Table Of ContentCNS Cancer
Models, Markers, Prognostic
Factors, Targets, and
Therapeutic Approaches
Edited by
Erwin G. Van Meir
, PhD
Cancer Drug Discovery and Development
Series Editor: Beverly A. Teicher
Forfurthervolumes:
http://www.springer.com/series/7625
Erwin G. Van Meir
Editor
CNS Cancer
Models, Markers, Prognostic Factors,
Targets, and Therapeutic Approaches
Editor
ErwinG.VanMeir
DepartmentofNeurosurgery
HematologyandMedicalOncology
andWinshipCancerInstitute
EmoryUniversitySchoolofMedicine
1365CCliftonRoadNE
Atlanta,GA30322
USA
[email protected]
ISBN978-1-60327-552-1 e-ISBN978-1-60327-553-8
DOI10.1007/978-1-60327-553-8
SpringerDordrechtHeidelbergLondonNewYork
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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
wholaunchedmyinterestinbraintumorsand
provided me with unique early career
opportunities, and Webster Cavenee for
givingmeagreattrainingenvironmentinhis
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.Theyarerecalcitranttoevenintensivemultimodalitytherapiesthat
include surgery, radiotherapy, and chemotherapy. Moreover, especially in
children, the consequences of these therapies can itself be devastating and
involveseriouscognitiveanddevelopmentaldisorders.Itissmallwonderthat
suchcancershavecomeundertheintensescrutinyofeachofthesubspecialties
of clinical care and investigation as well as attracting some of the best basic
researchscientists.Theirjointeffortsaregraduallypeelingawaythemysteries
surroundingthegenesisandprogressionofthesetumorsandinroadsarebeing
steadilymadeintounderstandingwhytheyresisttherapies.
This makes it an especially opportune time to assemble some of the best
investigatorsinthefieldtoreviewthe‘‘stateoftheart’’inthevariousarenasthat
comprisetheassaultonCNStumors.Thebreadthofthiseffortbytheclinical
and basic neuro-oncology community is quite simply amazing. To a large
extent,itevolvesfromtheknowledgeofthehumangenomeanditsregulation
thathasbeenhardwonoverthepasttwodecades. Thisinformationmakes it
possible to rapidly identify genes that are likely to play causative roles in the
initiationandmalignantprogressionofthedisease,totestthiscandidacyincells
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
tumorshasremaineddismaloverthepastdecades, thereisfinally real reason
foroptimismasourknowledgebasegrowsexponentiallylarger.
MostofthemajorareasofthisendeavoraredisplayedinCNSCancer
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
chaptersonincrediblyclevermousemodelsfordecipheringthegeneticwiring
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. Such
vii
viii Foreword
approachesarecomplementedbyotherexperimentalsystemsincludingcelland
tissue manipulation and transplantation, spontaneous tumor occurrence in
other organisms such as dogs 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 prognostic
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
wellandincludeRNAexpressionprofiling,proteomicanalysesofbothtumors
and biological fluids as well as profiling small non-coding RNAs and DNA
modification.Finally,severalchaptersexploreaspectsoftherapeutictargeting
employing small molecules and combinations thereof, various sorts of cells,
viruses,and immunemodulation.Insum,these treatisesrepresentthecutting
edge of research that is driven to be of benefit to patients with these dreaded
diseases.
TheaudiencethatwillbenefitfromtheinformationcontainedinCNSCancer
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
mosttimelyinformationfromleadersinthebattleagainstCNStumorsandits
timeliness fills a niche in a manner that is accessible and contemporary. The
authorsandespeciallytheeditor,Dr.ErwinVanMeir,aretobecongratulated
forprovidingthisservicetothecommunity.
SanDiego,CA WebsterK.Cavenee,Ph.D.
Preface
Theseareexcitingtimesinneuro-oncology.BythetimethisbookispublishedI
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
approachestothebraintumortreatmentandinvestigation.Treatmentoptions
were limited to surgery, radiotherapy, and a few modestly effective
chemotherapeuticagentssuchasBCNU.Overtheensuingdecades,the neuro-
oncologyfieldhasexpandedandtraversedanumberof‘‘waves’’,eachofwhich
wasexpectedtoyieldarapidcure.The1980susheredinresearchthattappedinto
the power of the immune system and promised immunotherapies, whether
antibody-based or cell-based. When I entered the field there was a strong
interestinidentifyingautocrinegrowthfactorsthatdrivetumorgrowthandthe
earlygroundbreakinggeneticstudieswerebeingperformed.Amplificationofthe
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
oftumorsuppressorlocionchromosomes9,10,and17.In1989,thep53genewas
identifiedasthetumorsuppressorlostfromchromosome17inglioblastomaand
othercancers.In1993thep16cellcycleinhibitorwasdescribedandin1997the
PTENphosphatasewasdiscoveredasacriticalgeneproductlostduetogenetic
alterationsonchromosome10.Geneticdiscoveriesingliomaspearheadedtheuse
of similar technology for the discovery of new signaling pathways in
medulloblastoma,meningioma,ependymoma,andotherbraintumors.
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-
ducedinclinicaltrials,yetledtonewgenerationsofvirotherapythroughtheuse
ofoncolyticviruses.Thedefinitionofangiogenicmechanismsandthediscoveryof
endogenous negative regulators of these processes have led directly to clinical
applications in which tumoral blood vessels are targeted by anti-angiogenic
therapies,astrategywhichisbearingfruitwithanti-VEGFantibodies.
ix
x Preface
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 impact of these discoveries
is in full bloom for glioblastoma multiforme with The Cancer Genome Atlas
(TCGA), an unprecedented, NIH-sponsored, effort to identify every possible
genetic and epigenetic alteration and gene expression change in 500
glioblastoma specimens. The initial results of the TCGA Research Network
aswellasanindependentefforttosequenceallgenesin22glioblastomahave
justbeenpublished.Theseimportantstudieshaveshownthat,notsurprisingly,
this disease is complex, with up to 60 mutated genes per tumor. Fortunately,
thesegenescanbedistilledtoalessernumberofpathwaysthatmaketheirstudy
morepalatable.Studying60genes,andevenfewerpathways,iscertainlyeasier
than30,000!Weknowthatwithenougheffortandresearchteamsfocusingon
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
imagingwillbenefitinthenearfuturefromtheemergenceofnanotechnology.
Independently,thelastdecadehasbroughtmajordiscoveriesoncelllineages
inthecentralnervoussystemandthedifferentiationeventsthattakeplacefrom
stem cells to neurons, astrocytes, and oligodendrocytes. The application of
markers identified in normal CNS development to the understanding of
tumorheterogeneitygavebirthtothe‘‘cancerstemcellhypothesis’’,aconcept
thathaspromotedarethinkingofthebasictenetsinoncologyandhasblended
thestudyofcancerandneuroscience.Thespeedofdiscoverysummarizedabove
is remarkable and gives no hint of slowing down. Many of these exciting
developmentsaredescribedwithinthisbook.
Todaytheprognosisofmalignantbraintumors,suchasglioblastoma,isstill
dismal,butwhathaschangedisthatthereisrealhopeforacure.Theresearch
effortstoucheduponaboveanddescribedinmuchmoreeloquentfashionbythe
authorsinthisbookarebearingfruit.Newbiomarkersandtherapeutictargets
are being identified. We are seeing successful therapies emerge from the use of
antibodies and cytotoxins, signaling pathway-targeted small molecules, anti-
angiogenesisstrategies,betteruseof‘‘old-fashioned’’alkylatingdrugsfollowing
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
devotedtopresentacomprehensiveselectionofthemodelscurrentlyavailable.
The light at the end of the tunnel is becoming visible. It is encouraging to
witness, and exciting to participate in, the dramatic improvements in brain
tumortreatmentthatarebeingmade.
Atlanta,GA ErwinG.VanMeir
March,2009
Editor
ErwinG.VanMeirisProfessorofNeurosurgeryandHematology&Medical
OncologyintheSchoolofMedicineatEmoryUniversity.AnativeofBelgium,
heobtainedBachelor’s degrees inBiologyandEducationattheUniversityof
Fribourg,Switzerland. HepursuedgraduatestudiesinMolecular 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
CancerResearchinSanDiego.In1994hewasgrantedhisfirstFacultyposition
as Director of the Laboratory of Brain Tumor Biology and Genetics in the
Neurosurgery Department at the University of Lausanne. In 1998 he joined
EmoryUniversityinAtlanta,wherehenowservesastheLeaderoftheWinship
CancerInstituteMolecularPathwaysandBiomarkersscientificprogramandis
co-DirectoroftheBrainTumorResearchGroup.
For the past 20 years Dr. Van Meir’s research has focused on defining the
biologicalsignificanceofspecificgeneticalterationsforbraintumordevelopment.
Heisparticularlyinterestedinhowtumorsdivertextracellularsignalsregulating
heterotypic cell communication for their own benefit such as occurs in tumor
angiogenesis, and in translating this new knowledge into novel therapeutic
approaches. His research is described in more than 140 peer-reviewed research
papers and review articles in internationally recognized journals that have
cumulatedover5,000 citationsand received severalawards.Thesecontributions
were presented in over 100 invited seminars worldwide 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
braintumorangiogenesis,hypoxia,andpseudopalisadingnecrosisformation.He
alsodiscoveredbiomarkersinthecerebrospinalfluidofbraintumorpatientsand
developed novel therapeutic agents including oncolytic hypoxia-activated
adenoviruses, pro-apoptotic galectin-3, anti-angiogenic vasculostatins, and small
molecule HIF inhibitors that are covered by several US and foreign patents.
Perhaps most importantly, over his 20-year independent career, Dr. Van Meir
has mentored and trained over 60 postdoctoral fellows, students, and visiting
scientists, many of which now hold independent leading positions in Academia
orIndustry.
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