovery and Development
Series Editor: Beverly A. Teicher
For further volumes:
/>Erwin G. Van Meir
Editor
CNS Cancer
Models, Markers, Prognostic Factors,
Targets, and Therapeutic Approaches
Editor
Erwin G. Van Meir
Department of Neurosurgery
Hematology and Medical Oncology
and Winship Cancer Institute
Emory University School of Medicine
1365C Clifton Road NE
Atlanta, GA 30322
USA

ISBN 978-1-60327-552-1 e-ISBN 978-1-60327-553-8
DOI 10.1007/978-1-60327-553-8
Springer Dordrecht Heidelberg London New York
Library of Congress Control Number: 2009920397
# Humana Press, a part of Springer ScienceþBusiness Media, LLC 2009
All rights reserved.This work may not be translated or copied in whole or in part without the written
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The use in this publication of trade names, trademarks, service marks, and similar terms, even if they

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While the advice and information in this book are believed to be true and accurate at the date of
going to press, neither the authors nor the editors nor the publisher can accept any legal
responsibility for any errors or omissions that may be made. The publisher makes no warranty,
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Cover design: The cover art was designed by Acilino F. Vieira, Rita G. de Noronha and Erwin
G. Van Meir.
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Springer is part of Springer ScienceþBusiness Media (www.springer.com)
This book is dedicated to my parents Annie
and Eugene and my sister Veerle who are
largely responsible for who I am, to my wife
Erika and children Jessica and Gwendolyn
who lovingly tolerate the long working days
and always show support for what I am
doing.
It is also dedicated to my scientific mentors,
the late Riccardo Wittek who taught me
careful experimentation, critical thinking
and molecular virology, Nicolas de Tribolet
who launched my interest in brain tumors and
provided me with unique early career
opportunities, and Webster Cavenee for
giving me a great training environment in his
laboratory. I also acknowledge the hard
work and dedication of all my collaborators,
several of them devoted their career to brain
tumors and are authors in this book.
Finally, it is dedicated to the many patients

and their families who have donated their
tissue for experimentation and have helped
raise funds to support brain tumor research.
Foreword
Cancers of the central nervous system are among the most lethal of human
neoplasms. They are recalcitrant to even intensive multimodality therapies that
include surgery, radiotherapy, and chemotherapy. Moreover, especially in
children, the consequences of these therapies can itself be devastating and
involve serious cognitive and developmental disorders. It is small wonder that
such cancers have come under the intense scrutiny of each of the subspecialties
of clinical care and investigation as well as attracting some of the best basic
research scientists. Their joint efforts are gradually peeling away the mysteries
surrounding the genesis and progression of these tumors and inroads are being
steadily made into understanding why they resist therapies.
This makes it an especially opportune time to assemble some of the best
investigators in the field to review the ‘‘state of the art’’ in the various arenas that
comprise the assault on CNS tumors. The breadth of this effort by the clinical
and basic neuro-oncology community is quite simply amazing. To a large
extent, it evolves from the knowledge of the human genome and its regulation
that has been hard won over the past two decades. This information makes it
possible to rapidly identify genes that are likely to play causative roles in the
initiation and malignant progression of the disease, to test this candidacy in cells
and animals, to use validated targets to design and develop both markers for
prognostication as well as therapeutic approaches—of a variety of kinds—
aimed directly and specifically at the targets and to use experimental and
clinical trials of these to test real hypotheses. While the lethality of these
tumors has remained dismal over the past decades, there is finally real reason
for optimism as our knowledge base grows exponentially larger.
Most of the major areas of this endeavor are displayed in CNS Cancer
Models, Markers, Prognostic Factors, Targets, and Therapeutic Approaches.

Each of the chapters in the book represents illustrative examples of the road
from discovery through translation to clinical importance, although many
begin the journey at different parts of this continuum. This includes several
chapters on incredibly clever mouse models for deciphering the genetic wiring
underlying the development of CNS tumors and how that wiring might be
targeted for therapeutic benefit. This is an area of explosive growth and
increasing sophistication that was unimaginable even a few years ago. Suc h
vii
approaches are complemented by other experimental systems including cell and
tissue manipulation and transplantation, spontaneous tumor occurrence in
other organisms such as dog s and flies. A great deal of attention has been
paid in the book to the development of genetic prognostic factors and
biomarkers that could be used for assessing individual responses to therapies
and so could lead to truly personalized medicine. Other possible progn ostic
factors/biomarkers that arise from an understanding of CNS tumor
pathophysiology are discussed in some detail and include tumor
vascularization and hypoxia. Several of the new and rapidly developing
methodologies that allow these rapid advances are detailed for the reader as
well and include RNA expression profiling, proteomic analyses of both tumors
and biological fluids as well as profiling small non-coding RNAs and DNA
modification. Finally, several chapters explore aspects of therapeutic targeting
employing small molecules and combinations thereof, various sorts of cells,
viruses, and immune modulation. In sum, these treatises represent the cutting
edge of research that is driven to be of benefit to patients with these dreaded
diseases.
The audience that will benefit from the information contained in CNS Cancer
Models, Markers, Prognostic Factors, Targets, and Therapeutic Approaches
includes clinicians, brain tumor scientists, medical residents, postdoctoral
researchers, and the informed patient. This is a wonderful compendium of the
most timely information from leaders in the battle against CNS tumors and its

timeliness fills a niche in a manner that is accessible and contemporary. The
authors and especially the editor, Dr. Erwin Van Meir, are to be congratulated
for providing this service to the community.
San Diego, CA Webster K. Cavenee, Ph.D.
viii Foreword
Preface
These are exciting times in neuro-oncology. By the time this book is published I
will have worked in this field for 20 years, giving me enough perspective to
contemplate significant changes during these two decades. In 1989 little was
known about brain tumors and the community of researchers was small.
Pioneers such as Charles Wilson had the foresight to foster inter-disciplinary
approaches to the brain tumor treatment and investigation. Treatment options
were limited to surgery, radiotherapy, and a few modestly effective
chemotherapeutic agents such as BCNU. Over the ensuing decades, the neuro-
oncology field has expanded and traversed a number of ‘‘waves’’, each of which
was expected to yield a rapid cure. The 1980s ushered in research that tapped into
the power of the immune system and promised immunotherapies, whether
antibody-based or cell-based. When I entered the field there was a strong
interest in identifying autocrine growth factors that drive tumor growth and the
early groundbreaking genetic studies were being performed. Amplification of the
EGFR gene on chromosome 7 in glioblastoma had been identified as an
important oncogenic event in 1984. In subsequent years, the application of
karyotypic analyses and loss of heterozygosity studies pinpointed the location
of tumor suppressor loci on chromosomes 9, 10, and 17. In 1989, the p53 gene was
identified as the tumor suppressor lost from chromosome 17 in glioblastoma and
other cancers. In 1993 the p16 cell cycle inhibitor was described and in 1997 the
PTEN phosphatase was discovered as a critical gene product lost due to genetic
alterations on chromosome 10. Genetic discoveries in glioma spearheaded the use
of similar technology for the discovery of new signaling pathways in
medulloblastoma, meningioma, ependymoma, and other brain tumors.

The 1990s witnessed the advent of cancer gene therapy and anti-angiogenic
therapies. The remarkable results obtained in mouse glioma models with
retroviral thymidine kinase/ganciclovir gene therapy systems were not repro-
duced in clinical trials, yet led to new generations of virotherapy through the use
of on colytic viruses. The d efinition of an giogenic mechanisms and the discovery of
endogenous negative regulators of these processes have led directly to clinical
applications in which tumoral blood vessels are targeted by an ti-angiogenic
therapies, a strategy which is bearing fruit with anti-VEGF antibodies.
ix
Subsequent breakthroughs have included the sequencing of the human
genome in 2003 and the use of new techniques that permit whole-genome
analyses for gene expression and alterations. The impac t of these discoveries
is in full bloom for glioblastoma multiforme with The Cancer Genome Atlas
(TCGA), an unprecedented, NIH-sponsored, effort to identify every pos sible
genetic and epigenetic alteration and gene expression change in 500
glioblastoma specimens. The initial results of the TCGA Research Network
as well as an independent effort to sequence all genes in 22 glioblastoma have
just been published. These important studies have shown that, not surprisingly,
this disease is complex, with up to 60 mutated genes per tumor. Fortunately,
these genes can be distilled to a lesser number of pathways that make their study
more palatable. Studying 60 genes, and even fewer pathways, is certainly easier
than 30,000! We know that with enough effort and research teams focusing on
all these new therapeutic targets, we will be able to fully comprehend the
biological complexity of the disease and further accelerate the discovery of
life-saving medicines. Novel targeted therapeutics and biomarker-based
imaging will benefit in the near future from the emergence of nanotechnology.
Independently, the last decade has brought major discoveries on cell lineages
in the central nervous syst em and the differentiation events that take place from
stem cells to neurons, astrocytes, and oligodendrocytes. The application of
markers identified in normal CNS development to the understanding of

tumor heterogeneity gave birth to the ‘‘cancer stem cell hypothesis’’, a concept
that has promoted a rethinking of the basic tenets in oncology and has blended
the study of cancer and neuroscience. The speed of discovery summarized above
is remarkable and gives no hint of slowing down. Many of these exciting
developments are described within this book.
Today the prognosis of malignant brain tumors, such as glioblastoma, is still
dismal, but what has changed is that there is real hope for a cure. The research
efforts touched upon above and described in much more eloquent fashion by the
authors in this book are bearing fruit. New biomarkers and therapeutic targets
are being identified. We are seeing successful therapies emerge from the use of
antibodies and cytotoxins, signaling pathway-targeted small molecules, anti-
angiogenesis strategies, better use of ‘‘old-fashioned’’ alkylating drugs following
increased knowledge of DNA repair pathways, and vaccination approaches
targeting unique tumor epitopes uncovered by genetic approaches. Further
development of novel therapies is advancing at rapid pace and there is an
increased need for animal models to evaluate them. A full third of the book is
devoted to present a comprehensive selection of the models currently available.
The light at the end of the tunnel is beco ming visible. It is encouragi ng to
witness, and exciting to participate in, the dramatic improvements in brain
tumor treatment that are being made.
Atlanta, GA Erwin G. Van Meir
March, 2009
x Preface
Editor
Erwin G. Van Meir is Professor of Neurosurgery and Hematology & Medical
Oncology in the School of Medicine at Emory University. A native of Belgium,
he obtained Bachelor’s degrees in Biology and Education at the University of
Fribourg, Switzerland. He pursued graduate studies in Molecular Virology at
the University of Lausanne, Switzerland where he obtained his PhD in 1989.
He then became interested in cancer Research and completed postdoctoral

work at the University Hospital in Lausanne and at the Ludwig Institute for
Cancer Research in San Diego. In 1994 he was granted his first Faculty position
as Director of the Laboratory of Brain Tumor Biology and Genetics in the
Neurosurgery Department at the University of Lausanne. In 1998 he joined
Emory University in Atlanta, where he now serves as the Leader of the Winship
Cancer Institute Molecular Pathways and Biomarkers scientific program and is
co-Director of the Brain Tumor Rese arch Group.
For the past 2 0 years D r. Van M eir’s research has focused o n defining t he
biological significance of specific genetic alterations for brain tumor development.
He is particularly interested in how tumors divert extracellular signals regulating
heterotypic cell communication for their own benefit such as occurs in tumor
angiogenesis, and in translating t his new knowled ge into novel therap eu tic
approaches. H is research is d escribed i nmorethan140peer-reviewedresearch
papers and review articles in internationally recognized journals that have
cumulated ove r 5,000 c itations an d rec eive d several a wards. These contribu tions
were presented in over 100 invited seminars w orldwide and have furthered the
understanding of cytokine expression for glioma biology, Turcot syndrome, the
role of p53, HIF, IL-8, thrombospondin-1 and brain angiogenesis inhibitor-1 in
brain tumor angiogenesis, hypoxia, and p seudopalisading necrosis formation. He
also discovered biomarkers in the c erebrospinal fluid of brain tumor patients and
developed novel therapeutic agents including o nco lytic h ypoxia-activated
adenoviruses, pro-apoptotic galectin-3, anti -an gioge nic vascu lo stat ins, and sma ll
molecule HIF i nhibitors t hat are covered by s everal US and foreign patents.
Perhaps most importantly, over his 20-year independent career, D r. Van Meir
has mentored and trained over 60 postdoctoral fellows, students, and v isiting
scientists, many of which now h old independent leading positions in Academia
or Industry.
xi
Dr. Van Meir is an active member of the international neuro-oncology
community and served on the Board of Directors of the Society for Neuro-

Oncology from 2004 to 2008. He organized several international conferences on
brain tumors, has served on the Scientific Committee of the European
Association for Neuro-Oncology, the Scientific Advisory Board of the
Southeastern Brain Tumor Foundation, and is a current or former member of
several other international cancer societies including the American Association
for Cancer Research, the European Association for Cancer Research, and the
American Society for Investigat ive Pathology.
Dr. Van Meir currently serves on the Editorial Board of Neuro-Oncology,
Frontiers in Bioscience, and International Journal of Oncology, and is a former
Associate Editor of the International Journal of Cancer. He has served a s a
reviewer for over 30 international scientific journals and for grant proposals
from public and private agencies including the US National Institutes of
Health, the US Department of Defense, the European Com mission, the Swiss
National Science Foundation, the Swiss Cancer Society, the Wellcome Trust of
the UK, Cancer Research UK, the Research Grants Council of Hong Kong, the
Israel Science Foundation, the Belgian Fournier-Majoie, and King Baudouin
Foundations, and the Italian Association for Cancer Research.
He acknowledges present and past support by multiple funding agencies for
his scientific work, including the US National Institutes of Health, the Swiss
National Science Foundation, the Goldhirsh Foundation, the Charlotte Geyer
Foundation, the Southeastern and National Brain Tumor Foundations, The
Brain Tumor Society, the Pediatric Brain Tumor Foundation of the US, the
American Brain Tumor Association, the Brain Tumor Foundation for Children,
the Al Musella, Wayne O Rollins and Frances Wood Wilson Foundations, the
Brain Tumor Trust, the Emory University Research Council and EmTechBio,
the Swiss Cancer League and Anti-Cancer Foundations, the San Salvatore,
Tossizza, Ott and Chuard-Smith Foundations, and the European Institute of
Oncology.
xii Editor
Contents

Part I Animal Models for Central Nervous Tumors
1 Modeling Gliomas Using PDGF-Expressing Retroviruses 3
Marcela Assanah, Kim A. Lopez, Jeffrey N. Bruce,
and Peter Canoll
2 Modeling Brain Tumors Using Avian Retroviral Gene
Transfer 29
Tod D. Holland and Eric C. Holland
3 Using Neurofibromatosis Type 1 Mouse Models to Understand
Human Pediatric Low-Grade Gliomas 45
David H. Gutmann
4 Transgenic Mouse Models of CNS Tumors: Using Genetically
Engineered Murine Models to Study the Role of p21-Ras
in Glioblastoma Multiforme 61
Diana Munoz, Sameer Agnihotri, and Abhijit Guha
5 Pten -Deficient Mouse Models for High-Grade Astrocytomas 77
Chang-Hyuk Kwon
6 The Nf1–/þ;Trp53–/þcis Mouse Model of Anaplastic
Astrocytoma and Secondary Glioblastoma: Dissecting Genetic
Susceptibility to Brain Cancer 93
Karlyne M. Reilly
7 Modeling Astrocytomas in a Family of Inducible Genetically
Engineered Mice: Implications for Preclinical Cancer Drug
Development 119
C. Ryan Miller, Natalie O. Karpinich, Qian Zhang,
Elizabeth Bullitt, Serguei Kozlov, and Terry Van Dyke
xiii
8 Human Brain Tumor Cell and Tumor Tissue Transplantation Models. . 147
Tomoko Ozawa and C. David James
9 Transformed Human Brain Cells in Culture as a Model
for Brain Tumors 163

Russell O. Pieper
10 Rat Glioma Models for Preclinical Evaluation of Novel
Therapeutic and Diagnostic Modalities 181
Balveen Kaur and Rolf F. Barth
11 Neuro-oncogenesis Induced by Nitroso Compound s in Rodents
and Strain-Specific Genetic Modifiers of Predisposition 207
Bernd U. Koelsch and Andrea Kindler-R
¨
ohrborn
12 The Murine GL261 Glioma Experimental Model to Assess
Novel Brain Tumor Treatments 227
Elizabeth W. Newcomb and David Zagzag
13 Spontaneous Occurrence of Brain Tumors in Animals:
Opportunities as Preclinical Model Systems 243
Simon R. Platt
Part II Prognostic Factors and Biomarkers
14 p53 Pathway Alterations in Brain Tumors 283
Shaoman Yin and Erwin G. Van Meir
15 The PTEN/PI3 Kinase Pathway in Human Glioma 315
David Stokoe and Frank B. Furnari
16 Value of 1p/19q and Other LOH Markers for Brain Tumor
Diagnosis, Prognosis, and Therapy 359
Jean-Louis Boulay and Adrian Merlo
17 Discovery of Genetic Markers for Brain Tumors by Comparative
Genomic Hybridization 373
Anjan Misra and Burt G. Feuerstein
18 Genomic Identification of Significant Targets in Brain Cancer 395
Rameen Beroukhim, Gaddy Getz, and Ingo K. Mellinghoff
19 Oncomodulatory Role of the Human Cytomegalovirus
in Glioblastoma 415

Liliana Soroceanu and Charles S. Cobbs
xiv Contents
20 Aberrant EGFR Signaling in Glioma 441
YeoHyeon Hwang, Khatr i Latha, Anupama Gururaj,
Marta Rojas, and Oliver Bogler
21 Mechanisms of Brain Tumor Angiogenesis 461
Bo Hu and Shi-Yuan Cheng
22 Vaso-occlusive Mechanisms that Intiate Hypoxia and Necrosis
in Glioblastoma: The Role of Thromb osis and Tissue Factor 507
Yuan Rong and Daniel J. Brat
23 Transcription Profiling of Brain Tumors: Tumor Biology
and Treatment Stratification 529
Erik P. Sulman, Marisol Guerrero, and Ken Aldape
24 Proteomic Profiling of Human Brain Tumors 553
Rongcai Jiang, Jian Yi Li, Gregory N. Fuller, and Wei Zhang
25 Proteomic Discovery of Biomarkers in the Cerebrospinal Fluid
of Brain Tumor Patients 577
Fatima W. Khwaja and Erwin G. Van Meir
26 Epigenetic Profiling of Gliomas 615
Raman P. Nagarajan and Joseph F. Costello
27 MicroRNAs in the Central Nervous System and Potential Roles
of RNA Interference in Brain Tumors 651
Benjamin Purow
28 Of Escherichia coli and Man: Understanding Glioma Resistance
to Temozolomide Therapy 679
Clark C. Chen, Kristopher T. Kahle, Kimberly Ng,
Masayuki Nitta, and Alan D’Andrea
29 Brain Tumor Stem Cell Markers 713
Jeremy N. Rich
Part III Therapeutic Targets and Targeting Approaches

30 Clinical Agents for the Targeting of Brain Tumor Vasculature 731
Elizabeth R. Gerstner and Tracy T. Batchelor
31 Bone M arrow-Derived Cells in GBM Neovascularization 749
Gabriele Bergers
Contents xv
32 Vascular Targeting of Brain Tumors – Bridging the Gap with
Phage Display 775
Michael G. Ozawa, Fernanda I. Staquicini, Richard L. Sidman,
Renata Pasqualini, and Wadih Arap
33 Impact of the Blood–Brain Barrier on Brain Tumor Imaging
and Therapy 789
James Provenzale
34 Targeting CXCR4 in Brain Tumors 813
Hyunsuk Shim
35 Molecular Targeting of IL-13Ra2 and EphA2 Receptor in GBM . . . 847
Waldemar Debinski and Jill Wykosky
36 Molecular Targets for Antibody-Mediated Immunotherapy
of Malignant Glioma 865
Joanne E. Ayriss, Chien-Tsun Kuan, Susan T. Boulton,
David A. Reardon, and Darell D. Bigner
37 Stat3 Oncogenic Signaling in Glioblastoma Multiforme 899
Saikh Jaharul Haque and Pankaj Sharma
38 Inhibition of Ras Signaling for Brain Tumor Therapy 919
Sameer Agnihotri, Diana Munoz, and Abhijit Guha
39 HGF/c-Met Signaling and Targeted Therapeutics in Brain
Tumors 933
Roger Abounader and John Laterra
40 Combinatorial Therapeutic Strategies for Blocking Kinase
Pathways in Brain Tumors 953
Paul H. Huang and Forest M. White

41 Targeting of TRAIL Apoptotic Pathways for Glioblastoma
Therapies 977
Anita C. Bellail, Patrick Mulligan, and Chunhai Hao
42 The NF-kB Signaling Pathway in GBMs: Implications for Apoptotic
and Inflammatory Responses and Exploitation for Therapy. . . . . . . . 1011
Travis Laver, Susan Nozell, and Etty N. Benveniste
43 Targeting Endoplasmic Reticulum Stress for Malignant Glioma
Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1037
Peter Pyrko, Axel H. Sch
¨
onthal, and Thomas C. Chen
xvi Contents
44 Brain Cancer Stem Cells as Targets of Novel Therapies . . . . . . . . . . 1057
Jennifer M. Atkinson, Richard J. Gilbertson,
and Jeremy N. Rich
45 The Use of Retinoids as Differentiation Agents Against
Medulloblastoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1077
Matthew Wortham and Hai Yan
46 Herpes Simplex Virus 1 (HSV-1) for Glioblastoma Multiforme
Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1105
Costas G. Hadjipanayis
47 The Development of Targeted Cancer Gene-Therapy
Adenoviruses for High-Grade Glioma Treatment . . . . . . . . . . . . . . . . 1137
Dawn E. Post and Erwin G. Van Meir
48 Harnessing T-Cell Immunity to Target Brain Tumors . . . . . . . . . . . . 1165
Paul R. Walker, Robert M. Prins, Pierre -Yves Dietrich,
and Linda M. Liau
49 Glioma Invasion: Mechanisms and Therapeutic Challenges . . . . . . . . 1219
Mariano S. Viapiano and Sean E. Lawler
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1253

Contents xvii
Contributors
Roger Abounader Department of Neurology and Microbiology, University
of Virginia, Charlottesville, VA 22908, USA,
Sameer Agnihotri Hospital for Sick Children, University of Toronto, Toronto,
ON, Canada
Ken Aldape Department of Pathology and Radiation Oncology, The
University of Texas M.D. Anderson Cancer Center, Houston, TX, USA,

Wadih Arap David H. Koch Center, The University of Texas M.D. Anderson
Cancer Center, Houston, TX 77030, USA,
Marcela Assanah Department of Neurological Surgery, Columbia University
Medical Center and the Columbia Brain Tumor Center, New York, NY 10032,
USA
Jennifer M. Atkinson Department of Developmental Neurobiology, St Jude
Children’s Research Hospital, Memphis, TN 38105, USA
Joanne E. Ayriss Department of Pathology, Duke University Medical Center,
181A Medical Sciences Research Building, Durham, NC 27710, USA,

Rolf F. Barth Depart ment of Pathology, The Ohio State University, 165
Hamilton Hall, Columbus, OH 43210, USA,
Tracy T. Batchelor Division of Hematology and Oncology, Department
of Neurology and Radiation Oncology, Massachusetts General Hospital
Cancer Center and Harvard Medical School, Boston, MA, USA,

Anita C. Bellail Department of Pathology & Laboratory Med icine, Winship
Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322,
USA,
xix
Etty N. Benveniste Department of Cell Biology, University of Alabama,

Birmingham, AL 35294-0004, USA,
Gabriele Bergers Department of Neurological Surgery, Brain Tumor Research
Center and UCSF Helen Diller Family Comprehensive Cancer Center,
University of California San Francisco, San Francisco, CA 94143-0520, USA,
gabriele.bergers@ucsf .edu
Rameen Beroukhim Broad Institute, Massachusetts Institute of Technology
and Harvard University, Cambridge, MA 02142; Department of Medicine,
Harvard Medical School and Division of Medical Oncology, Dana–Farber
Cancer Institute, Boston, MA 02115,
Darell D. Bigner Department of Pathology, 177 Medical Sciences Research
Building, Duke University Medical Center, Box 3156, Durham,
North Carolina 27710,
Oliver Bogler Department of Neurosurgery and Department of Neuro-
Oncology, Brain Tumor Center, University of Texas M.D. Anderson Cancer
Center, Houston, TX 77030, USA,
Jean-Louis Boulay Laboratory of Neuro-Oncolo gy, Department
of Biomedicine and Neurosurgery, University Hospital, CH-4031 Basel,
Switzerland,
Susan T. Boulton Duke University Medical Center, Box 3624, The Preston
Robert Tisch Brain Tumor Center, Department of Surgery/Neuro-oncology,
Room 047 Baker House, Trent Drive Durham, North Carolina 27710,

Daniel J. Brat Department of Pathology and Laboratory Medicine, Winship
Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA,

Jeffrey N. Bruce Department of Neurological Surgery, Columbia University
Medical Center and the Columbia Brain Tumor Center, New York, NY 10032,
USA
Elizabeth Bullitt Division of Neurosurgery, Lineberger Comprehensive Cancer
Center, University of North Carolina, Chapel Hill, NC, USA

Peter Canoll Department of Pathology and Cell Biology, Columbia University
Medical Center, New York, NY, USA,
Clark C. Chen Division of Neurosurgery, Beth Israel Deaconess Medical
Center, Harvard Medical School, Boston, MA, USA; Department of Radiation
Oncology, Dana Farber Cancer Institute, Boston, MA, USA,

xx Contributors
Thomas C. Chen Department of Neurosurgery, University of Southern
California Keck School of Medici ne, Los Angeles, CA, USA,

Shi-Yuan Cheng Cancer Institute and Department of Pathology, University
of Pittsburgh, Pittsburgh, PA 15213, USA,
Charles S. Cobbs Department of Neuroscience, California Pacific Medical
Center Research Institute, San Francisco, CA 94107, USA; Department
of Neurological Surgery, Unive rsity of California, San Francisco, CA 94143,
USA,
Joseph F. Costello Brain Tumor Research Center, Depart ment
of Neurosurgery, University of California San Francisco, San Francisco,
CA 94143, USA,
Alan D’Andrea Department of Radiation Oncology, Dana Farber Cancer
Institute, Boston, MA, USA,
Waldemar Debinski Brain Tumor Center of Excellence, Wake Forest
University School of Medicine, Winston-Salem, NC 27157, USA,

Pierre-Yves Dietrich Centre of Oncology, Geneva University Hospitals and
University of Geneva, rue Micheli-du-Crest 24, 1211 Geneva 14, Switzerland,

Terry Van Dyke Department of Genetics, Lineberger Comprehensive Cancer
Center, University of North Carolina, Chapel Hill, NC, USA; Mouse Cance r
Genetics Program, Centers for Cancer Research and Advanced Preclinical

Research, National Cancer Institute, Frederick, MD, USA,

Burt G. Feuerstein Barrow Neurological Institute, St. Joseph’s Hospital
and Medical Center, Phoenix, AZ, USA,
Gregory N. Fuller Department of Pathology, University of Texas M.D.
Anderson Cancer Center, Houston, TX, USA,
Frank B. Furnari Ludwig Institute for Cancer Research, Department
of Medicine, Cancer Center, University of California-San Diego, La Jolla,
CA 92093-0660, USA,
Elizabeth R. Gerstner Division of Hematology and Oncology, Department of
Neurology, Massachusetts General Hospital Cancer Center and Harvard
Medical School, Boston, MA, USA
Gaddy Getz Broad Institute, Massachusetts Institute of Technology
and Harvard University, 7 Cambridge Center, Cambridge, MA 02142, USA
Contributors xxi
Richard J. Gilbertson Department of Developmental Neurobiology, and
Oncology, St Jude Children’s Research Hospital, Memphis, TN 38105, USA,

Marisol Guerrero Department of Pathology, The University of Texas M.D.
Anderson Cancer Center, Houston, TX, USA
Abhijit Guha Hospital for Sick Children, University of Toronto, Toronto, ON,
Canada,
Anupama Gururaj Department of Neurosurgery, Brain Tumor Center,
University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA
David H. Gutmann Department of Neurology, Washington University School
of Medicine, St. Louis, MO 63110,
Costas G. Hadjipanayis Department of Neurological Surgery, Winship Cancer
Institute, Emory University School of Medicine, Atlanta, GA 30322, USA,

Chunhai Hao Department of Pathology & Laboratory Medicine, Winship

Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322,
USA,
Saikh Jaharul Haque Department of Cancer Biology, Lerner Research
Institute; Brain Tumor and Neuro-Oncology Center, Division
of Neurosciences, Cleveland Clinic, Cleveland, OH 44195, USA,

Eric C. Holland Department of Neurosurgery, Neurology, Surgery and Cancer
Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York,
NY 10021, USA,
Tod D. Holland Department of Neurosurgery, Neurology, Surgery and Cancer
Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York,
NY 10021, USA
Bo Hu Cancer Institute and Department of Medicine, University of
Pittsburgh, Pittsburgh, PA 15213, USA
Paul H. Huang Department of Biological Engineering, Massachusetts Institute
of Technology, Cambridge, MA 02139, USA,
YeoHyeon Hwang Department of Neurosurgery, Brain Tumor Center,
University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA
C. David James Department of Neurological Surgery and Brain Tumor
Research Center, University of California, San Francisco, CA 94143, USA,

xxii Contributors
Rongcai Jiang Department of Neurosurgery, Tianjin Medical University
General Hospital, Tianjin 300052, China,
Kristopher T. Kahle Department of Neurosurgery, Massachusetts General
Hospital, Boston, MA, USA
Natalie O. Karpinich Department of Genetics, Lineberger Comprehensive
Cancer Center, University of Nort h Carolina, Chapel Hill, NC, USA
Balveen Kaur Dardinger Laboratory of Neurosciences, Department of
Neurological surgery, The Ohio State University, Columbus, OH 43210, USA,

Fatima W. Khwaja Laborator y of Molecular Neuro-Oncology, Department of
Neurosurgery, Hematology and Medical Oncology, and Winship Cancer
Institute, Emory University School of Medicine, Atlanta, GA 30322, USA;
Basic Science Lab, Shaukat Khanum Memorial Cancer Hospital & Research
Center, Lahore, Pakistan,
Andrea Kindler-R
¨
ohrborn Institute of Pat hology and Neuropathology,
University Hospital of Essen, University of Duisburg-Essen, Hufelandstr. 55,
45122 Essen, Germany,
Bernd U. Koelsch Institute of Pathology and Neuropathology, University
Hospital of Essen, University of Duisburg-Essen, Hufelandstr. 55, 45122 Essen,
Germany,
Serguei Kozlov Mouse Cancer Genetics Program, Centers for Cancer Research
and Advanced Preclinical Research, National Cancer Institute, Frederick, MD,
USA,
Chien-Tsun Kuan Department of Pathology, 181C Medical Sciences Research
Building, Duke University Medical Center, Box 3156, Durham, North
Carolina 27710,
Chang-Hyuk Kwon Department of Neurological Sur gery, Tumor
Microenvironment Program and Dardinger Center for Neuro-oncology
and Neurosciences, James Comprehensive Cancer Center, The Ohio State
University Medical Center, Columbus, OH 43210, USA,

John Laterra Kennedy Krieger Research Institute and Johns Hopkins
University School of Medicine, Baltimore, MD 21205, USA,

Khatri Latha Department of Neurosurgery, Brain Tumor Center, University
of Texas M.D. Anderson Cancer Cent er, Houston, TX 77030, USA

Contributors xxiii
Travis Laver Department of Cell Biology, University of Alabama,
Birmingham, AL 35294-0005, USA
Sean E. Lawler Dardinger Laboratory for NeuroOncology and Neurosciences,
Department of Neurological Surgery, The Ohio State University Medical
Center and James Comprehensive Cancer Center, Columbus, OH 43210, USA,

Jian Yi Li Department of Pathology, Harvey Cushi ng Brain Tumor Institute,
Feinstein Institute for Medical Research, North Shore-LIJ Health System,
North Shore University Hospital, Manhasset, NY, USA,
Linda M. Liau UCLA Department of Neurosurgery, David Geffen School
of Medicine at UCLA, 10833 Le Conte Avenue, CHS 74-145, Los Angeles,
CA 90095-6901, USA,
Kim A. Lopez Department of Neurological Surgery, Columbia University
Medical Center and the Columbia Brain Tumor Center, New York, NY 10032,
USA
Ingo K. Mellinghoff Human Oncology and Pathogenesis Program
and Department of Neurology, Memorial Sloan-Kettering Cancer Center,
New York, NY 10065, USA,
Adrian Merlo Laboratory of Neuro-Oncology, Departments of Biomedicine
and Neurosurgery, University Hospital, CH-4031 Basel, Switzerland,

C. Ryan Miller Department of Pathology & Laboratory Medicine and
Lineberger Comprehensi ve Cancer Center, University of North Carolina,
Chapel Hill, NC,
Anjan Misra Barrow Neurological Institute, St. Joseph’s Hospital and Medical
Center, Phoenix, AZ, USA,
Patrick Mulligan Department of Pathology & Laboratory Medicine, Winshi p
Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322,
USA,

Diana Munoz Hospital for Sick Children, University of Toronto, Toronto,
ON, Canada
Raman P. Nagarajan Brain Tumor Research Center, Department
of Neurosurgery, University of California San Francisco, San Francisco,
CA 94143, USA
Elizabeth W. Newcomb Department of Pathology, New York University
Cancer Institute, New York University School of Medicine, New York,
NY 10016, USA, newcoe01@me d.nyu.edu
xxiv Contributors
Kimberly Ng Department of Radiation Oncology, Dana Farber Cancer
Institute, Boston, MA, USA
Masayuki Nitta Department of Radiation Oncology, Dana Far ber Cancer
Institute, Boston, MA, USA
Susan Nozell Department of Cell Biology, University of Alabama,
Birmingham, AL 35294-0004, USA,
Michael G. Ozawa David H. Koch Center, The University of Texas M.D.
Anderson Cancer Center, Houston, TX 77 030, USA
Tomoko Ozawa Department of Neurological Surgery and Brain Tumor
Research Center, University of California, San Francisco, CA 94143, USA,

Renata Pasqualini David H. Koch Center, The University of Texas M.D.
Anderson Cancer Center, Houston, TX 77030, USA,

Russell O. Pieper Brain Tumor Research Center, Department of Neurological
Surgery, and The UCSF Cancer Center, University of California – San
Francisco, San Francisco, CA 94115- 0875, USA,
Simon R. Platt Department of Small Animal Medicine & Surgery, College
of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA,

Dawn E. Post Departments of Neurosurgery and Microbiology &

Immunology, State University of New York Upstate Medical University,
Syracuse, NY, USA,
Robert M. Prins UCLA Department of Neurosurgery, David Geffen School
of Medicine at UCLA, 10833 Le Conte Avenue, CHS 74-145, Los Angeles,
CA 90095, USA,
James Provenzale Department of Radiology, Biomedical Engineering and
Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA;
Department of Radiology, Duke University Medical Center, Durham, NC
27710, USA,
Benjamin Purow Neuro-Oncology Division, Neurology Department,
University of Virginia, Charlottesville, VA 22908, USA,

Peter Pyrko Department of Neurosurgery, Universit y of Southern California
Keck School of Medicine, Los Angeles, CA, USA,
Contributors xxv
David A. Reardon Duke University Medical Center, Box 3624, The Preston
Robert Tisch Brain Tumor Center, Department of Surgery, Department of
Pediatrics, Room 047, Baker House, Trent Drive, Durham, North Carolina
27710,
Karlyne M. Reilly Mouse Cancer Genetics Program, National Cance r
Institute, Frederick, MD 21702, USA,
Jeremy N. Rich Department of Stem Cell Biology and Regenerative Medicine,
Cleveland Clinic, Clevela nd, OH 44195, USA,
Marta Rojas Department of Neurosurgery, Brain Tumor Center, University
of Texas M.D. Anderson Cancer Cent er, Houston, TX 77030, USA
Yuan Rong Department of Pathology and Laboratory Medicine, Winship
Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA,

Axel H. Sch
¨

onthal Department of Molecular Microbiology and Immunology,
University of Southern California Keck School of Medicine, Los Angeles,
California, USA
Pankaj Sharma Department of Cancer Biology, Lerner Research Institute,
Cleveland Clinic, Clevela nd OH 44195, USA,
Hyunsuk Shim Department of Radiology, Winship Cancer Institute, Emory
University School of Medicine, Atlanta, GA 30322, USA,
Richard L. Sidman Harvard Medical School and Department of Neurology,
Beth Israel Deaconess Medical Center, Center for Life Science, Boston, MA
02215, USA
Liliana Soroceanu Department of Neuroscience, Calif ornia Pacific Medical
Center Research Institute, San Francisco, CA 94107, USA,

Fernanda I. Staquicini David H. Koch Center, The University of Texas M.D.
Anderson Cancer Center, Houston, TX 77030, USA
David Stokoe Department of Molecular Biology, Genentech Inc., 1 DNA
Way, South San Francisco, CA 94080, USA,
Erik P. Sulman Department of Radiation Oncology, The University of Texas
M.D. Anderson Cancer Center, Houston, TX, USA
Erwin G. Van Meir Department of Neurosurgery, Hematology and Medical
Oncology, and Winship Cancer Institute, Emory University School
of Medicine, Atlanta, GA, USA,
xxvi Contributors
Mariano S. Viapiano Department of Neurological Surgery, Center for Molecular
Neurobiology, The Ohio State University Medical Center and James
Comprehensive Cancer C enter, Columbus, OH 43210, USA, v
Paul R. Walker Centre of Oncology, Geneva University Hospi tals and
University of Geneva, rue Micheli-du-Crest 24, 1211 Geneva 14, Switzerland,

Forest M. White Department of Biological Engineering, Massachusetts

Institute of Technology, Cambridge, MA 02139, USA,
Matthew J. Wortham Department of Pathology, Duke University Medical
Center, 189 Medical Sciences Research Building, Durham, NC 27710, USA,

Jill Wykosky Brain Tumor Center of Excellence, Wake Forest University
School of Medicine, Winston-Salem, NC 27157, USA
Hai Yan Department of Pathology, Duke University Medical Center,
199B Medical Sciences Research Building, Durham, NC 27710, USA,

Shaoman Yin Department of Neurosurgery, Emory University School
of Medicine, Atlanta, GA, USA,
David Zagzag Department of Pathology and Division of Neurop athology
and Department of Neurosurgery, New York University Cancer Institute,
New York University School of Medicine, New York, NY 10016, USA,

Qian Zhang Mouse Cancer Genetics Program, Centers for Cancer Research
and Advanced Preclinical Research, National Cancer Institute, Frederick, MD,
USA
Wei Zhang Department of Pathology, University of Texas M.D. Anderson
Cancer Center, Houston, TX, USA,
Contributors xxvii