Therapeutic Ribonucleic Acids in Brain Tumors PDF
Preview Therapeutic Ribonucleic Acids in Brain Tumors
Volker A. Erdmann 1 Guido Reifenberger Jan Barciszewski Editors TThheerraappeeuuttiicc RRiibboonnuucclleeiicc AAcciiddss iinn BBrraaiinn TTuummoorrss 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 SpringerDordrechtHeidelbergLondonNewYork LibraryofCongressControlNumber:2009926188 #Springer-VerlagBerlinHeidelberg2009 Thisworkissubjecttocopyright.Allrightsarereserved,whetherthewholeorpartofthematerialis concerned,specificallytherightsoftranslation,reprinting,reuseofillustrations,recitation,broadcasting, reproductiononmicrofilmorinanyotherway,andstorageindatabanks.Duplicationofthispublication orpartsthereofispermittedonlyundertheprovisionsoftheGermanCopyrightLawofSeptember9, 1965,initscurrentversion,andpermissionforusemustalwaysbeobtainedfromSpringer.Violationsare liabletoprosecutionundertheGermanCopyrightLaw. Theuseofgeneraldescriptivenames,registerednames,trademarks,etc.inthispublicationdoesnotimply, evenintheabsenceofaspecificstatement,thatsuchnamesareexemptfromtherelevantprotectivelaws andregulationsandthereforefreeforgeneraluse. Product liability: The publishers cannot guarantee the accuracy of any information about dosage and applicationcontained in thisbook.In everyindividualcasethe usermust checksuchinformationby consultingtherelevantliterature. Coverdesign:WMXDesign,Heidelberg,Germany Printedonacid-freepaper SpringerispartofSpringerScience+BusinessMedia(www.springer.com) 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
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