2024
PARG inhibition induces nuclear aggregation of PARylated PARP1
Paradkar S, Purcell J, Cui A, Friedman S, Noronha K, Murray M, Sundaram R, Bindra R, Jensen R. PARG inhibition induces nuclear aggregation of PARylated PARP1. Structure 2024 PMID: 39406247, DOI: 10.1016/j.str.2024.09.006.Peer-Reviewed Original ResearchNAPRT Silencing in FH-Deficient Renal Cell Carcinoma Confers Therapeutic Vulnerabilities via NAD+ Depletion
Noronha K, Lucas K, Paradkar S, Edmonds J, Friedman S, Murray M, Liu S, Sajed D, Sachs C, Spurrier J, Raponi M, Liang J, Zeng H, Sundaram R, Shuch B, Vasquez J, Bindra R. NAPRT Silencing in FH-Deficient Renal Cell Carcinoma Confers Therapeutic Vulnerabilities via NAD+ Depletion. Molecular Cancer Research 2024, 22: of1-of16. PMID: 38949523, PMCID: PMC11445649, DOI: 10.1158/1541-7786.mcr-23-1003.Peer-Reviewed Original ResearchRenal cell carcinomaCellular processesCell carcinomaFumarate hydrataseImpact diverse cellular processesAlpha-ketoglutarate-dependent dioxygenasesDiverse cellular processesAccumulation of fumaratePreiss-Handler pathwayMultiple cellular processesLoss of function mutationsAssociated with silencingNicotinamide phosphoribosyl transferase inhibitorPattern of hypermethylationFH-deficient renal cell carcinomasSynergistic tumor cell killingAggressive subtype of renal cell carcinomaLoss of FHSubtype of renal cell carcinomaDNA repair processesPoly(ADP)-ribose polymerase inhibitorsCpG islandsTumor cell killingPreiss-HandlerCell line modelsMechanism of Action of KL-50, a Candidate Imidazotetrazine for the Treatment of Drug-Resistant Brain Cancers
Huseman E, Lo A, Fedorova O, Elia J, Gueble S, Lin K, Sundaram R, Oh J, Liu J, Menges F, Rees M, Ronan M, Roth J, Batista V, Crawford J, Pyle A, Bindra R, Herzon S. Mechanism of Action of KL-50, a Candidate Imidazotetrazine for the Treatment of Drug-Resistant Brain Cancers. Journal Of The American Chemical Society 2024, 146: 18241-18252. PMID: 38815248, PMCID: PMC11409917, DOI: 10.1021/jacs.3c06483.Peer-Reviewed Original ResearchDNA repair capacityDifferential DNA repair capacityDNA interstrand cross-linksRepair capacityInterstrand cross-linksDisplacement of fluorideDNA repairCross-linkingAberrant DNA repairLesionsHealthy tissueBrain cancerRing openingHealthy cellsMGMTSelective chemotherapyGenotoxic agentsTumorChemical DNA modificationsCancerMultistep processRepairExploiting Metabolic Defects in Glioma with Nanoparticle-Encapsulated NAMPT Inhibitors
Murray M, Noronha K, Wang Y, Friedman A, Paradkar S, Suh H, Sundaram R, Brenner C, Saltzman W, Bindra R. Exploiting Metabolic Defects in Glioma with Nanoparticle-Encapsulated NAMPT Inhibitors. Molecular Cancer Therapeutics 2024, 23: 1176-1187. PMID: 38691846, PMCID: PMC11292319, DOI: 10.1158/1535-7163.mct-24-0012.Peer-Reviewed Original ResearchConvection-enhanced deliveryCentral nervous systemTreatment of primary central nervous systemPrimary central nervous systemSustained drug release in vitroTumor growth delayAssociated with lower survival ratesBone marrow suppressionComplex mutational profilesNAMPT inhibitorsRelease in vitroIntracranial GBM xenograftsBlood-brain barrierDrug release in vitroRetinal toxicityMarrow suppressionNAMPTiGrowth delayTherapeutic vulnerabilitiesExtended survivalLow survival rateGBM xenograftsMutation profilesPromoter methylationAnticancer activity in vitroDNA damage response in brain tumors: A Society for Neuro-Oncology consensus review on mechanisms and translational efforts in neuro-oncology
Rahman R, Shi D, Reitman Z, Hamerlik P, de Groot J, Haas-Kogan D, D’Andrea A, Sulman E, Tanner K, Agar N, Sarkaria J, Tinkle C, Bindra R, Mehta M, Wen P. DNA damage response in brain tumors: A Society for Neuro-Oncology consensus review on mechanisms and translational efforts in neuro-oncology. Neuro-Oncology 2024, 26: 1367-1387. PMID: 38770568, PMCID: PMC11300028, DOI: 10.1093/neuonc/noae072.Peer-Reviewed Original ResearchConsensus reviewDNA damage responseIDH wild-type glioblastomaIDH-mutant gliomasClinical trial design considerationsMechanisms of resistanceTrial design considerationsCombination therapyDevelopment of DDR inhibitorsDNA damage response pathwayPreclinical modelsDamage responseDDR inhibitorsNeuro-oncologyBrain tumorsBiomarker developmentTherapyResponse to DNA damageDNA damageTranslational effortsTumor
2023
CTNI-41. PHASE II AND PHASE 0 RESULTS OF ABTC 1801: A MULTI-ARM CLINICAL TRIAL OF THE PARP INHIBITOR PAMIPARIB WITH VERY LOW DOSE METRONOMIC TEMOZOLOMIDE IN RECURRENT IDH MUTANT GLIOMAS
Schiff D, Bindra R, Li J, Ye X, Ellingson B, Walbert T, Campian J, Nabors B, Lieberman F, Ozer B, Desai A, Omuro A, Wen P, Desideri S, Danda N, Grossman S. CTNI-41. PHASE II AND PHASE 0 RESULTS OF ABTC 1801: A MULTI-ARM CLINICAL TRIAL OF THE PARP INHIBITOR PAMIPARIB WITH VERY LOW DOSE METRONOMIC TEMOZOLOMIDE IN RECURRENT IDH MUTANT GLIOMAS. Neuro-Oncology 2023, 25: v84-v84. PMCID: PMC10639307, DOI: 10.1093/neuonc/noad179.0323.Peer-Reviewed Original ResearchObjective response rateArm AMetronomic temozolomideArm BGrade 3Non-enhancing tumorMeaningful objective response rateTumor/plasma ratioCumulative hematologic toxicityGrade 3 anemiaGrade 3 thrombocytopeniaGrade 4 neutropeniaPhase II componentArm clinical trialPhase IIKPS 90Median PFSHematologic toxicityPrimary endpointAlkylator therapyProgressive diseaseARM patientsMedian ageBRCAness phenotypeClinical trialsMODL-02. DEVELOPMENT OF RODENT GLIOBLASTOMA MODELS OF MGMT-MEDIATED TEMOZOLOMIDE RESISTANCE
Lee T, Bhatt D, Sundaram R, Saltzman W, Bindra R, Vasquez J. MODL-02. DEVELOPMENT OF RODENT GLIOBLASTOMA MODELS OF MGMT-MEDIATED TEMOZOLOMIDE RESISTANCE. Neuro-Oncology 2023, 25: v298-v298. PMCID: PMC10640218, DOI: 10.1093/neuonc/noad179.1153.Peer-Reviewed Original ResearchMouse glioma modelPotential therapeutic targetMGMT overexpressionGlioma modelTherapeutic targetTumor growthDaily x 5 daysMGMT expressionMGMT inhibitorsUseful preclinical toolTumor immune microenvironmentImportant prognostic biomarkerFischer 344 ratsHuman GBM cell linesDelays tumor growthHigh MGMT expressionMouse glioma cellsRodent glioblastoma modelsSyngeneic Fischer 344 ratsGBM cell linesAlkylator therapyO6-methylguanine-DNA methyltransferaseChemoimmunotherapy combinationImmune microenvironmentSyngeneic model
2020
Baseline requirements for novel agents being considered for phase II/III brain cancer efficacy trials: conclusions from the Adult Brain Tumor Consortium’s first workshop on CNS drug delivery
Grossman SA, Romo CG, Rudek MA, Supko J, Fisher J, Nabors LB, Wen PY, Peereboom DM, Ellingson BM, Elmquist W, Barker FG, Kamson D, Sarkaria JN, Timmer W, Bindra RS, Ye X. Baseline requirements for novel agents being considered for phase II/III brain cancer efficacy trials: conclusions from the Adult Brain Tumor Consortium’s first workshop on CNS drug delivery. Neuro-Oncology 2020, 22: 1422-1424. PMID: 32506123, PMCID: PMC7566550, DOI: 10.1093/neuonc/noaa142.Peer-Reviewed Original ResearchOncometabolites suppress DNA repair by disrupting local chromatin signalling
Sulkowski PL, Oeck S, Dow J, Economos NG, Mirfakhraie L, Liu Y, Noronha K, Bao X, Li J, Shuch BM, King MC, Bindra RS, Glazer PM. Oncometabolites suppress DNA repair by disrupting local chromatin signalling. Nature 2020, 582: 586-591. PMID: 32494005, PMCID: PMC7319896, DOI: 10.1038/s41586-020-2363-0.Peer-Reviewed Original ResearchConceptsDNA repairDNA breaksFumarate hydrataseDownstream repair factorsHistone 3 lysine 9Homology-dependent repairPoly (ADP-ribose) polymeraseRecruitment of TIP60Deregulation of metabolismChromatin signalingSuccinate dehydrogenase genesGenome integrityLysine 9Repair factorsDehydrogenase geneEnd resectionIsocitrate dehydrogenase 1Aberrant hypermethylationMechanistic basisSomatic mutationsDehydrogenase 1GenesHuman malignanciesProper executionMutationsPersistent STAG2 mutation despite multimodal therapy in recurrent pediatric glioblastoma
Hong CS, Vasquez JC, Kundishora AJ, Elsamadicy AA, Beckta JM, Sule A, Marks AM, Leelatian N, Huttner A, Bindra RS, DiLuna ML, Kahle KT, Erson-Omay EZ. Persistent STAG2 mutation despite multimodal therapy in recurrent pediatric glioblastoma. Npj Genomic Medicine 2020, 5: 23. PMID: 32528726, PMCID: PMC7264170, DOI: 10.1038/s41525-020-0130-7.Peer-Reviewed Original ResearchPediatric patientsStandard chemoradiationSTAG2 mutationsTumor clonesPediatric glioblastomaGross total resectionMultiple surgical resectionsTime of recurrenceHigh-grade gliomasDNA damage repair defectsWhole-exome sequencingVariety of treatmentsSurgical resectionNovel deleterious mutationsStandard therapyTotal resectionVaccine therapyClinical evidencePreclinical dataTreatment optionsMultimodal therapyPreclinical studiesClinical settingTherapyAdult counterpartsEstimation of the carrier frequency of fumarate hydratase alterations and implications for kidney cancer risk in hereditary leiomyomatosis and renal cancer
Shuch B, Li S, Risch H, Bindra RS, McGillivray PD, Gerstein M. Estimation of the carrier frequency of fumarate hydratase alterations and implications for kidney cancer risk in hereditary leiomyomatosis and renal cancer. Cancer 2020, 126: 3657-3666. PMID: 32413184, PMCID: PMC10316675, DOI: 10.1002/cncr.32914.Peer-Reviewed Original ResearchConceptsFumarate hydrataseExome Aggregation ConsortiumAllele frequenciesFH geneGenome ProjectDifferent world populationsFH alterationsHereditary leiomyomatosisKidney cancer riskCancer penetranceMissense alterationsGenesOverall allele frequencyRare variantsLow penetranceRenal cancerExACKidney cancerCancer riskPenetranceGermline mutationsLethal formWorld populationCancer syndromesAlterationsGray Areas in the Gray Matter: IDH1/2 Mutations in Glioma.
van den Bent MJ, Mellinghoff IK, Bindra RS. Gray Areas in the Gray Matter: IDH1/2 Mutations in Glioma. American Society Of Clinical Oncology Educational Book 2020, 40: 1-8. PMID: 32186930, PMCID: PMC7673204, DOI: 10.1200/edbk_280967.Peer-Reviewed Original ResearchConceptsAcute myeloid leukemiaMutant IDH inhibitorsIDH inhibitorsMutant acute myeloid leukemiaPhase III trialsDistinct clinical characteristicsClinical characteristicsIII trialsCombination therapyPharmacologic blockadeClinical trialsMutant cancer cellsMyeloid leukemiaDiagnostic groupsGray matterCancer developmentMetabolic changesAntitumor activityCancer cellsGliomasHuman cancersClass inhibitorMutant gliomasTumorsIntracellular changesGlioblastoma in adults: a Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) consensus review on current management and future directions
Wen PY, Weller M, Lee EQ, Alexander BM, Barnholtz-Sloan JS, Barthel FP, Batchelor TT, Bindra RS, Chang SM, Chiocca EA, Cloughesy TF, DeGroot JF, Galanis E, Gilbert MR, Hegi ME, Horbinski C, Huang RY, Lassman AB, Le Rhun E, Lim M, Mehta MP, Mellinghoff IK, Minniti G, Nathanson D, Platten M, Preusser M, Roth P, Sanson M, Schiff D, Short SC, Taphoorn MJB, Tonn JC, Tsang J, Verhaak RGW, von Deimling A, Wick W, Zadeh G, Reardon DA, Aldape KD, van den Bent MJ. Glioblastoma in adults: a Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) consensus review on current management and future directions. Neuro-Oncology 2020, 22: 1073-1113. PMID: 32328653, PMCID: PMC7594557, DOI: 10.1093/neuonc/noaa106.Peer-Reviewed Original ResearchConceptsNeuro-oncologyConsensus reviewCurrent managementMalignant primary brain tumorIsocitrate dehydrogenase-wildtype glioblastomaPrimary brain tumorsNovel therapiesViral therapyBrain tumorsImportant causeMolecular pathogenesisMolecular therapyEuropean AssociationTherapyEuropean SocietyCommon formGlioblastomaWildtype glioblastomaTumorsFuture directionsImportant advancesImmunotherapyMorbidityPatientsDNA damage response
2019
Targeting DNA repair in gliomas.
Beckta JM, Bindra RS, Chalmers AJ. Targeting DNA repair in gliomas. Current Opinion In Neurology 2019, 32: 878-885. PMID: 31592790, DOI: 10.1097/wco.0000000000000760.Peer-Reviewed Original ResearchConceptsLocal controlPoor local controlBlood-brain barrierTreatment of gliomaOverall survivalSystemic treatmentClinical outcomesDismal prognosisAggressive entityPreclinical dataPatient outcomesRadiation therapyGliomasOutcomesDNA repair targetsTreatmentRepair mechanismsRepair targetsNovel chemoCurrent understandingPatientsPrognosisDNA damage responseMalignancyTemozolomide Sensitizes MGMT-Deficient Tumor Cells to ATR Inhibitors
Jackson CB, Noorbakhsh SI, Sundaram RK, Kalathil AN, Ganesa S, Jia L, Breslin H, Burgenske DM, Gilad O, Sarkaria JN, Bindra RS. Temozolomide Sensitizes MGMT-Deficient Tumor Cells to ATR Inhibitors. Cancer Research 2019, 79: 4331-4338. PMID: 31273061, PMCID: PMC6810597, DOI: 10.1158/0008-5472.can-18-3394.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic Agents, AlkylatingAntineoplastic Combined Chemotherapy ProtocolsAtaxia Telangiectasia Mutated ProteinsCell Cycle CheckpointsCell Line, TumorCheckpoint Kinase 1DNA Breaks, Double-StrandedDNA DamageDNA Modification MethylasesDNA Repair EnzymesDrug SynergismFemaleHumansIsoxazolesMice, NudePyrazinesTemozolomideTumor Suppressor ProteinsXenograft Model Antitumor AssaysConceptsMGMT-deficient cellsPPM1D mutations silence NAPRT gene expression and confer NAMPT inhibitor sensitivity in glioma
Fons NR, Sundaram RK, Breuer GA, Peng S, McLean RL, Kalathil AN, Schmidt MS, Carvalho DM, Mackay A, Jones C, Carcaboso ÁM, Nazarian J, Berens ME, Brenner C, Bindra RS. PPM1D mutations silence NAPRT gene expression and confer NAMPT inhibitor sensitivity in glioma. Nature Communications 2019, 10: 3790. PMID: 31439867, PMCID: PMC6706443, DOI: 10.1038/s41467-019-11732-6.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic AgentsBrain Stem NeoplasmsCell Line, TumorChildCytokinesDiffuse Intrinsic Pontine GliomaDNA MethylationEpigenetic RepressionFemaleGene Expression Regulation, NeoplasticHumansMiceNicotinamide PhosphoribosyltransferasePonsPrimary Cell CultureProtein Phosphatase 2CSynthetic Lethal MutationsXenograft Model Antitumor AssaysConceptsNicotinic acid phosphoribosyltransferaseSynthetic lethal interactionsNAMPT inhibitorsTumor-specific cell killingProtein phosphataseEpigenetic silencingMutant cellsKey genesCpG islandsLethal interactionsNAD biosynthesisGene expressionInhibitor sensitivityNAD metabolismOncogenic rolePediatric gliomasMutationsModel systemCell killingDriver mutationsPediatric high-grade gliomasMutant tumorsOncogenic driver mutationsNicotinamide phosphoribosyltransferase (NAMPT) inhibitionGenomeQuantitative Profiling of Oncometabolites in Frozen and Formalin-Fixed Paraffin-Embedded Tissue Specimens by Liquid Chromatography Coupled with Tandem Mass Spectrometry
Bao X, Wu J, Shuch B, LoRusso P, Bindra RS, Li J. Quantitative Profiling of Oncometabolites in Frozen and Formalin-Fixed Paraffin-Embedded Tissue Specimens by Liquid Chromatography Coupled with Tandem Mass Spectrometry. Scientific Reports 2019, 9: 11238. PMID: 31375752, PMCID: PMC6677826, DOI: 10.1038/s41598-019-47669-5.Peer-Reviewed Original ResearchDNMT3A co-mutation in an IDH1-mutant glioblastoma
Fomchenko EI, Erson-Omay EZ, Zhao A, Bindra RS, Huttner A, Fulbright RK, Moliterno J. DNMT3A co-mutation in an IDH1-mutant glioblastoma. Molecular Case Studies 2019, 5: a004119. PMID: 31371348, PMCID: PMC6672028, DOI: 10.1101/mcs.a004119.Peer-Reviewed Original ResearchMeSH KeywordsAdultBiomarkers, TumorBrain NeoplasmsDNA (Cytosine-5-)-MethyltransferasesDNA MethylationDNA Methyltransferase 3ADNA Modification MethylasesEpigenesis, GeneticGene Expression ProfilingGene Expression Regulation, NeoplasticGlioblastomaGliomaHumansIsocitrate DehydrogenaseMaleMutationMutation, MissensePromoter Regions, GeneticConceptsIDH1-mutant glioblastomaEpigenetic controlHistone modificationsTranscriptional regulationDNA methylationExpression profilesGlioblastoma biologySomatic mutationsDe novoMutationsMutant glioblastomasTumor landscapeMutational profileTargeted therapeutic approachesGlioblastomaImportant roleMethylationDNMT3ABiologyGliomagenesisMissenseRegulationNovoPrimary brain tumorsTherapeutic approachesDefining an Intermediate-risk Group for Low-grade Glioma: A National Cancer Database Analysis
JAIRAM V, KANN BH, PARK HS, MICCIO JA, BECKTA JM, YU JB, PRABHU RS, GAO SJ, MEHTA MP, CURRAN WJ, BINDRA RS, CONTESSA JN, PATEL KR. Defining an Intermediate-risk Group for Low-grade Glioma: A National Cancer Database Analysis. Anticancer Research 2019, 39: 2911-2918. PMID: 31177129, DOI: 10.21873/anticanres.13420.Peer-Reviewed Original ResearchConceptsIntermediate-risk groupInferior overall survivalOverall survivalAdjuvant therapyLow-grade gliomasTumor sizePrognostic featuresMultivariate analysisPre-operative tumor sizeNational Cancer Database AnalysisNational Cancer DatabaseLow-risk patientsCohort of patientsKaplan-Meier methodPoor prognostic featuresGross total resectionHigh-risk groupPatterns of careAdditional prognostic featuresRTOG 9802Clinical factorsTotal resectionCancer DatabaseRisk groupsClinical classificationAssembling the brain trust: the multidisciplinary imperative in neuro-oncology
Ludmir EB, Mahajan A, Ahern V, Ajithkumar T, Alapetite C, Bernier-Chastagner V, Bindra RS, Bishop AJ, Bolle S, Brown PD, Carrie C, Chalmers AJ, Chang EL, Chung C, Dieckmann K, Esiashvili N, Gandola L, Ghia AJ, Gondi V, Grosshans DR, Harrabi SB, Horan G, Indelicato DJ, Jalali R, Janssens GO, Krause M, Laack NN, Laperriere N, Laprie A, Li J, Marcus KJ, McGovern SL, Merchant TE, Merrell KW, Padovani L, Parkes J, Paulino AC, Schwarz R, Shih HA, Souhami L, Sulman EP, Taylor RE, Thorp N, Timmermann B, Wheeler G, Wolden SL, Woodhouse KD, Yeboa DN, Yock TI, Kortmann RD, McAleer MF. Assembling the brain trust: the multidisciplinary imperative in neuro-oncology. Nature Reviews Clinical Oncology 2019, 16: 521-522. PMID: 31150024, DOI: 10.1038/s41571-019-0235-z.Peer-Reviewed Original Research