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Center for Hematology and Oncology Molecular TherapeuticsResearch at the Taussig Cancer Center
clevelandclinic.org/cancer
Cleveland Clinic is at the forefront of the cancer drug
discovery and development revolution. We have
identified new molecules with anti-tumor effects,
developed collaborative ties with biotechnology
companies, begun training more young scientists,
and expanded our base of financial support. These
bold steps will result in discovery and application
of new therapies to help us eliminate cancer as a
significant cause of mortality.
Principal Investigators:
Ernest C. Borden, M.D. Daniel J. Lindner, M.D., Ph.D. Pierre L. Triozzi, M.D.
Jaroslaw P. Maciejewski, Ram Ganapathi, Ph.D. M.D., Ph.D.
CONTENTS
01 Introduction
03 DrugDiscoveryand
Development
05 BordenLaboratory
07 LindnerLaboratory
09 TriozziLaboratory
11 ExperimentalHematology
andHematopoiesis
13 ClinicalPharmacology-
ExperimentalTherapeutics
As a result of our improved understanding of the human genome and its significance for cancerbiology,wehavefoundabnormalitieswithinthemalignantcellthatpresentmoretargetsforwhichnewdrugsanddiagnosticscanbedeveloped.
InvestigatorswithintheCenterforHematologyOncologyMolecularTherapeutics(CHOMT)and the Taussig Cancer Center will continue to translate these findings into bedside applications.Theultimateresultwillbeahighercurerateforcancerand,itishoped,fewertreatmentsideeffects.
TheuniquefeatureofCHOMTisitsintimaterelationshipwiththephysiciansandsupportstaffof the Taussig Cancer Center, which facilitates the delivery of “first in man” studies and the translationofideasfromthelaboratorytotheclinic.
DerekRaghavan,M.D.,Ph.D.,FACPM. Frank & Margaret Domiter Rudy Distinguished Chair; Director, Taussig Cancer Center; Chairman, Cancer Division, Cleveland Clinic
From the Director
Cleveland Clinic Taussig Cancer Center Center for Hematology and Oncology Molecular Therapeutics
Taussig Joins Case Comprehensive Cancer Center
In 2004, the Taussig Cancer Center finalized a partnership with Ireland
CancerCenterandCaseWesternReserveUniversitytoformathirdpartof
theNCI-designatedCaseComprehensiveCancerCenter.Thispartnership
strengthenedthetechnologiesforbasicresearch,increasedcollaborative
researchopportunities,facilitatedanenlargedclinicaltrialsprogram,and
enhancedexternalfundingopportunities.Anotherimportantpartnerindrug
discoveryanddevelopmentinitiativesistheClevelandClinicLernerResearch
Institutewhosescientistsworkonmanycommonandcomplementary
projectswiththeinvestigatorsatTaussig.
clevelandclinic.org/cancer 1
The Center for Hematology and Oncology Molecular Therapeutics (CHOMT)wasformedin2005,spurred
by a surge in both human and financial resources for therapeutic and diagnostic bench research on new
therapeuticsandtheirtargets.TheCentercomprisessixresearchlaboratoriesfocusingondrugdiscovery
anddevelopment,clinicalpharmacologyandexperimentaltherapeutics,andexperimentalhematology
andhematopoiesis.
Designedasapremiertranslationalmolecularresearchunit,CHOMT will enhance the scientific and academic
statureoftheClevelandClinicTaussigCancerCenter,produceanewgenerationofphysicianscientistsand
augmentavailabilityofnewdiagnosticandtherapeuticmodalitiesforourpatients.
Withintheirindividuallaboratories,CHOMTinvestigatorsarefocusedonbuildingupontheremarkableadvances
inmolecularbiologicaltechniquesofthelast30years.Theseadvancesarebeingappliedtonewpharmaco-
logical,immunological,biologicalandcellularapproachestotherapeuticsanddiagnostics.Togetherwiththeir
colleaguesatLernerResearchInstitute,particularlyinthedepartmentsofCancerBiology,CellBiology,
ImmunologyandMolecularBiologyandGenetics,newtherapeuticanddiagnosticapproachesbased
on targeting specific genes and gene products are emerging into preclinical and clinical development.
Frominception,thestrategicapproachofresearchprogramswithintheTaussigCancerCenterlaboratoriesis
the translation of research findings from bench to clinic and the pursuit of clinical observations at the bench.
Research on new drugs and diagnostics targeted at defined molecular structures will continue to increase both
qualityoflifeandlengthoflifeforpatients.Ourvisionistocreateanenvironmentofscholarshipforadvancing
knowledgetowardcurativetreatmentforourpatients.Thefollowingareexamplesofourresearchactivities
and advancements as we work to discover and translate laboratory findings into clinical trials and, ultimately,
reducecancermorbidityandmortality.WearepositioningCHOMTtobecomeoneofthemajorcentersinthe
worldforresearchonbiologicallytargetedtherapeutics.
Inaddition,ClevelandClinicparticipatesintheSouthwestOncologyGroup,RadiationTherapyOncologyGroup,
Children’sOncologyGroup,Blood-BrainBarrierConsortium,NewApproachestoBrainTumorTherapyandthe
GynecologicOncologyGroup.Throughphysicianparticipation,cancerpatientshaveaccesstoavarietyof
clinicaltrialsinvestigatingnoveltherapeutics.
Introduction
Cleveland Clinic Taussig Cancer Center Center for Hematology and Oncology Molecular Therapeutics
Collaboration
clevelandclinic.org/cancer 3
Drug Discovery and Development
CHOMTwasanaturaloutgrowthoftheCenterforCancerDrugDiscoveryandDevelopment,foundedin1998
attheTaussigCancerCenter.Itenlargedourscopeofactivitiestobuildforthefuturebutremainsfocusedon
asimplemission:tobringcancerpatientsnew,novelandeffectivedrugsforcancertreatment.Theintentis
todiscoveranddeveloptherapeuticswithaparticularfocusonbiologicalagentstargetedatgenesorgene
productsthatdeterminethecourseofcancerdevelopment.Weaimtotranslateinnovativeapproachesinto
rigorousclinicaltrials,thusofferingphysiciansnewmethodsofcombatingcancer.Thecenterprovidesafocus
forinvestigationofnewmoleculesinpreclinicalscreeningsystemsandtotranslatetheinformationaboutnovel
cancer-relatedmoleculestoclinicaltrials.Byusingtheprinciplesofpharmacologyandtheknowledgeofcancer
biology,wedesignanddevelopnewcompoundsorcombinationsofnewbiologicallytargetedcompoundsthat
willreducemorbidityfromoldertreatmentsandreduceboththecomplicationsandmortalityfromcancer.
Someofthesemoleculeshavealreadyprogressedintoclinicaltrialsinourambulatoryclinicsandatthe
NIH-fundedGeneralClinicalResearchCenteratClevelandClinic.
Weuseinnovativebiostatisticalmethodologiestoexpediteevaluationofdrugtherapies.Oureffortsinclude
thedevelopmentofonlinenetworkstoacquireclinicaldataforrapid,comprehensiveanalysis.Collaborationis
key.InadditiontothoseatLernerResearchInstituteandCaseComprehensiveCancerCenter,preclinicaland
clinicalresearchonnewmoleculesisunderwayinassociationwithorganizationsandcompaniesinChina,
Switzerland,IsraelandacrosstheU.S.These,andcollaborationswithbiotechnologycompaniesinCleveland
andacrosstheU.S.providenewdrugsthatinhibittumorcellgrowth.Thus,asadvancesfromCHOMTare
ready for the more advanced stages of clinical trials, Phase II and Phase III, a rapid and efficient process can
be initiated for the final steps in bringing new drugs to patients. Our objectives are to develop innovative drug
screeningtechnologieswhilecontinuingourresearchinthedesignofsmallmoleculestargetedatcellular
signaltransduction.Weaimtousenormalprogrammedcelldeath(apoptosis)asameansbywhichtocurtail
tumor development through induction of identified genes. Over the next few years, new investigators will be
recruitedforCHOMTtoaddtoexistingexpertise.
Linkingresearchtocure,thecenteriscontributingtotheemergenceoftheTaussigCancerCenterasoneof
theleadingcancerresearchcentersinthecountry.
Collaboration
Cleveland Clinic Taussig Cancer Center Center for Hematology and Oncology Molecular Therapeutics
Evolution
CTscansofapatientwithmetastaticrenalcarcinomasuccess-
fullytreatedattheTaussigCancerCenterwithanewtypeof
interferonbeinginvestigatedinCHOMTlaboratories.(A)Chest
CTatbaselinedemonstratingrightupperlobepulmonary
metastasis.(B)RepeatCTshowingnearresolutionofmetastatic
lesion.(C)AbdominalCTatbaselinedemonstratingtense
ascites.(D)AbdominalCTafter12weeksoftherapyshowing
reductioninascites.Inadditiontotumorresponse,studies
demonstrateincreasedinterferon-stimulatedgenesandbetter
patienttolerancewiththistypeofinterferon.Theresearchisa
collaborativeeffortbetweentheMinistryofHealthinShanghai,
whichproducestheinterferonbyrecombinantDNAtechnology,
andCHOMT,conductedasanFDA-approvedinvestigationaltrial.
A B C D
clevelandclinic.org/cancer 5
Interferons(IFNs)haveprovenanimportantparadigmforestablishingtheroleofbiologicalsaseffective
therapyinhumanmalignancies.IFNsarepossiblythemostpotentmodulatorsofgeneexpressionusedin
clinical medicine. Through gene profiling, our laboratory and others have identified over 300 IFN-stimulated
genes that influence apoptosis, immune responses and angiogenesis, and are induced in expression by IFNs.
These newly identified genes may be particularly critical in mediating the anti-tumor effects of not only IFNs but
alsoothercancertherapeutics.Asaresultofgenemodulation,IFNsareaprototypefortherapeuticsthatwork
throughregulationofcellularsignalingpathways.Despitesubstantialprogress,westilldonotunderstandthe
underlyingmechanismsoftumorsensitivityandresistance.HowtoovercomeresistancetoIFNsandother
cytokinesinnon-respondingpatientswithmelanomaandothermalignancieshasbeenlittleexplored.
Our goal is to define defects in expression or activation of signal transduction components and extend our studies
ofinterventionstocorrectabnormalities.TheseincludestudiesofreversalofsilencingofIFN-stimulatedgenesby
methylationoftumorDNAandtoenhancetheeffectivenessofIFN-stimulatedgenesbyinhibitionofsignaling
phosphatases.Todetermineeffectivenessoftheseapproaches,inadditiontostudiesatthelaboratorybench,we
areassessingIFN-stimulatedgenesinpatientsreceivingIFNsandotherbiologicallytargetedtherapeutics.We
anticipatethatthesestudieswilltranslateintomoreeffectivetherapieswithIFNsandothercytokines.
Borden LaboratoryPrincipal Investigator: Ernest C. Borden, M.D.
Malahov MP, Kim K, Malakhova OA, Jacobs BS, Borden EC,ZhangD.High-throughputimmunoblotting-ubiquitin-likeproteinISG15 modifies key regulators of signal transduction. J Biol Chem. 2003;278:16608-16613.
Leaman DW, Ozdemir A, Chawla-Sarkar M, Borden EC. Novelgrowthanddeath-relatedIFNstimulatedgenes(ISGs)inmelano-ma:GreaterpotencyofIFN-betacomparedtoIFN-alpha.JInter-feron&CytokineRes.2003;23:745-756.
Chawla-SarkarM,BaeSI,ReuFJ,JacobsBS,LindnerDJ,BordenEC.Down-regulationofBcl-2,FLIP,orIAPs(XIAPandsurvivin)bysiRNAs sensitizes resistantmelanomacells toApo2L/TRAIL-in-ducedapoptosis.CellDeathDiffer.2004;11:915-923.
WengDE,MasciPA,RadkaSF,JacksonTE,WeissPA,GanapathiR,ElsonP,CapraWB,ParkerVP,SandbergJA,CowensJW,Us-manN,BordenEC.AphaseIclinicaltrialofaribozyme-basedangiogenesisinhibitortargetingVEGFR-1forpatientswithrefrac-torysolidtumors.MolCancerTher.2004;4:948-955.
RohatinerAZS,GregoryWM,PetersonB(CALGB+ECOG),Bor-denE (ECOG),Solal-CelignyP (GELA),HagenbeekA (EORTC),Fisher RI (SWOG), Unterhalt M (GLSG), Arranz R (LNH-PRO),ChisesiT,AvilesA,ListerTA.Ameta-analysistoevaluatetheroleof interferon (IFN-a2) in follicular lymphoma. J Clin Oncol.2005;23:2215-2223.
ReuFJ,LeamanDW,MaitraRR,BaeSI,CherkasskyL,FoxMW,RempinskiDR,BeaulieuN,MacLeodAR,BordenEC.ExpressionofRASSF1A,anepigeneticallysilencedtumorsuppressor,over-comes resistance to apoptosis induction by interferons. CancerRes.2006;66:2785-2793.
FanK,ZhouM,PathakMK,LindnerDJ,BordenEC,YiT.SodiumstibogluconateinteractswithIL-2inanti-RencatumoractionviaaTcell-dependentmechanisminconnectionwithinductionoftu-mor-infiltrating macrophages. J Immun. 2005;175:7003-7008.
Publications:
Cleveland Clinic Taussig Cancer Center Center for Hematology and Oncology Molecular Therapeutics
ImaginationDrs.JosephBauerandDanielLindnerwererecentlyawardedanNIHRAID(RapidApplicationtoInterventionDevelopment)awardtofurtherthepreclinicaldevelopmentofnitrosylcobalamin(NO-Cbl).
clevelandclinic.org/cancer 7
Abetterunderstandingofhowinterferons(IFNs)induceapoptosismayallowtheirimprovedclinicalutilization
asanti-tumoragents.IFNsinducecytotoxicityinseveraltumorcelllinesincultureandinvivo.Themechanism
bywhichthisoccursrequiresthefunctionofIFN-inducedgeneproducts.Toidentifyfunctionallyrelevant
death-associatedgeneproducts,thislaboratoryhasemployedanantisensetechnicalknockoutstrategy.
In this approach, specific death-inducing genes, termed Regulators of Interferon-induced Death (RIDs)
areinactivatedbyantisensegeneproducts,thusprovidingagrowthadvantagetotransfectedcellsinthe
presenceofIFNs.Currently,wearestudyingoneofthesegenes,inositolhexakisphosphatekinase2,to
determinehowitpromotesappoptosis.
In order to potentiate their clinical efficacy, IFNs are increasingly being utilized in combination therapy. In col-
laborationwithDr.ErnestBorden’slaboratory,ourresearchhasshownthatcombinationofIFNswithanti-es-
trogenssuchastamoxifenorwithretinoidssuchasall-transretinoicacidresultsinenhancedanti-tumoreffects,
bothincellcultureandinxenograftmodels.Partoftheincreasedanti-tumoractivityisduetodirectanti-cellular
effectsmediatedbythedrugcombination,andaportionoftheanti-tumoreffectissecondarytoenhancedhost
effects.Oneofthemostimportantanti-tumoreffectsmediatedbyIFNsistheinhibitionoftumor-inducedangio-
genesis.Onamolarbasis,IFNsarethemostpowerfulanti-angiogenicagentscurrentlyknown.
Ourlaboratoryisalsoactiveintheareaofcancerdrugdevelopment.Dr.JosephBauerhassynthesizedanovel
chemotherapeuticcompound,nitrosylcobalamin(NO-Cbl),thatconsistsofnitricoxideboundtovitaminB12.
NO-Cbl acts as a “Trojan Horse,” and we believe this approach may target tumors through their high require-
mentforvitaminB12.TherecentRAIDawardfromNIHwillmoveNO-CbIrapidlytowardclinicaldevelopment.
Lindner LaboratoryPrincipal Investigator: Daniel J. Lindner, M.D., Ph.D.
Lindner,DJ,TaylorKL,ReuF,MasciP,BordenEC.Interferons.InBAChabnerandDLLongo,eds.CancerChemotherapyandBiotherapy.Philadelphia:Lippencott-RavenPress,2005.
Morrison,BH,TangZ,JacobsBS,BauerJA,LindnerDJ.Apo2L/TRAIL induction and nuclear translocation of inositol hexaki-sphosphatekinase2duringIFN-beta-inducedapoptosisinovar-iancarcinoma.BiochemJ.2005;385:595-603.
Chawla-Sarkar,M,BaeSI,ReuFJ,JacobsBS,LindnerDJ,Bor-denEC.DownregulationofBcl-2,FLIPorIAPs(XIAPandsur-vivin)bysiRNAssensitizesresistantmelanomacellstoApo2L/TRAIL-inducedapoptosis.CellDeathDiffer.2004;11:915-923.
Whitmore,MM,DeVeerMJ,EdlingA,OatesRK,SimonsB,Lind-nerDJ,WilliamsBR.Synergisticactivationof innate immunityby double-stranded RNA and CpG DNA promotes enhancedanti-tumoractivity.CancerRes.2004;64:5850-5860.
Markman, M, Belinson J, Webster K, Zanotti K, Morrison B,JacobsB,BordenEC,LindnerDJ.Phase2 trial of interferon-Betaassecond-linetreatmentofovariancancer,fallopiantubecancer, or primary carcinoma of the peritoneum. Oncol.2004;66:343-346.
Chawla-Sarkar,M,BauerJA,LupicaJA,MorrisonBH,TangZ,Oates RK, Almasan A, DiDonato JA, Borden EC, Lindner DJ.
SuppressionofNF-kappaBsurvivalsignalingbynitrosylcobala-min sensitizes neoplasms to the anti-tumor effects of Apo2L/TRAIL.JBiolChem.2003;278:39461-39469.
Chawla-Sarkar, M, Lindner DJ, Liu YF, Williams BR, Sen GC,Silverman RH, Borden EC. Apoptosis and interferons: Role ofinterferon-stimulatedgenesasmediatorsofapoptosis(review).Apoptosis.2003;8:237-249.
BauerJA,MorrisonBH,GraneRW,JacobsBS,BordenEC,andLindnerDJ. Interferonalpha2band thalidomide synergisticallyinhibittumor-inducedangiogenesis.JInterferon&CytokineRes.2003;23:3-10.
BauerJA,BHMorrison,RWGrane,BSJacobs,DabneyS,Gam-ero A, Carnevale KA, Smith DJ, Drazba J, Seetharam B, andLindnerDJ.Effectsof interferonbetaon transcobalamin II-re-ceptorexpressionandantitumoractivityofnitrosylocbalamin.JNatlCancerInst.2002;94:1010-1019.
Lindner, DJ. Interferons as antiangiogenic agents. Curr OncolRep.2002;4:510-514.
Pathak,MK,DhawanD,LindnerDJ,BordenEC,FarverC,andYiT.PentamidineisaninhibitorofPRLphosphataseswithanti-canceractivity.MolCancerTher.2002;1:1255-1264.
Publications:
Cleveland Clinic Taussig Cancer Center Center for Hematology and Oncology Molecular Therapeutics
Progress
clevelandclinic.org/cancer 9
Vaccineshavebeenanattractiveandaggressivelypursuedapproachtothemanagementofcancer.Anumber
ofvaccineshavebeenshowntogenerateimmuneresponsesincancerpatients.Todate,however,therehas
beenlittleevidenceofclinicalactivity.Amajorproblemisthatantigensexpressedbytumorsarepoorimmuno-
gens. Whereas viral antigens are “foreign” and highly immunogenic, tumor antigens are “self antigens,” for
whichahighdegreeofimmunologictoleranceexists.Itisalsobecomingincreasinglyapparentthattumors
canexpresspropertiesthatenablethemtoescapeimmuneresponses.Thislaboratory’sresearch,which
involvespreclinicallaboratorystudiesinanimalmodelsandclinicaltrialsincancerpatients,hasfocused
onhowtoimprovetheabilitytobreaktoleranceanddealwithtumorescapephenomena.
Anincreasingbodyofevidenceindicatesthatwhetherornotimmunetoleranceisbrokenandanti-tumor
Tcellresponsesareeffectivelygenerateddependsonthefunctionofdendriticcells,widelydistributed
antigen-presenting cells that are far more efficient than other antigen-presenting cells in stimulating critical
cellularimmuneresponses.Thislaboratoryisexaminingmethodsofstudyingdendriticcellsubpopulations
andmethodsoftargetingandactivatingdendriticcellsinpatientswithcancer.Thelaboratoryisusinga
novelassaytoidentifyactivatedcirculatingdendriticcells,acellulartargetforCSF-GMfunctionthatleads
toenhancedimmunerecognition.Clinicaltrialsapplyingnovelmethodsofassessingdendriticcellfunction
areinprogressinpatientswithprostatecancer.
Cancervaccinesmimickingvirusesmayprovetobeaneffectiveapproachtobreakingtolerance.Thislaboratory
isstudyingrecombinantviralvectorsencodingfull-lengthtumorantigenstoexploittheinherentimmunogenicity
ofthevirusaswellastheendogenousprocessingandpresentationofseveraltumorantigens.Ourresearchers
alsohavebeenevaluatingtheuseofanon-pathogenicvirus,adeno-associatedvirus,asavaccinevector.
Preclinicalstudiestargetingcarcinoembryonicantigeninmodelsofcoloncancerareinprogress.
Triozzi LaboratoryPrincipal Investigator: Pierre L. Triozzi, M.D.
TriozziPL,KhurramR,AldrichA,WalkerMJ,KimJ,andJaynesS.Intratumoralinjectionofdendriticcellsderivedinvitroinpa-tientswithmetastaticcancer.Cancer,89:2646-2654,2000.
MoultonHM,YoshiharaPH,MasonDH,IversenPL,TriozziPL.Active specific immunotherapy with a ß-human chorionic gona-dotropinpeptidevaccine inpatientswithmetastaticcolorectalcancer:Antibodyresponseisassociatedwithimprovedsurvival.Clin Cancer Res,8:2044-51,2002.
PonnazhaganS,MahendraG,LimaJ,AldrichW,JenkinsC,RenC,KallmanL,StrongTV,ShawDR,TriozziPL.Augmentationofanti-tumoractivityofarecombinantadeno-associatedviruscar-cinoembryonic antigen vaccine with plasmid adjuvants. Hum Gene Ther,15:856-64,2004.
PereboevAV,NagleJM,ShakhmatovMA,TriozziPL,CurielDT,Blackwell JL. Enhanced gene transfer to mouse dendritic cellusingadenoviralvectorscoatedwithanoveladaptermolecule.Molecular Therapy,9:712-720,2004
TriozziPL,BolgerGB,NeidhartJ,RinehartJJ,SalehM,AllenKO,SellersS,andWaddellMJ.Effectofdocetaxelchemothera-pyontheactivityofagonadotropinreleasinghormonevaccinein patients with advanced prostate cancer. The Prostate, 65:316-21,2005.
Triozzi PL, Allen KO, Carlisle RR, Craig M, LoBuglio AF, andConryRM.PhaseIstudyof the intratumoraladministrationofrecombinantcanarypoxvirusesexpressingB7.1andinterleukin-12 in patients with metastatic melanoma. Clin Cancer Res, 11:4168-75,2005.
AldrichW,RenC,WhiteA,ZhouS-Z,KumarS,JenkinsC,ShawDR,StrongTV,TriozziPL,andPonnazhaganS.Enhancedtrans-duction of mouse bone marrow-derived dendritic cells by re-petitive infection with self-complementary adeno-associatedvirus6combinedwithimmunostimulatoryligands.Gene Ther, 13:29-39,2006
Publications:
Progress
Cleveland Clinic Taussig Cancer Center Center for Hematology and Oncology Molecular Therapeutics
Plat
elet
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Improvement in platelet count in a patient with aplasticanemia treated with immunosuppressive therapy
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Improvementinplateletcountinapatientwith
aplasticanemiatreatedwithimmunosuppres-
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Hematologicrecovery(improvementofabsolute
neutrophilcount)inapatientwithsevere
neutropeniaduetolargegranularlymphocyte
leukemia.
Inthispatientpresumedtohavemyelodys-
plasticsyndrome,largegranularlymphocyte
leukemiawasdiagnosedinthelaboratory
andsuccessfullytreatedwithcytoxan.
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In this patient presumed to have MDS, large granular lyphocyte leukemia was diagnosed, in the laboratory andsuccessfully treated with cytoxan.
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TRANSFUSIONS
In this patient presumed to have MDS, large granular lyphocyte leukemia was diagnosed, in the laboratory andsuccessfully treated with cytoxan.
Pioneering
clevelandclinic.org/cancer 11
Researchersinthislaboratoryconducttranslationalinvestigationsofthepathophysiologyofbonemarrowfailure
syndromes,includingaplasticanemia,paroxysmalnocturnalhemoglobinuria,myelodysplasticsyndromesand
relateddiseases.Bonemarrowfailuresyndromes,asstemcelldisorders,areinstructivewithregardtothefunc-
tionofthestemcellcompartment,factorsthatregulatebloodcellproductionandcausesofmalignantclonal
diseasesofthehematopoieticsystem.Twopathophysiologicaspectsarethefocusofourresearch:defective
hematopoieticstemcellfunctionanditsconsequencesandimmunepathogenesisofstemcelldamage.
Inaplasticanemia,stemcelldestructionismediatedbycytotoxicTcells.Weareemployingmolecularmethods
ofTcellreceptor(TCR)analysistoidentifyandcharacterizeautoimmuneTcellclones.TheirTCRclonotypes
havediagnosticutility,andresearchersaredevelopingtestsforautoimmuneconditionsbasedonthemeasure-
ment of the frequency of the pathogenic clones in blood and tissues affected by the disease. Identification of
expandedTcellsclonesbasedontheiruniqueTCRstructurecanalsobeappliedtostudyanti-tumorimmune
surveillancesuchasthatseenfollowingallogeneicbonemarrowtransplantationintheformofthegraftversus
leukemiaeffect.Usingthistechnology,variousstudiesareconductedinclonalTcellmalignanciessuchaslarge
granularlymphocyteleukemia,hairycellleukemiaandTcelllymphomas.
Defectivestemcellfunctionmayresultnotonlyinaplasticanemiabutalsoinotherhematologicconditions.
Myelodysplasticsyndromeoftenevolvesfromaplasticanemia.Geneticdamageisakeyaspectinthepatho-
genesisofmyelodysplasiathatoftenprogressesintoleukemia.Duetothehighincidenceofthisconditionin
theelderly,ourstudiesalsodealwiththefunctionofstemcellcompartmentinage.Stemcellsenescence
andexhaustioninageorduringdiseaseareimportanttargetsofthislaboratory’sinvestigations,conducted
usinghigh-densityexpressionandSNP-arrays.
Experimental Hematology and Hematopoiesis
Principal Investigator: Jaroslaw P. Maciejewski, M.D., Ph.D.
WlodarskiMW,GondekLP,NearmanZP,PlasilovaKalaycioM,MaciejewskiJP.Molecularstrategiesfordetectionandquantita-tionofclonalcytotoxicTcellresponsesinaplasticanemiaandmyelodysplasticsyndrome.Blood.2006EpubApr.13,2006.
SchadeAE,PowersJJ,WlodarskiMW,MaciejewskiJP.Phosphatidylinositol-3-phosphatekinasepathwayactivationprotectsleukemiclargegranularlymphocytesfromundergoinghomeostaticapoptosis.Blood.2006;107(12):4834-4840.
WlodarskiM,O’KeefeCL,HoweE,RodriguezA,WarshawskyI,LoughranT,MaciejewskiJP.PathologicclonalcytotoxicTcellresponses-nonrandomnatureoftheTcellrecep-torrestrictioninlargegranularlymphocyteleukemia.Blood.2005;106(8):2769-2780.
RisitanoAM,MaciejewskiJP,GreenS,PlasilovaM,ZengW,YoungNS.Invivodominantimmuneresponsesinaplasticanemiapatients:moleculartrackingofputativelypathogenicTcellclonesby TCRß-CDR3 sequencing. Lancet. 2004;364:355-364.
SzpurkaH,TiuR,MurugesanG,DolaS,HsiED,TheilKS,SekeresMA,MaciejewskiJP.Refractoryanemiawithringedsideroblastsassociatedwithmarkedthrombocytosis(RARS-T),anothermyeloproliferativeconditioncharacterizedbyJAK2V617Fmutation.Blood.EpubJune1,2006.
O’KeefeCL,PlasilovaM,RisitanoAM,RodriguezAR,WlodarskiM,YoungNS,MaciejewskiJP.MolecularanalysisofTcellreceptorclonotypesinLGL-aclonalmodelforpolyclonalresponses.JImmunol.2004;172:1960-1969.
ZengW,ChenG,ZengW,BillingsE,YoungNS,MaciejewskiJP.GeneexpressioninducedinCD34cellsbyInterferon-g,identification of cytokine-specific profiles in immune-mediated bonemarrowfailure.Blood.2006;107(1):167-175.
SloandEM,ScheinbergP,MaciejewskiJP,YoungN.Successfultreatmentofpureredaplasiawithanti-IL-2receptorantibody(daclizumab).AnnInternMed.2006;144:181-185.
Publications:
Cleveland Clinic Taussig Cancer Center Center for Hematology and Oncology Molecular Therapeutics
Invention
clevelandclinic.org/cancer 13
This laboratory is focused on finding a key in biochemical change in phosphorylation of topoisomerase II,
aDNAreplicationenzyme,fortherapeuticactivitiesofthechemotherapies,doxorubicinoretoposide.Aclassic
example of translating research findings into clinical care, this discovery may lead to development of an
antibodythatmightbepredictiveoftherapeuticresponsetotopoisomeraseIIinhibitors.
IntheareaofClinicalPharmacology-ExperimentalTherapeutics,researchcurrentlyisbeingconductedin
theregulationoftopoisomerasesduringcellgrowthanddifferentiation,thegoalofwhichistodetermine
the regulatory function of topoisomerase II∂ and ß as downstream effectors of all trans retinoic acid in cell
growthanddifferentiation.Intheareaofmolecularpharmacologyoftopoisomeraseinhibitors,researchers
are testing the functional role of site-specific phosphorylation of topoisomerase II isozymes in cell prolifera-
tionanddrugstabilizedDNAcleavablecomplexformation.Finally,novelagentsforthetreatmentofcancer
arebeingevaluatedduringPhaseIandPhaseIItrialsinpatients.Promisingpre-clinicalleadsareactively
being pursued in translational studies to maximize efficacy and reduce toxicity of cancer chemotherapy.
Clinical Pharmacology- Experimental Therapeutics
Principal Investigator: Ram Ganapathi, Ph.D.
AoyamaM.,GrabowskiDR,IsaacsRJ,KrivacicKA,RybickiLA,BukowskiRM,GanapathiMK,HicksonID,GanapathiR.Alteredexpressionandactivityoftopoisomerasesduringalltransretin-oic acid induced differentiation of HL-60 cells. Blood.1998;92:2863-2870.
TabataM,TabataR,GrabowskiDR,BukowskiRM,GanapathiMK,GanapathiR.RolesofNF-kBand26Sproteasomeinapop-totic cell death induced by topoisomerase I and II poisons inhuman non-small cell lung carcinoma. J Biol Chem.2001;276:8029-8036.
Chikamori K, Grabowski DR, Kinter M, Willard BB, Yadav S,AebersoldRH,BukowskiRM,HicksonID,AndersenAH,Ganap-athiR,GanapathiMK.PhosphorylationofSerine1106 in theCatalytic Domain of Topoisomerase II∂ Regulates Enzymatic Ac-tivity and Drug Sensitivity. J Biol Chem. 2003;278:12696-12702.
Publications:
Cleveland Clinic Taussig Cancer Center Center for Hematology and Oncology Molecular Therapeutics
Taussig Cancer Center: One of the Nations Best
TheClevelandClinicTaussigCancerCenterisrecognizedbyU.S.News & World Report asoneof
thetop15cancercentersinthecountryandtheNo.1cancercenterinOhioinitsannualhospital
survey.The2006surveyalsorankedClevelandClinicthe3rdbesthospitalinthecountry.
Fordetails,visitclevelandclinic.org.
The Cleveland Clinic Taussig Cancer Center, whichwasdedicatedinJuly2000,isoneofthe
world’snewestandmostadvancedcenterforcancertreatment,researchandeducation.Designed
byworld-renownedarchitectCesarPelli,the$50millionfacilityoccupies165,000squarefeet
on Cleveland Clinic’s main campus. Two hundred fifty physicians at Cleveland Clinic in a variety
ofspecialtiesareinvolvedinthetreatmentofcancer,andscoresofbasicandclinicalresearch
projectsareunderwayhereatanygiventime.
The Cleveland Clinic Lerner Research Institutehousesstate-of-the-artresourcesforscientists
astheyinvestigatethecausesofdiseaseanddevelopnewtreatmentstoprolongandimprove
thelivesofpatients.Theinstituteoverseesmorethan1,000researchprojectswithabudgetof
over $124 million. Four-fifths of this budget are received from external grants and contracts —
adramaticendorsementforthequalityofClevelandClinicresearch.Residentsandfellows
arefrequentlyinvolvedintheseprojects.
clevelandclinic.org/cancer 15
sixresearchlaboratories focusingondrug
discovery anddevelopment, clinical phar-
macology and experimental therapeutics,
andexperimentalhematologyandhemat-
opoiesis.
From inception, the strategic approach of research programs within
the Taussig Cancer Center laboratories have focused on translation
of research findings from bench to clinic and the pursuit of clinical
observations at the bench. This research on new drugs and diagnostics
targeted at defined molecular structures will continue to increase both
quality of life and length of life of patients at Cleveland Clinic
and worldwide.
For more information on collaboration, training opportunities or clinical
trials, please call Dr. Ernest Borden at 216.444.8183 or 800.553.5056,
ext. 48183, or any of the other investigators through these numbers.
Our vision is to create a premier translational molecular research unit that
will enhance the scientific and academic stature of the Taussig Cancer
Center, produce a new generation of physician scientists, and augment
availability of new diagnostic and therapeutic modalities for our patients.
For more information, visit the Taussig Cancer Center Web site at
clevelandclinic.org/cancer.
05-CNR-015