2023
A study of using epigenetic modulators to enhance response to pembrolizumab (MK-3475) in microsatellite stable advanced colorectal cancer
Baretti M, Murphy A, Zahurak M, Gianino N, Parkinson R, Walker R, Lopez-Vidal T, Zheng L, Rosner G, Ahuja N, Kurt S, Azad N. A study of using epigenetic modulators to enhance response to pembrolizumab (MK-3475) in microsatellite stable advanced colorectal cancer. Clinical Epigenetics 2023, 15: 74. PMID: 37120591, PMCID: PMC10149019, DOI: 10.1186/s13148-023-01485-x.Peer-Reviewed Original ResearchConceptsColorectal cancer patientsAdvanced colorectal cancer patientsImmune checkpoint inhibitor therapyMedian progression-free survivalDurable partial responseHematological adverse eventsMMR-proficient tumorsCheckpoint inhibitor therapyAdvanced colorectal cancerProgression-free survivalImmune cell infiltrationHistone deacetylasesImmunologic shiftCheckpoint inhibitorsRECIST criteriaAdverse eventsCheckpoint therapyOverall survivalPartial responseInhibitor therapyMedian ageColorectal cancerFurther mechanistic investigationsCancer patientsCell infiltrationUtility of promoter hypermethylation in malignant risk stratification of intraductal papillary mucinous neoplasms
Chhoda A, Sharma A, Sailo B, Tang H, Ruzgar N, Tan W, Ying L, Khatri R, Narayanan A, Mane S, De Kumar B, Wood L, Iacobuzio-Donahue C, Wolfgang C, Kunstman J, Salem R, Farrell J, Ahuja N. Utility of promoter hypermethylation in malignant risk stratification of intraductal papillary mucinous neoplasms. Clinical Epigenetics 2023, 15: 28. PMID: 36803844, PMCID: PMC9942382, DOI: 10.1186/s13148-023-01429-5.Peer-Reviewed Original ResearchConceptsPapillary mucinous neoplasmMalignant risk stratificationCACNA1G geneRisk stratificationMucinous neoplasmsBiomarker panelBackgroundIntraductal papillary mucinous neoplasmIntraductal papillary mucinous neoplasmEarly detectionPrevious case-control studyHigh-grade dysplasiaCase-control studyPancreatic cancer precursorsReceiver Operating Characteristic (ROC) curve analysisSignificant diagnostic challengeCross-sectional imagingCharacteristic curve analysisOperating Characteristic curve analysisG geneHigh diagnostic specificityPrior validation studiesSignificant procedural riskIPMN tissuesSurgical resectionAdvanced neoplasia
2022
A randomized, phase II trial of oral azacitidine (CC-486) in patients with resected pancreatic adenocarcinoma at high risk for recurrence
Heumann T, Baretti M, Sugar E, Durham J, Linden S, Lopez-Vidal T, Leatherman J, Cope L, Sharma A, Weekes C, O’Dwyer P, Reiss K, Monga D, Ahuja N, Azad N. A randomized, phase II trial of oral azacitidine (CC-486) in patients with resected pancreatic adenocarcinoma at high risk for recurrence. Clinical Epigenetics 2022, 14: 166. PMID: 36463226, PMCID: PMC9719150, DOI: 10.1186/s13148-022-01367-8.Peer-Reviewed Original ResearchConceptsResectable pancreatic ductal adenocarcinomaCC-486OBS patientsMetastatic settingAdjuvant therapyTreatment-related grade 3Randomized phase II studyMedian age 66Next-line therapyResultsForty-nine patientsMedian treatment durationPhase II studyEvidence of diseaseHigh-risk featuresPhase II trialProgression-free survivalStandard adjuvant therapyPancreatic ductal adenocarcinomaCancer recursEvaluable patientsMedian OSMedian PFSOral azacitidineR1 resectionSubsequent chemotherapy
2019
Promoter methylation of ADAMTS1 and BNC1 as potential biomarkers for early detection of pancreatic cancer in blood
Eissa MAL, Lerner L, Abdelfatah E, Shankar N, Canner JK, Hasan NM, Yaghoobi V, Huang B, Kerner Z, Takaesu F, Wolfgang C, Kwak R, Ruiz M, Tam M, Pisanic TR, Iacobuzio-Donahue CA, Hruban RH, He J, Wang TH, Wood LD, Sharma A, Ahuja N. Promoter methylation of ADAMTS1 and BNC1 as potential biomarkers for early detection of pancreatic cancer in blood. Clinical Epigenetics 2019, 11: 59. PMID: 30953539, PMCID: PMC6451253, DOI: 10.1186/s13148-019-0650-0.Peer-Reviewed Original ResearchConceptsStage IIB diseasePancreatic cancerIIB diseaseStage IIACA 19Stage IBiomarker panelBlood-based biomarker panelPre-operative CA 19Stage I patientsCell-free tumor DNAHigh-risk populationPotential blood biomarkersMost pancreatic cancersBackgroundDespite improvementsCurative resectionSurgical resectionI patientsTwo-gene panelPancreas cancerBlood biomarkersCurative potentialCancer managementAdvanced stageCombination panelAging-like Spontaneous Epigenetic Silencing Facilitates Wnt Activation, Stemness, and Braf V600E-Induced Tumorigenesis
Tao Y, Kang B, Petkovich DA, Bhandari YR, In J, Stein-O'Brien G, Kong X, Xie W, Zachos N, Maegawa S, Vaidya H, Brown S, Yen R, Shao X, Thakor J, Lu Z, Cai Y, Zhang Y, Mallona I, Peinado MA, Zahnow CA, Ahuja N, Fertig E, Issa JP, Baylin SB, Easwaran H. Aging-like Spontaneous Epigenetic Silencing Facilitates Wnt Activation, Stemness, and Braf V600E-Induced Tumorigenesis. Cancer Cell 2019, 35: 315-328.e6. PMID: 30753828, PMCID: PMC6636642, DOI: 10.1016/j.ccell.2019.01.005.Peer-Reviewed Original ResearchMeSH KeywordsAdenocarcinomaAge FactorsAgingAnimalsCell Transformation, NeoplasticColonic NeoplasmsDNA MethylationGene Expression Regulation, NeoplasticGene SilencingGenetic Predisposition to DiseaseHumansMice, Inbred NODMice, Mutant StrainsMice, SCIDMutationPhenotypeProto-Oncogene Proteins B-rafStem CellsTime FactorsTissue Culture TechniquesWnt Signaling PathwayConceptsCell fate changesPromoter DNA hypermethylationStem-like stateAging-like phenotypesCpG island methylationFate changesDifferentiation defectsEpigenetic abnormalitiesDNA hypermethylationSimultaneous inactivationWnt pathwayWnt activationPromoter hypermethylationTumorigenesisGenesHypermethylationMethylator phenotypeColon tumorigenesisPhenotypeOrganoidsPrecursor roleCRISPRMethylationSupStemness
2018
A Phase I Trial of a Guadecitabine (SGI-110) and Irinotecan in Metastatic Colorectal Cancer Patients Previously Exposed to Irinotecan
Lee V, Wang J, Zahurak M, Gootjes E, Verheul H, Parkinson R, Kerner Z, Sharma A, Rosner G, De Jesus-Acosta A, Laheru D, Le DT, Oganesian A, Lilly E, Brown T, Jones P, Baylin S, Ahuja N, Azad N. A Phase I Trial of a Guadecitabine (SGI-110) and Irinotecan in Metastatic Colorectal Cancer Patients Previously Exposed to Irinotecan. Clinical Cancer Research 2018, 24: 6160-6167. PMID: 30097434, DOI: 10.1158/1078-0432.ccr-18-0421.Peer-Reviewed Original ResearchConceptsMetastatic colorectal cancerNeutropenic feverMetastatic colorectal cancer patientsDurable partial responseMost common toxicitiesDose-escalation studyColorectal cancer patientsInjection site reactionsOngoing phase IIPhase I trialInitial disease progressionCycles of treatmentCommon toxicitiesDrain infectionEvaluable patientsStable diseaseColonic obstructionPartial responseI trialMulticenter trialColorectal cancerGastrointestinal cancerSite reactionsCancer patientsDisease progressionEpigenetics of gastrointestinal diseases: notes from a workshop
Marks DL, Olson RL, Urrutia R, Billadeau DD, Roy N, Calin GA, Fabbri M, Koutsioumpa M, Iliopoulos D, Ordog T, Huebert R, Sarmento O, Bamidele AO, Faubion W, Lomberk GL, Siveke J, Ahuja N, Iovanna J, Hlady RA, Robertson K, Kisiel J, Pin CL, Fernandez-Zapico ME. Epigenetics of gastrointestinal diseases: notes from a workshop. Epigenetics 2018, 13: 449-457. PMID: 30056798, PMCID: PMC6140811, DOI: 10.1080/15592294.2018.1464351.Peer-Reviewed Original ResearchDNA Methylation Patterns Separate Senescence from Transformation Potential and Indicate Cancer Risk
Xie W, Kagiampakis I, Pan L, Zhang YW, Murphy L, Tao Y, Kong X, Kang B, Xia L, Carvalho FLF, Sen S, Yen R, Zahnow CA, Ahuja N, Baylin SB, Easwaran H. DNA Methylation Patterns Separate Senescence from Transformation Potential and Indicate Cancer Risk. Cancer Cell 2018, 33: 309-321.e5. PMID: 29438699, PMCID: PMC5813821, DOI: 10.1016/j.ccell.2018.01.008.Peer-Reviewed Original ResearchConceptsDevelopmental genesDNA methylation patternsPromoter hypermethylation eventsEpigenetic patternsMethylation gainMethylation patternsMethylation changesHypermethylation eventsEpigenetic changesTissue agingSenescenceMetabolic regulatorTissue typesGenesTransformation potentialCellsHypermethylationRegulatorCancer risk
2017
The Roles of DNA Methylation in the Stages of Cancer
McMahon KW, Karunasena E, Ahuja N. The Roles of DNA Methylation in the Stages of Cancer. The Cancer Journal 2017, 23: 257-261. PMID: 28926425, PMCID: PMC5657558, DOI: 10.1097/ppo.0000000000000279.Peer-Reviewed Original ResearchInhibiting DNA methylation activates cancer testis antigens and expression of the antigen processing and presentation machinery in colon and ovarian cancer cells
Siebenkäs C, Chiappinelli KB, Guzzetta AA, Sharma A, Jeschke J, Vatapalli R, Baylin SB, Ahuja N. Inhibiting DNA methylation activates cancer testis antigens and expression of the antigen processing and presentation machinery in colon and ovarian cancer cells. PLOS ONE 2017, 12: e0179501. PMID: 28622390, PMCID: PMC5473589, DOI: 10.1371/journal.pone.0179501.Peer-Reviewed Original ResearchConceptsSubset of patientsOvarian cancer cell linesAntigen processingCancer cell linesImmune therapyCancer testisSolid tumorsCell linesCancer cellsCancer-testis antigensHost immune systemOvarian cancer cellsTreatment time pointsEpigenetic therapyRelevant low dosesPresentation machineryImmune cellsOvarian cancerAntigen presentationMurine modelTestis antigensInnovative therapiesImmune systemLow dosesTherapyHypomethylating 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 assayChemotherapyA Four-Gene Promoter Methylation Marker Panel Consisting of GREM1, NEURL, LAD1, and NEFH Predicts Survival of Clear Cell Renal Cell Cancer Patients
van Vlodrop IJH, Joosten SC, De Meyer T, Smits KM, Van Neste L, Melotte V, Baldewijns MMLL, Schouten LJ, van den Brandt PA, Jeschke J, Yi JM, Schuebel KE, Ahuja N, Herman JG, Aarts MJ, Bosman FT, Van Criekinge W, van Engeland M. A Four-Gene Promoter Methylation Marker Panel Consisting of GREM1, NEURL, LAD1, and NEFH Predicts Survival of Clear Cell Renal Cell Cancer Patients. Clinical Cancer Research 2017, 23: 2006-2018. PMID: 27756787, DOI: 10.1158/1078-0432.ccr-16-1236.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAutoantigensBiomarkers, TumorCarcinoma, Renal CellDisease-Free SurvivalDNA MethylationFemaleHigh-Throughput Nucleotide SequencingHumansIntercellular Signaling Peptides and ProteinsKaplan-Meier EstimateKidney NeoplasmsMaleMiddle AgedNeurofilament ProteinsNon-Fibrillar CollagensOligonucleotide Array Sequence AnalysisPrognosisPromoter Regions, GeneticProportional Hazards ModelsUbiquitin-Protein LigasesConceptsClear cell renal cell carcinomaPrognostic modelNonmetastatic clear cell renal cell carcinomaMethylation markersCox proportional hazards modelPrimary clear cell renal cell carcinomaIndependent patient seriesCause-specific survivalOutcomes of patientsCell renal cell carcinomaPrognosis of patientsKaplan-Meier curvesLog-rank testConfidence intervalsCurrent prognostic modelsRenal cell carcinomaProportional hazards modelClin Cancer ResCcRCC cell linesCancer Genome AtlasClinicopathologic featuresPatient seriesCell carcinomaMethylation-specific PCRPoor survivalEpigenetically 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 activity
2016
Tumors with unmethylated MLH1 and the CpG island methylator phenotype are associated with a poor prognosis in stage II colorectal cancer patients
Fu T, Liu Y, Li K, Wan W, Pappou EP, Iacobuzio-Donahue CA, Kerner Z, Baylin SB, Wolfgang CL, Ahuja N. Tumors with unmethylated MLH1 and the CpG island methylator phenotype are associated with a poor prognosis in stage II colorectal cancer patients. Oncotarget 2016, 5: 86480-86489. PMID: 27880934, PMCID: PMC5349928, DOI: 10.18632/oncotarget.13441.Peer-Reviewed Original ResearchConceptsDisease-free survivalStage II colorectal cancer patientsStage II CRC patientsCpG island methylator phenotypeMLH1 methylation statusColorectal cancer patientsOverall survivalLymphovascular invasionCRC patientsCancer patientsMucin productionMethylator phenotypeKaplan-Meier analysisPoor clinical outcomeMethylation statusDuodenal adenocarcinomaClinical outcomesAggressive featuresPoor prognosisPrognostic valuePatient subgroupsTumor locationMultivariate analysisPatientsM groupMethylation of MGMT Is Associated with Poor Prognosis in Patients with Stage III Duodenal Adenocarcinoma
Fu T, Sharmab A, Xie F, Liu Y, Li K, Wan W, Baylin SB, Wolfgang CL, Ahuja N. Methylation of MGMT Is Associated with Poor Prognosis in Patients with Stage III Duodenal Adenocarcinoma. PLOS ONE 2016, 11: e0162929. PMID: 27643594, PMCID: PMC5028050, DOI: 10.1371/journal.pone.0162929.Peer-Reviewed Original ResearchConceptsDisease-free survivalCpG island methylator phenotypeDuodenal adenocarcinomaOverall survivalMethylation of MGMTMGMT methylationMicrosatellite instabilityPoor prognosisKRAS mutationsCox proportional hazards modelMGMT unmethylated groupTumor molecular featuresChemotherapy/radiotherapyIndependent prognostic factorO6-methylguanine-DNA methyltransferase methylation statusWorse overall survivalPossible prognostic valueProportional hazards modelMGMT methylation statusPrognostic factorsClinicopathological characteristicsTumor characteristicsMethylation statusPrognostic valueTumor differentiationIGFBP-3 Gene Methylation in Primary Tumor Predicts Recurrence of Stage II Colorectal Cancers
Fu T, Pappou EP, Guzzetta AA, de Freitas Calmon M, Sun L, Herrera A, Li F, Wolfgang CL, Baylin SB, Iacobuzio-Donahue CA, Tong W, Ahuja N. IGFBP-3 Gene Methylation in Primary Tumor Predicts Recurrence of Stage II Colorectal Cancers. Annals Of Surgery 2016, 263: 337-344. PMID: 25822686, PMCID: PMC4648704, DOI: 10.1097/sla.0000000000001204.Peer-Reviewed Original ResearchConceptsStage II colorectal cancerRisk of recurrenceIGFBP-3 methylationLymph nodesColorectal cancerHazard ratioPrimary tumorHigh riskIndependent cohortFive-year recurrence-free survival ratesRecurrence-free survival ratesHigh-risk patientsSignificant prognostic factorsIdentification of patientsProportional hazards modelIGFBP-3Prognostic factorsTumor characteristicsPredicts RecurrenceHazards modelPatientsRecurrenceSurvival rateMultivariate analysisSurgeryEpigenetic Therapeutics: A New Weapon in the War Against Cancer
Ahuja N, Sharma AR, Baylin SB. Epigenetic Therapeutics: A New Weapon in the War Against Cancer. Annual Review Of Medicine 2016, 67: 73-89. PMID: 26768237, PMCID: PMC4937439, DOI: 10.1146/annurev-med-111314-035900.Peer-Reviewed Original ResearchConceptsEpigenetic therapyPrimary base sequenceNucleosome positioningEpigenetic regulationCellular regulationHeritable patternsEpigenetic mechanismsDNA methylationExplosion of discoveriesGene expressionCancer initiationBase sequenceEpigenomeRegulationFrequent mutationsGenetic abnormalitiesNormal maturationTumor cellsPotent toolChromatinCellsNeoplastic cellsGenesMethylationProtein
2015
Promoter Methylation of CDO1 Identifies Clear-Cell Renal Cell Cancer Patients with Poor Survival Outcome
Deckers IA, Schouten LJ, Van Neste L, van Vlodrop IJ, Soetekouw PM, Baldewijns MM, Jeschke J, Ahuja N, Herman JG, van den Brandt PA, van Engeland M. Promoter Methylation of CDO1 Identifies Clear-Cell Renal Cell Cancer Patients with Poor Survival Outcome. Clinical Cancer Research 2015, 21: 3492-3500. PMID: 25904753, PMCID: PMC4612631, DOI: 10.1158/1078-0432.ccr-14-2049.Peer-Reviewed Original ResearchConceptsCDO1 promoter methylationNetherlands Cohort StudyCysteine dioxygenase type 1Prognostic markerPromoter methylationCcRCC casesRenal cell cancer patientsProspective Netherlands Cohort StudyMultivariate modelRelative prognostic valueKaplan-Meier curvesPopulation-based seriesClear cell renal cell cancer (ccRCC) patientsCurrent prognostic markersPoor survival outcomesConfidence intervalsRelevant prognostic informationIndividual patient outcomesMultivariate HRCohort studyMethylation-specific PCR analysisCancer Genome AtlasPrognostic factorsPrognostic valuePromoter methylation statusEpigenetic 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 cellsPolypeptide