2020
Neoantigen-based EpiGVAX vaccine initiates antitumor immunity in colorectal cancer
Kim VM, Pan X, Soares KC, Azad NS, Ahuja N, Gamper CJ, Blair AB, Muth S, Ding D, Ladle BH, Zheng L. Neoantigen-based EpiGVAX vaccine initiates antitumor immunity in colorectal cancer. JCI Insight 2020, 5: e136368. PMID: 32376802, PMCID: PMC7253020, DOI: 10.1172/jci.insight.136368.Peer-Reviewed Original ResearchConceptsMetastatic colorectal cancerColorectal cancerDNA methyltransferase inhibitorAntitumor efficacyAntigen-specific antitumor immune responsesAntitumor T-cell responsesCancer testis antigen expressionAntitumor immune responseT cell responsesAntitumor immunityCancer vaccinesSurvival outcomesCombination therapyAntigen expressionImmune responseMurine modelCTA expressionCell responsesNeoantigensImproved efficacyTumor cellsVaccineEfficacyGVAXMethyltransferase inhibitor
2018
A novel epigenetic modulating agent sensitizes pancreatic cells to a chemotherapy agent
Thakar M, Hu Y, Morreale M, Lerner L, Lin W, Sen R, Cai Y, Karunasena E, Thakar M, Saggi S, Keer H, Ahuja N. A novel epigenetic modulating agent sensitizes pancreatic cells to a chemotherapy agent. PLOS ONE 2018, 13: e0199130. PMID: 29927979, PMCID: PMC6013229, DOI: 10.1371/journal.pone.0199130.Peer-Reviewed Original ResearchConceptsPancreatic ductal adenocarcinomaDNA methyltransferase 1Chemotherapeutic agent irinotecanEpigenetic modulating agentsPDAC cell linesCell viabilityMechanism of actionSystemic chemotherapyCancer mortalityChemotherapy responseDuctal adenocarcinomaChemotherapy agentsEpigenetic sensitizationModulating agentsGuadecitabineAdditional studiesPancreatic cellsSerial concentrationsRest periodCell linesNanomolar concentrationsImproved responseEpigenetic modulatorsSensitizationMethyltransferase 1
2017
Hypomethylating agents synergize with irinotecan to improve response to chemotherapy in colorectal cancer cells
Sharma A, Vatapalli R, Abdelfatah E, McMahon K, Kerner Z, Guzzetta A, Singh J, Zahnow C, Baylin S, Yerram S, Hu Y, Azad N, Ahuja N. Hypomethylating agents synergize with irinotecan to improve response to chemotherapy in colorectal cancer cells. PLOS ONE 2017, 12: e0176139. PMID: 28445481, PMCID: PMC5405959, DOI: 10.1371/journal.pone.0176139.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic AgentsATP-Binding Cassette TransportersAzacitidineCaco-2 CellsCamptothecinCell AdhesionCell Line, TumorCell ProliferationColorectal NeoplasmsDNA MethylationDNA RepairGene ExpressionGene Expression ProfilingHCT116 CellsHumansIrinotecanLong Interspersed Nucleotide ElementsMiceMice, Inbred NODMice, SCIDConceptsCRC cell linesColorectal cancerMultiple CRC cell linesPhase 1/2 clinical trialCell linesMetastatic colorectal cancerMajority of patientsNOD-SCID miceColorectal cancer cellsSoft agar assayInitial therapyMetastatic settingCytotoxic chemotherapyCRC treatmentClinical efficacyCancer deathTumor regressionClinical trialsDNA demethylating agentVivo xenograftsChemotherapeutic agentsCancer cellsHCT116 cell linesAgar assayChemotherapyEpigenetically altered miR-1247 functions as a tumor suppressor in pancreatic cancer
Yi JM, Kang EJ, Kwon HM, Bae JH, Kang K, Ahuja N, Yang K. Epigenetically altered miR-1247 functions as a tumor suppressor in pancreatic cancer. Oncotarget 2017, 5: 26600-26612. PMID: 28460450, PMCID: PMC5432282, DOI: 10.18632/oncotarget.15722.Peer-Reviewed Original ResearchConceptsCpG island hypermethylationTumor suppressorEctopic expressionPancreatic cancer cellsIsland hypermethylationPancreatic cancer cell linesHuman cancersPutative target genesCancer cell linesNumber of miRNAsChromosome condensation 2Role of miRNAsCell linesMolecular functional roleCancer cellsCpG island methylationPotential tumor suppressorTarget genesEpigenetic alterationsGene expressionMalignant human cancersIsland methylationDirect targetLuciferase reporterFunctional roleCombination epigenetic therapy in metastatic colorectal cancer (mCRC) with subcutaneous 5-azacitidine and entinostat; a phase 2 consortium/stand Up 2 cancer study
Azad NS, el-Khoueiry A, Yin J, Oberg AL, Flynn P, Adkins D, Sharma A, Weisenberger DJ, Brown T, Medvari P, Jones PA, Easwaran H, Kamel I, Bahary N, Kim G, Picus J, Pitot HC, Erlichman C, Donehower R, Shen H, Laird PW, Piekarz R, Baylin S, Ahuja N. Combination epigenetic therapy in metastatic colorectal cancer (mCRC) with subcutaneous 5-azacitidine and entinostat; a phase 2 consortium/stand Up 2 cancer study. Oncotarget 2017, 5: 35326-35338. PMID: 28186961, PMCID: PMC5471058, DOI: 10.18632/oncotarget.15108.Peer-Reviewed Original ResearchConceptsCombination epigenetic therapyMetastatic colorectal cancerRECIST responseCRC patientsMedian progression-free survivalCycles of therapySignificant clinical activityMetastatic CRC patientsProgression-free survivalSubset of patientsM2 days 1Serial tumor biopsiesMulti-institutional studyHistone deacetylase inhibitor entinostatEpigenetic therapyColorectal cell linesSubcutaneous azacitidinePrimary endpointPrior therapyLiver involvementOverall survivalTolerable therapySerial biopsiesColorectal cancerClinical activityDifferential expression of hENT1 and hENT2 in colon cancer cell lines
Liu Y, Zuo T, Zhu X, Ahuja N, Fu T. Differential expression of hENT1 and hENT2 in colon cancer cell lines. Genetics And Molecular Research 2017, 16 PMID: 28218790, DOI: 10.4238/gmr16019549.Peer-Reviewed Original ResearchConceptsColon cancer cell linesCancer cell linesMetastatic CRCColorectal cancerHENT1 expressionCell linesHigh hENT1 expressionLow hENT1 expressionMetastatic colorectal cancerNucleoside analoguesHuman equilibrative nucleoside transporter 1Equilibrative nucleoside transporter 1Real-time polymerase chain reactionDrug-based treatmentQuantitative real-time polymerase chain reactionHuman colon cancer cell linesNucleoside transporter 1Clinical responseMost patientsMetastatic cell linesMetastatic sitesMetastatic tumorsTransporter expression profilesPolymerase chain reactionDifferent drug responses
2015
Epigenetic silencing of neurofilament genes promotes an aggressive phenotype in breast cancer
Calmon MF, Jeschke J, Zhang W, Dhir M, Siebenkäs C, Herrera A, Tsai HC, O'Hagan HM, Pappou EP, Hooker CM, Fu T, Schuebel KE, Gabrielson E, Rahal P, Herman JG, Baylin SB, Ahuja N. Epigenetic silencing of neurofilament genes promotes an aggressive phenotype in breast cancer. Epigenetics 2015, 10: 622-632. PMID: 25985363, PMCID: PMC4622480, DOI: 10.1080/15592294.2015.1050173.Peer-Reviewed Original ResearchConceptsNeurofilament medium polypeptideNeurofilament heavy polypeptideDNA methylation-associated silencingDNA methylation-mediated silencingNeurofilament genesMethylation-mediated silencingMethylation-associated silencingMethylation-mediated inactivationGo/G1 phaseEpigenetic silencingMedium polypeptideEpigenetic inactivationCell cycleMajor subunitBreast cancer cellsCell typesGenesSilencingHeavy polypeptideG1 phaseFunctional significanceCandidate DNAMature neuronsCancer cellsPolypeptideSpectrin Repeat Containing Nuclear Envelope 1 and Forkhead Box Protein E1 Are Promising Markers for the Detection of Colorectal Cancer in Blood
Melotte V, Yi JM, Lentjes MH, Smits KM, Van Neste L, Niessen HE, Wouters KA, Louwagie J, Schuebel KE, Herman JG, Baylin SB, van Criekinge W, Meijer GA, Ahuja N, van Engeland M. Spectrin Repeat Containing Nuclear Envelope 1 and Forkhead Box Protein E1 Are Promising Markers for the Detection of Colorectal Cancer in Blood. Cancer Prevention Research 2015, 8: 157-164. PMID: 25538088, PMCID: PMC4316751, DOI: 10.1158/1940-6207.capr-14-0198.Peer-Reviewed Original ResearchAgedArea Under CurveBiomarkers, TumorCell Line, TumorColorectal NeoplasmsCytoskeletal ProteinsDNA MethylationFemaleForkhead Transcription FactorsHumansMaleMiddle AgedNerve Tissue ProteinsNuclear ProteinsPromoter Regions, GeneticReal-Time Polymerase Chain ReactionROC CurveSensitivity and SpecificityTransfection
2014
Immune regulation by low doses of the DNA methyltransferase inhibitor 5-azacitidine in common human epithelial cancers
Li H, Chiappinelli KB, Guzzetta AA, Easwaran H, Yen RW, Vatapalli R, Topper MJ, Luo J, Connolly RM, Azad NS, Stearns V, Pardoll DM, Davidson N, Jones PA, Slamon DJ, Baylin SB, Zahnow CA, Ahuja N. Immune regulation by low doses of the DNA methyltransferase inhibitor 5-azacitidine in common human epithelial cancers. Oncotarget 2014, 5: 587-598. PMID: 24583822, PMCID: PMC3996658, DOI: 10.18632/oncotarget.1782.Peer-Reviewed Original ResearchConceptsDNA methyltransferase inhibitorImmune gene setsImmune-stimulatory roleCytokines/chemokinesCancer-testis antigensGene expression subsetsMethyltransferase inhibitorEpigenetic therapyHuman epithelial cancersMechanism of actionCancer cell linesPrimary tumorGene Set Enrichment AnalysisImmunomodulatory pathwaysImmune regulationPotential therapyTestis antigensPatient biopsiesSolid tumorsEpithelial cancersMultiple cancersLow dosesTumor expression dataAntigen processingTherapy
2013
Novel Methylation Biomarker Panel for the Early Detection of Pancreatic Cancer
Yi JM, Guzzetta AA, Bailey VJ, Downing SR, Van Neste L, Chiappinelli KB, Keeley BP, Stark A, Herrera A, Wolfgang C, Pappou EP, Iacobuzio-Donahue CA, Goggins MG, Herman JG, Wang TH, Baylin SB, Ahuja N. Novel Methylation Biomarker Panel for the Early Detection of Pancreatic Cancer. Clinical Cancer Research 2013, 19: 6544-6555. PMID: 24088737, PMCID: PMC4310572, DOI: 10.1158/1078-0432.ccr-12-3224.Peer-Reviewed Original ResearchADAM ProteinsADAMTS1 ProteinBiomarkers, TumorCarcinoma in SituCell Line, TumorCell MovementCell ProliferationCpG IslandsDNADNA MethylationDNA-Binding ProteinsEarly Detection of CancerEpigenesis, GeneticFemaleGene Expression ProfilingGene Expression Regulation, NeoplasticHumansMaleMolecular Diagnostic TechniquesPancreatic NeoplasmsPromoter Regions, GeneticProportional Hazards ModelsSensitivity and SpecificitySequence Analysis, DNATranscription FactorsTranscriptomeCHFR silencing or microsatellite instability is associated with increased antitumor activity of docetaxel or gemcitabine in colorectal cancer
Pelosof L, Yerram SR, Ahuja N, Delmas A, Danilova L, Herman JG, Azad NS. CHFR silencing or microsatellite instability is associated with increased antitumor activity of docetaxel or gemcitabine in colorectal cancer. International Journal Of Cancer 2013, 134: 596-605. PMID: 23873170, PMCID: PMC3830586, DOI: 10.1002/ijc.28390.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic AgentsBase SequenceCell Cycle ProteinsCell Line, TumorColorectal NeoplasmsDeoxycytidineDNA MethylationDNA PrimersDocetaxelFemaleGemcitabineGene SilencingHumansMiceMicrosatellite InstabilityNeoplasm ProteinsPoly-ADP-Ribose Binding ProteinsPromoter Regions, GeneticReal-Time Polymerase Chain ReactionTaxoidsUbiquitin-Protein LigasesXenograft Model Antitumor AssaysConceptsTumor growth inhibitionColorectal cancerCombination therapyCHFR methylationCell linesAdditive tumor growth inhibitionBiomarker-selected patient populationsMicrosatellite instabilityGrowth inhibitionOngoing clinical trialsCRC cell linesCell line xenograftsMSI-H cell linesCRC patientsChemotherapy responsePatient populationPredictive markerClinical trialsDifferential sensitivityTherapeutic effectHuman xenograftsVivo treatmentMSI statusChemotherapy sensitivityGemcitabineFrequent Inactivation of Cysteine Dioxygenase Type 1 Contributes to Survival of Breast Cancer Cells and Resistance to Anthracyclines
Jeschke J, O'Hagan HM, Zhang W, Vatapalli R, Calmon MF, Danilova L, Nelkenbrecher C, Van Neste L, Bijsmans IT, Van Engeland M, Gabrielson E, Schuebel KE, Winterpacht A, Baylin SB, Herman JG, Ahuja N. Frequent Inactivation of Cysteine Dioxygenase Type 1 Contributes to Survival of Breast Cancer Cells and Resistance to Anthracyclines. Clinical Cancer Research 2013, 19: 3201-3211. PMID: 23630167, PMCID: PMC3985391, DOI: 10.1158/1078-0432.ccr-12-3751.Peer-Reviewed Original ResearchConceptsBreast cancer cellsEpigenetic eventsDNA methylationGenome-wide DNA methylation analysisCancer cellsDNA methylation-associated silencingKey epigenetic eventsDetoxification of ROSCritical epigenetic eventsComprehensive functional analysisDNA methylation analysisDNA methylation dataMethylation-associated silencingRepressive chromatinOxygen species productionFunctional analysisMethylation dataLevels of ROSMethylation analysisReduced viabilityMissense mutationsFunctional significanceFrequent inactivationSpecies productionMethylation
2012
A DNA hypermethylation module for the stem/progenitor cell signature of cancer
Easwaran H, Johnstone SE, Van Neste L, Ohm J, Mosbruger T, Wang Q, Aryee MJ, Joyce P, Ahuja N, Weisenberger D, Collisson E, Zhu J, Yegnasubramanian S, Matsui W, Baylin SB. A DNA hypermethylation module for the stem/progenitor cell signature of cancer. Genome Research 2012, 22: 837-849. PMID: 22391556, PMCID: PMC3337430, DOI: 10.1101/gr.131169.111.Peer-Reviewed Original ResearchMeSH KeywordsCell Line, TumorChromatinCluster AnalysisCpG IslandsDNA MethylationEmbryonic Stem CellsEpigenesis, GeneticGene Expression ProfilingGene Expression Regulation, NeoplasticGenes, NeoplasmGenes, RegulatorHistonesHumansMesenchymal Stem CellsNeoplasmsOligonucleotide Array Sequence AnalysisOsteoblastsPolycomb-Group ProteinsPromoter Regions, GeneticRepressor ProteinsSequence Analysis, DNAConceptsEmbryonic stem cellsBivalent chromatinDevelopmental regulatorsPcG target genesKey developmental regulatorsGenome-wide analysisSubset of genesPolycomb repressor complexesStem cellsAdult stem/progenitor cellsStem-like stateStem/progenitor cellsTranscription statePcG genesRepressor complexNormal stem cellsChromatin statusHypermethylated genesTarget genesDNA hypermethylationCancer genesGlobal methylationChromatinGenesMethylation statusTransient Low Doses of DNA-Demethylating Agents Exert Durable Antitumor Effects on Hematological and Epithelial Tumor Cells
Tsai HC, Li H, Van Neste L, Cai Y, Robert C, Rassool FV, Shin JJ, Harbom KM, Beaty R, Pappou E, Harris J, Yen RW, Ahuja N, Brock MV, Stearns V, Feller-Kopman D, Yarmus LB, Lin YC, Welm AL, Issa JP, Minn I, Matsui W, Jang YY, Sharkis SJ, Baylin SB, Zahnow CA. Transient Low Doses of DNA-Demethylating Agents Exert Durable Antitumor Effects on Hematological and Epithelial Tumor Cells. Cancer Cell 2012, 21: 430-446. PMID: 22439938, PMCID: PMC3312044, DOI: 10.1016/j.ccr.2011.12.029.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntimetabolites, AntineoplasticApoptosisAzacitidineBone Marrow CellsBreast NeoplasmsCell CycleCell Line, TumorCell Transformation, NeoplasticDecitabineDNA DamageDNA MethylationDNA Modification MethylasesGene SilencingHumansLeukemiaMiceMolecular Sequence DataNeoplastic Stem CellsPromoter Regions, GeneticSignal TransductionTumor Cells, CulturedConceptsKey cellular regulatory pathwaysDNA methylation inhibitorPromoter DNA hypermethylationCellular regulatory pathwaysDNA demethylating agentEpithelial tumor cellsPromoter DNA methylationRapid DNA damageCancer stem-like cellsGene reexpressionDNA methylationStem-like cellsMethylation inhibitorDNA hypermethylationRegulatory pathwaysCancer therapy approachesAssociated geneDNA damageTumor cellsImmediate cytotoxicityNanomolar dosesTransient exposureCellsGenesMethylationDNA methylation biomarker candidates for early detection of colon cancer
Yi JM, Dhir M, Guzzetta AA, Iacobuzio-Donahue CA, Heo K, Yang KM, Suzuki H, Toyota M, Kim HM, Ahuja N. DNA methylation biomarker candidates for early detection of colon cancer. Tumor Biology 2012, 33: 363-372. PMID: 22238052, PMCID: PMC3593674, DOI: 10.1007/s13277-011-0302-2.Peer-Reviewed Original ResearchConceptsPromoter DNA hypermethylationCpG island hypermethylationDNA hypermethylationColon cancer cell linesCancer cell linesGene expressionIsland hypermethylationCell linesDNA microarray approachEpigenetic therapeutic targetsGenome-wide platformsPromoter CpG island hypermethylationCancer-specific methylationTumor suppressor geneCancer-specific eventBisulfite sequencingCpG islandsTCERG1LMicroarray approachPromoter regionSuppressor geneGenesColorectal cancer cell linesHuman cancersCommon hallmark
2011
Genomic and Epigenomic Integration Identifies a Prognostic Signature in Colon Cancer
Yi JM, Dhir M, Van Neste L, Downing SR, Jeschke J, Glöckner SC, de Freitas Calmon M, Hooker CM, Funes JM, Boshoff C, Smits KM, van Engeland M, Weijenberg MP, Iacobuzio-Donahue CA, Herman JG, Schuebel KE, Baylin SB, Ahuja N. Genomic and Epigenomic Integration Identifies a Prognostic Signature in Colon Cancer. Clinical Cancer Research 2011, 17: 1535-1545. PMID: 21278247, PMCID: PMC3077819, DOI: 10.1158/1078-0432.ccr-10-2509.Peer-Reviewed Original ResearchConceptsDNA methylationExtracellular matrixDNA methylation analysisEpigenetic mechanismsKey genesEpigenomic alterationsCore pathwaysEpigenetic abnormalitiesPathway genesECM genesMultiple genesEpigenetic alterationsPathway componentsPathway analysisIntegrative analysisLarge CRC cohortsGenesMethylationMethylation analysisSimultaneous methylationPathway disruptionPathwayAggregate roleNovel prognostic biomarkerEVL
2009
Prognostic Significance of Gremlin1 (GREM1) Promoter CpG Island Hypermethylation in Clear Cell Renal Cell Carcinoma
van Vlodrop IJ, Baldewijns MM, Smits KM, Schouten LJ, van Neste L, van Criekinge W, van Poppel H, Lerut E, Schuebel KE, Ahuja N, Herman JG, de Bruïne AP, van Engeland M. Prognostic Significance of Gremlin1 (GREM1) Promoter CpG Island Hypermethylation in Clear Cell Renal Cell Carcinoma. American Journal Of Pathology 2009, 176: 575-584. PMID: 20042676, PMCID: PMC2808066, DOI: 10.2353/ajpath.2010.090442.Peer-Reviewed Original ResearchConceptsClear cell renal cell carcinomaCell renal cell carcinomaRenal cell carcinomaCcRCC cell linesCell carcinomaIndependent patient seriesSignificant worse survivalMean vessel densityCell linesOverall survivalWorse survivalClinical outcomesPatient seriesTumor characteristicsPrognostic significanceTumor sizeBone morphogenetic protein antagonistFuhrman gradeMethylation-specific PCRUnivariate analysisVessel densityAngiogenic parametersMultivariate analysisActive angiogenesisTumor angiogenesis
2008
Convergence of Mutation and Epigenetic Alterations Identifies Common Genes in Cancer That Predict for Poor Prognosis
Chan TA, Glockner S, Yi JM, Chen W, Van Neste L, Cope L, Herman JG, Velculescu V, Schuebel KE, Ahuja N, Baylin SB. Convergence of Mutation and Epigenetic Alterations Identifies Common Genes in Cancer That Predict for Poor Prognosis. PLOS Medicine 2008, 5: e114. PMID: 18507500, PMCID: PMC2429944, DOI: 10.1371/journal.pmed.0050114.Peer-Reviewed Original ResearchConceptsTumor suppressor geneUnbiased genome-wide approachSuppressor geneGenome-wide approachesKey tumor suppressor genesBreast cancer cell linesSet of genesCancer cell linesLarge-scale sequencingTumor suppressor statusPromoter CpG island hypermethylationCell linesCpG island hypermethylationTumor-type specificRecent sequencingBiology of cancerEpigenetic eventsCancer genomesEpigenetic analysisEpigenetic alterationsCommon genesTumor suppressorSignificant genesGenetic changesIsland hypermethylationEpigenetic Inactivation of the Canonical Wnt Antagonist SRY-Box Containing Gene 17 in Colorectal Cancer
Zhang W, Glöckner S, Guo M, Machida EO, Wang DH, Easwaran H, Van Neste L, Herman JG, Schuebel KE, Watkins DN, Ahuja N, Baylin SB. Epigenetic Inactivation of the Canonical Wnt Antagonist SRY-Box Containing Gene 17 in Colorectal Cancer. Cancer Research 2008, 68: 2764-2772. PMID: 18413743, PMCID: PMC2823123, DOI: 10.1158/0008-5472.can-07-6349.Peer-Reviewed Original ResearchConceptsGene 17T-cell factor-dependent transcriptionHigh-mobility group transcription factorsFactor-dependent transcriptionMethylation-dependent silencingRegulation of developmentOverexpression of Sox17Cell linesCpG island hypermethylationWnt pathway activityPrecursor cell functionRepression domainHMG boxTranscription factorsDeletion analysisCpG islandsGene silencingDNA hypermethylationGene expressionPromoter regionEpigenetic inactivationCanonical WntGenetic changesIsland hypermethylationSOX17
2007
Methylation-induced silencing of ASC/TMS1, a pro-apoptotic gene, is a late-stage event in colorectal cancer
Riojas MA, Guo M, Glöckner SC, Machida EO, Baylin SB, Ahuja N. Methylation-induced silencing of ASC/TMS1, a pro-apoptotic gene, is a late-stage event in colorectal cancer. Cancer Biology & Therapy 2007, 6: 1710-1716. PMID: 17986858, DOI: 10.4161/cbt.6.11.4829.Peer-Reviewed Original ResearchConceptsASC/TMS1Normal colorectal tissue samplesCRC cell linesColorectal tissue samplesColorectal cancerColorectal adenomasMethylation-specific PCRCell linesMRNA expressionPro-apoptotic genesPrimary colorectal cancer specimensStage 1 cancerStage 2 cancerStage 3 cancerRight-sided tumorsPrimary colorectal cancerStage 4 cancerColorectal cancer specimensTissue samplesColorectal cancer cell linesNormal colorectal tissuesUnmethylated cell linesDifferent human neoplasmsCancer cell linesLate-stage event