Table Of ContentVolker A. Erdmann
1
Guido Reifenberger
Jan Barciszewski
Editors
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123
Therapeutic Ribonucleic Acids in Brain Tumors
Volker A. Erdmann Guido Reifenberger
l
Jan Barciszewski
Editors
Therapeutic Ribonucleic
Acids in Brain Tumors
Editors
Prof.Dr.VolkerA.Erdmann Univ.Prof.Dr.GuidoReifenberger
FUBerlin UniversitätsklinikumDüsseldorf
Inst.ChemieundBiochemie Inst.Neuropathologie
Thielallee63 Moorenstr.5
14195Berlin 40225Düsseldorf
Germany Germany
[email protected] [email protected]
Prof.Dr.JanBarciszewski
PANPoznan
Inst.BioorganicChemistry
ul.Z.Noskowskiego12/14
61-704Poznan
Poland
[email protected]
ISBN978-3-642-00474-2 e-ISBN978-3-642-00475-9
DOI:10.1007/978-3-642-00475-9
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Preface
Althoughprimaryneoplasmsofthecentralnervoussystemcollectivelyaccountfor
only 2–3% ofallhuman malignancies,they are neverthelessresponsible forupto
7% of lives lost from cancer before the age of 70. Gliomas are the most common
primarybraintumors,themajorityofwhicharemalignantneoplasmsthatdiffusely
infiltrate the surrounding brain tissue, have an inheriting tendency for recurrence,
andeventuallyleadtodeathbycausingincreasedintracranialpressurefollowedby
central regulatory failure. Glioblastoma multiforme represents the most common
types of gliomas in adults and it is one of the most aggressive human cancers.
Despitemultimodaltreatment,includingneurosurgicalresection,localirradiation,
and systemic chemotherapy, glioblastoma patients presently cannot be cured and
stillfaceanexceptionallypoorprognosisasindicatedbyamediansurvivaltimeof
less than one year in population-based analyses. Furthermore, both tumor growth
and aggressive therapy may harm the brain, which is the organ that defines the
personalselfandisthesourceofbasichumanabilitiessuchasreasoning,remem-
bering, and emotion. Thus, glioma patients often experience profound changes in
their neurological and cognitive abilities, which in turn may dramatically reduce
theirqualityoflife.Thepoorprognosisofpatientswithmalignantgliomaurgently
callsforthedevelopmentofnovel,moreeffectivebutlessneurotoxic,treatments.
Atthesametime,newmolecularmarkersareneededtofacilitateanindividualized
therapyandhelptostratifypatientsintothebestavailabletreatmentregimens.To
achievetheseimportantgoals,abetterunderstandingofthemolecularandcellular
pathmechanismsinvolvedintheinitiationandmalignantprogressionofgliomasis
an indispensable prerequisite. Fortunately, molecular studies over the past two
decades have identified a variety of chromosomal, genetic, epigenetic, and tran-
scriptional aberrations that are specifically associated with the individual types of
gliomas. In addition, certain molecular aberrations have been linked to therapy
response and patient survival, thereby establishing clinically important predictive
andprognosticbiomarkers.
Themainobjectiveofthisbookistoprovideastateoftheartupdateconcerning
novel molecular and cellular approaches for the treatment of malignant gliomas,
withaparticularfocusontargetedRNA-basedstrategies.Internationallydistinguished
v
vi Preface
expertsworkinginthebasicsciences,neuropathology,andclinicalneurooncology
havecontributedcomprehensivechapterstothisbookcoveringthemajortopicsof
thecurrentresearchinthefield.
Thefirstchapterofthebookismainlyfocusedonrecentprogressinmolecular
neurooncologyandtheclinicalsignificanceofmolecularmarkersinthediagnostic
andprognosticassessmentofgliomas.C.Belda-Iniestaetal.provideanupdateon
themolecularbiologyofmalignantgliomas,includingrecentresultsobtainedfrom
large-scalegeneexpressionprofilingusingmicroarray-basedtechnologies.Inaddi-
tion,theconceptofgliomastemcellsisdiscussed,whichmayhaveverypromising
implications for the future for targeted gliomas treatment and overcoming the
inherentresistancetotherapy.
Novel pathogenesis-based strategies for brain tumor treatment, including anti-
angiogenic approaches, vaccination strategies, cellular therapies, and targeted
inhibition of growth factor receptor pathways, are all topics covered in detail in
thechaptersbyM.HuttererandG.StockhammeraswellasbyK.K.Jain.
A critical review on the role of gene and oncolytic viral therapy for malignant
glioma and the present scientific challenges in this particular field of research is
contributedbyA.M.Sonabendandco-authors.
R.Yamanaka’schapteralsoaddressesgenetherapeuticapproaches,focusingon
theroleofalphaviralvectorsforgliomaimmunotherapy.
The chapter by A.M. Barciszewska and co-authors discusses the changes in
DNA methylation patterns that are associated with glioma progression and their
potentialroleinthediagnosticassessmentofbraintumormalignancy.
M.Eolietal.reportonthecurrentstatusconcerningtheclinicalsignificanceof
molecular markers in gliomas. A particular focus of this chapter is placed on the
prognostic roleofcombined deletion of 1pand 19q inoligodendroglialtumors as
wellastheMGMT promotermethylationstatusasapredictivemarkerforsensiti-
vity to alkylating chemotherapy in glioblastomas. Additional molecular markers
that are addressed include the EGFR, TP53 and PTEN genes, as well as the stem
cell-associatedantigenCD133/prominin-1.
Widegrenetal.usingmicroarrayandproteomicanalysesidentifiedmanygenes
showinginterestingnovelpotentialtargetsaswellasseveralproteinsalreadybeing
investigatedforimmunotherapy.
ThenextpartofthebookisspecificallydevotedtothepotentialrolesofRNA-
based strategies in glioma treatment. D. Schulze and A. Aigner focus on novel
developments concerning nonviral, nanoparticle delivery systems, including lipo-
somal-,lipid-andpolymer-basedstrategiesfortheeffectivetransportofRNAiinto
thebrainandintobraintumors.
Inatreatmentapproachinhumans(Rolleetal.),tenascin-C(TN-C)wasselected
whichhadbeenshownpreviouslytobeupregulatedinglioblastomaandhasbeen
suggested to be correlated with the grade of malignancy and to shorten patient
survival. After surgical resection of the tumor, patients were treated with dsRNA
(ATN-RNA) complementary to a part of the sequence of tenascin-C mRNA.
A significant improvement inoverall survival without losing the quality of life of
thepatientswasobserved.
Preface vii
R.J. Boado and W.M. Pardrige discuss the possibilities for facilitating the
transportofRNAiacrosstheblood–brainbarrier,includingsophisticatedmethods
suchasthe“TrojanHorseLiposome”technology,whichisbasedonimmunolipo-
somescarryingshRNAexpressionplasmidsforRNAitransfer.
Thechaptersby A.E.Lovett-Racke aswell asbyS.P.Mathupalaet al. provide
moregeneraloverviewsonthetherapeuticpotentialofRNAiforbraindiseasesand
outlinepotentialstrategiesfortheeffectivetherapeuticapplicationofRNAi-based
methodsintheclinicalsetting.Sinceprimaryglioblastomasfrequentlyshowgene
amplification, rearrangement and overexpression of the epidermal growth factor
receptor (EGFR) gene, the EGFR molecule constitutes an interesting target for
specificinhibitionbyantisenseRNAandRNAiapproaches.
The chapter by B. Malzkorn et al. provides a comprehensive overview on the
biogenesisandregulationofmicroRNAsandtheirinvolvementinthepathogenesis
ofprimarybraintumors,suchasgliomas,medulloblastomas,andpituitarytumors.
Aberrations in microRNA expression and function are increasingly being recog-
nizedinbraintumorsandmanyothercancers,withfirstresultssuggestingamajor
impactofmicroRNAprofilesinmoleculartumorclassification.Inaddition,modu-
lationofmicroRNAactivitymaybeapromisingnewapproachfortargetedcancer
therapy.
The following chapters in the book deal with treatment options for malignant
gliomas, ranging from the standard combined modality therapy to a variety of
experimental preclinical and early clinical treatments. The current standard of
care for high-grade glioma patients is summarized by J. Drappatz et al., who
illustrate ongoing therapeutic approaches selectively targeting signaling pathways
thatareknowntobeaberrantinmalignantgliomas.
Targeted therapy of gliomas using oligonucleotides is the topic of the chapters
byP.Jachimczaketal.andT.Schneider.P.Jachimczaketal.provideinformation
onantisenseoligonucleotide-basedstrategiesthatarealreadyinclinicaltrials.For
example, ongoing prospective trials evaluate the tolerability and efficacy of adju-
vant treatment directed against transforming growth factor beta in patients with
high-grade gliomas. T. Schneider’s chapter outlines the general strategy of anti-
sense oligonucleotide-based treatments and discusses promising gene targets that
areaberrantlyactivatedinmalignantgliomas.
ThechapterbyP.Puetal.alsoaddressesthisissueandinadditiondiscussesthe
possibility of combining conventional therapy with siRNA-based inhibition of
aberrantlyactivatedoncogenesinmalignantgliomas.
It is known that noncoding RNAs (ncRNAs) are important components of
regulatory networks governing gene expression in all organisms. M. Szymanski
describes many ncRNAs which regulate key processes associated with the devel-
opmentandmaintenanceofspecificgeneexpressionprofiles.Inadditionitisshown
thatalsointhenervoussystemmanyvariousclassesofncRNAsexistwhichplaya
roleinneuralcellsdifferentiationandactivity.
Y. Fellig et al. address the H19 non-coding RNA gene, which is located at
11p15.5andsubjectedtogenomicimprinting.Theirchapterreportsonchangesof
theH19imprintingstatusandaberrantexpressioninbraintumors,aswellasonthe
viii Preface
relationship of H19 alterations with hypoxia and p53 function. Furthermore,
promisingnewfindingsconcerningH19-mediatedcytotoxicgenetherapy, aswell
as RNAi-based strategies to reduce H19 overexpression in cancer cells, are
discussed.
In summary, this book will be of great interest not only for researchers
working in molecular and translational neurooncology but also for clinicians
involved in the treatment of brain tumor patients. The book provides a state of
the art review concerning the molecular pathogenesis of gliomas and the transla-
tion of these advances into clinical applications, namely the identification of
novel diagnostic, prognostic and predictive biomarkers and the development of
innovative pathogenesis-based therapeutic strategies. However, despite the tre-
mendous advances in the molecular genetics of gliomas, we are still far from
fully understanding the complex mechanisms that underlie tumor initiation and
progression in the individual patient. Nevertheless, recent technological advances
permitever morerefinedandcomprehensive analyses ofthe genomic,epigenetic,
transcriptional, and proteomic changes associated with the individual types and
malignancy grades of gliomas. First results obtained from systematic genomic
and expression profiling studies already provided interesting novel markers and
signatures, which most likely will refine glioma diagnostics and help to guide
therapy. A better knowledge of glioma pathomechanisms facilitates the rational
design of therapies targeting specific cell populations, such as the glioma stem
cells, or cellular mechanisms on which the tumors are dependent for their growth
and progression. In this respect, RNA-based strategies represent promising tools,
which will hopefully help to identify ways of specifically eradicating tumor cells
but leaving the surrounding functional cells of the brain intact.
Berlin,Germany VolkerA.Erdmann
Du¨sseldorf,Germany GuidoReifenberger
Poznan,Poland JanBarciszewski
February2009
Contents
MolecularBiologyofMalignantGliomas ...................................... 1
Cristo´balBelda-Iniesta,RosarioPerona,andJorgeBarriuso
MolecularNeurooncologyandNeoangiogenesisof
MalignantGliomas .............................................................. 23
MarkusHuttererandGu¨ntherStockhammer
MolecularTherapiesforMalignantGliomas ................................. 57
MarkusHuttererandGu¨ntherStockhammer
NovelStrategiesfortheTreatmentofBrainCancer ........................ 85
KewalK.Jain
GeneTherapyforMalignantGlioma ....................................... 103
AdamM.Sonabend,IlyaV.Ulasov,KarenDana,
andMaciejS.Lesniak
ImmunotherapeuticApproachforGliomabyAlphaviruses
asPositiveStrandRNAViruses ............................................. 125
RyuyaYamanaka
DiagnosisofBrainTumorsThroughGlobalSpecificDNA
MethylationAnalysis ......................................................... 141
Anna-MariaBarciszewska,StanislawNowak,IwonaGawronska,
andMiroslawaZ.Barciszewska
MolecularMarkersofGliomas .............................................. 157
M.Eoli,A.DiStefano,andG.Finocchiaro
ix
x Contents
MicroarrayandProteomicAnalysisofGliomas:
TargetStrategies .............................................................. 179
BengtWidegren,OscarPersson,XiaolongFan,andLeifG.Salford
NanosystemsfortheDeliveryofRNAi ...................................... 197
DanielSchulzeandAchimAigner
InterferenceRNAInterventioninBrainTumors ........................... 221
KatarzynaRolle,StanislawNowak,ElizaWyszko,MonikaNowak,
RyszardZukiel,RafalPiestrzeniewicz,IwonaGawronska,
MiroslawaZ.Barciszewska,andJanBarciszewski
Blood-BrainBarrierTransportforRNAi .................................. 255
RubenJ.BoadoandWilliamM.Pardridge
TherapeuticPotentialofSmallInterferingRNAforBrainDiseases ..... 275
AmyE.Lovett-Racke
RNAInterference-BasedTherapiesAgainstBrainTumors:
PotentialClinicalStrategies .................................................. 297
SarojP.Mathupala,SandeepMittal,MuraliGuthikonda,
andAndrewE.Sloan
MicroRNA:Biogenesis,Regulation,andRoleinPrimary
BrainTumors ................................................................. 327
BastianMalzkorn,MariettaWolter,andGuidoReifenberger
TreatmentofHigh-GradeGliomasinAdults ............................... 355
JanDrappatz,AndrewD.Norden,andPatrickY.Wen
TreatmentofMalignantGliomaswithAntisense
Oligonucleotides ............................................................... 383
PiotrJachimczak,UlrichBogdahn,andPeterHau
SuppressionofEGFRExpressionbyAntisenseRNAandRNAi ......... 407
PeiyuPu,ChungshengKang,andHaoJiang
BrainTumorTherapywithAntisenseOligonucleotides ................... 425
ThomasSchneider
NoncodingRNAsintheDevelopment,Functionand
PathologiesoftheCentralNervousSystem ................................. 453
MaciejSzyman´skiandJanBarciszewski
TheNon-CodingOncofetalH19GeneinBrainTumors ................... 471
Y.Fellig,D.Amit,I.J.Matouk,J.Kopolovic,V.A.Erdmann,
andA.Hochberg
Index ........................................................................... 485
