2025
Current Advances in PARP1‐Targeted Theranostics
Tong J, Chen B, Volpi T, Li Y, Ellison P, Cai Z. Current Advances in PARP1‐Targeted Theranostics. Journal Of Labelled Compounds And Radiopharmaceuticals 2025, 68: e4135. PMID: 39995212, DOI: 10.1002/jlcr.4135.Peer-Reviewed Original ResearchConceptsPoly (ADP-ribose) polymerase 1Blood-brain barrierCentral nervous systemBlood-tumor barrierPotential clinical useBRCA mutationsHomologous recombination repair pathwayPARP inhibitorsPharmacodynamic evaluationPatient stratificationPersonalized oncologyPharmacological characteristicsClinical useBrain tumorsBrain barrierDiagnostic imagingPET imagingCancerNervous systemTherapeutic interventionsBrain cancerPathophysiological conditionsTreatment assessmentPARPiNeurological disorders
2024
Human HDAC6 senses valine abundancy to regulate DNA damage
Jin J, Meng T, Yu Y, Wu S, Jiao C, Song S, Li Y, Zhang Y, Zhao Y, Li X, Wang Z, Liu Y, Huang R, Qin J, Chen Y, Cao H, Tan X, Ge X, Jiang C, Xue J, Yuan J, Wu D, Wu W, Jiang C, Wang P. Human HDAC6 senses valine abundancy to regulate DNA damage. Nature 2024, 637: 215-223. PMID: 39567688, DOI: 10.1038/s41586-024-08248-5.Peer-Reviewed Original ResearchConceptsHuman histone deacetylase 6Active DNA demethylationDNA demethylationValine deprivationDNA damageTen-eleven translocationRegulating DNA damageHistone deacetylase 6Repeat domainTherapeutic efficacy of PARP inhibitorsBind valineEfficacy of PARP inhibitorsCellular functionsPatient-derived xenograft modelsCytoplasmic shuttlingInduce DNA damageBranched amino acidsProtein synthesisAmino acidsIntracellular levelsPARP inhibitorsDNALevels of valineTumor growthTherapeutic efficacyFirst-in-human phase I trial of the oral first-in-class ubiquitin specific peptidase 1 (USP1) inhibitor KSQ-4279 (KSQi), given as single agent (SA) and in combination with olaparib (OLA) or carboplatin (CARBO) in patients (pts) with advanced solid tumors, enriched for deleterious homologous recombination repair (HRR) mutations.
Yap T, Lakhani N, Patnaik A, Lee E, Gutierrez M, Moore K, Carneiro B, Hays J, Huang M, LoRusso P, Wylie A, Cadzow L, Goulet M, Tobin E, Krieter O, Schmid D, Blake S, Dieterich M, Jamois C, Harris P. First-in-human phase I trial of the oral first-in-class ubiquitin specific peptidase 1 (USP1) inhibitor KSQ-4279 (KSQi), given as single agent (SA) and in combination with olaparib (OLA) or carboplatin (CARBO) in patients (pts) with advanced solid tumors, enriched for deleterious homologous recombination repair (HRR) mutations. Journal Of Clinical Oncology 2024, 42: 3005-3005. DOI: 10.1200/jco.2024.42.16_suppl.3005.Peer-Reviewed Original ResearchUbiquitin specific peptidase 1Treatment-emergent adverse eventsHomologous recombination repair mutationsSingle agentPARP inhibitorsHomologous recombination repairFirst-in-human phase I trialPreliminary anti-tumor activityPaired tumor biopsiesTNBC PDX modelsDisease control ratePhase I trialAUC 4Olaparib concentrationsRECIST PRDose escalationExpansion cohortCancer ptsDose proportionalityTumor biopsiesI trialMaculopapular rashPDX modelsDiscontinued treatmentDNA damage response pathwayMutational signature-based identification of DNA repair deficient gastroesophageal adenocarcinomas for therapeutic targeting
Prosz A, Sahgal P, Huffman B, Sztupinszki Z, Morris C, Chen D, Börcsök J, Diossy M, Tisza V, Spisak S, Likasitwatanakul P, Rusz O, Csabai I, Cecchini M, Baca Y, Elliott A, Enzinger P, Singh H, Ubellaker J, Lazaro J, Cleary J, Szallasi Z, Sethi N. Mutational signature-based identification of DNA repair deficient gastroesophageal adenocarcinomas for therapeutic targeting. Npj Precision Oncology 2024, 8: 87. PMID: 38589664, PMCID: PMC11001913, DOI: 10.1038/s41698-024-00561-6.Peer-Reviewed Original ResearchNucleotide excision repairGastric cancer cell linesNucleotide excision repair-deficientPlatinum chemotherapyHR deficiencyCancer cell linesPARP inhibitorsHomologous recombinationGenome sequence dataSensitivity to platinum chemotherapySingle-cell RNA sequencingCell linesHR-deficient cancersDNA repair pathwaysSensitivity to cisplatinRad51 foci assaysMutational signature analysisSequence dataGenomic featuresWhole exomeInduce apoptosisRNA sequencingGastroesophageal adenocarcinomaRepair pathwaysHRD score
2023
Intrathecal delivery of nanoparticle PARP inhibitor to the cerebrospinal fluid for the treatment of metastatic medulloblastoma
Khang M, Lee J, Lee T, Suh H, Lee S, Cavaliere A, Rushing A, Geraldo L, Belitzky E, Rossano S, de Feyter H, Shin K, Huttner A, Roussel M, Thomas J, Carson R, Marquez-Nostra B, Bindra R, Saltzman W. Intrathecal delivery of nanoparticle PARP inhibitor to the cerebrospinal fluid for the treatment of metastatic medulloblastoma. Science Translational Medicine 2023, 15: eadi1617. PMID: 37910601, PMCID: PMC11078331, DOI: 10.1126/scitranslmed.adi1617.Peer-Reviewed Original ResearchConceptsCerebrospinal fluidDelivery of drugsEffective therapyTherapeutic indexPARP inhibitorsBlood-brain barrierSite of tumorRapid systemic clearanceXenograft mouse modelSolvent evaporation processAdministration of substancesLeptomeningeal spreadIntrathecal deliveryLeptomeningeal metastasesBrain penetrationSystemic clearanceTumor regressionPolymer nanoparticlesMetastatic medulloblastomaMouse modelPediatric medulloblastomaDrug accumulationCSF turnoverEncapsulated drugsPET imagingTransforming Growth Factor Beta and Epithelial to Mesenchymal Transition Alter Homologous Recombination Repair Gene Expression and Sensitize BRCA Wild-Type Ovarian Cancer Cells to Olaparib
Roberts C, Rojas-Alexandre M, Hanna R, Lin Z, Ratner E. Transforming Growth Factor Beta and Epithelial to Mesenchymal Transition Alter Homologous Recombination Repair Gene Expression and Sensitize BRCA Wild-Type Ovarian Cancer Cells to Olaparib. Cancers 2023, 15: 3919. PMID: 37568736, PMCID: PMC10417836, DOI: 10.3390/cancers15153919.Peer-Reviewed Original ResearchEpithelial ovarian cancerRepair gene expressionPARP inhibitorsHomologous recombinationGene expressionDNA repair gene expressionCancer cellsLethal gynecologic malignancyDrug-resistant recurrenceDownregulation of genesOvarian cancer cellsGrowth factor betaWild-type cancer cellsDose-dependent mannerDNA repair genesGynecologic malignanciesMesenchymal tumorsOvarian tumorsEpithelial cell lineOvarian cancerMetastatic spreadClinical utilityEOC cellsFunctions of EMTFactor betaQuantitative DNA Repair Biomarkers and Immune Profiling for Temozolomide and Olaparib in Metastatic Colorectal Cancer
Cecchini M, Zhang J, Wei W, Sklar J, Lacy J, Zhong M, Kong Y, Zhao H, DiPalermo J, Devine L, Stein S, Kortmansky J, Johung K, Bindra R, LoRusso P, Schalper K. Quantitative DNA Repair Biomarkers and Immune Profiling for Temozolomide and Olaparib in Metastatic Colorectal Cancer. Cancer Research Communications 2023, 3: 1132-1139. PMID: 37387791, PMCID: PMC10305782, DOI: 10.1158/2767-9764.crc-23-0045.Peer-Reviewed Original ResearchConceptsWhole-exome sequencingMGMT protein expressionColorectal cancerStable diseaseQuantitative immunofluorescenceT cellsProtein expressionPromoter hypermethylationLow MGMT protein expressionPARP inhibitorsRadiographic tumor regressionMetastatic colorectal cancerAdvanced colorectal cancerPretreatment tumor biopsiesEffector T cellsTumor-infiltrating lymphocytesMGMT proteinDNA repair biomarkersBaseline CD8Eligible patientsIncreased CD8Methylguanine-DNA methyltransferaseObjective responseProgressive diseaseImmune markersNCI 7977: A Phase I Dose-Escalation Study of Intermittent Oral ABT-888 (Veliparib) Plus Intravenous Irinotecan Administered in Patients with Advanced Solid Tumors
Cecchini M, Walther Z, Wei W, Hafez N, Pilat M, Boerner S, Durecki D, Eder J, Schalper K, Chen A, LoRusso P. NCI 7977: A Phase I Dose-Escalation Study of Intermittent Oral ABT-888 (Veliparib) Plus Intravenous Irinotecan Administered in Patients with Advanced Solid Tumors. Cancer Research Communications 2023, 3: 1113-1117. PMID: 37377610, PMCID: PMC10292219, DOI: 10.1158/2767-9764.crc-22-0485.Peer-Reviewed Original ResearchConceptsDose-limiting toxicityHomologous recombination deficiencyPARP inhibitorsStable diseaseWeekly irinotecanObjective responseDay 1Day 3Solid tumorsPhase I dose-escalation studyTwice daily days 1I dose-escalation studyPhase I clinical trialDaily days 1Dose level 1Doses of veliparibGrade 3 neutropeniaMultiple-dose schedulesProgression-free survivalAdvanced solid tumorsDose-escalation studyEvaluable patientsNonoverlapping toxicitiesDose scheduleSystemic treatmentHRD signature and HRD genomic landscape of tumors from 896 patients with early-stage breast cancer (BC).
Jeon J, Chen K, Madison R, Schrock A, Sokol E, Levy M, Oxnard G, Huang R, Pusztai L. HRD signature and HRD genomic landscape of tumors from 896 patients with early-stage breast cancer (BC). Journal Of Clinical Oncology 2023, 41: 539-539. DOI: 10.1200/jco.2023.41.16_suppl.539.Peer-Reviewed Original ResearchEarly-stage breast cancerPrimary breast cancerEarly breast cancerBreast cancerStage IHR-/HER2HRR deficiencyPALB2 mutationsEarly-stage primary breast cancerPARP inhibitorsStage IV diseaseHormone receptor statusMonths of diagnosisPositive breast cancerHomologous recombination repairComprehensive genomic profilingHRD signaturesClinical trial dataHigh rateSEER studySomatic BRCAAdjuvant therapyAdvanced diseaseReceptor statusBC subtypesReal-World Efficacy and Safety of PARP Inhibitors in Recurrent Ovarian Cancer Patients With Somatic BRCA and Other Homologous Recombination Gene Mutations
Pan Y, Hood A, Ahmad H, Altwerger G. Real-World Efficacy and Safety of PARP Inhibitors in Recurrent Ovarian Cancer Patients With Somatic BRCA and Other Homologous Recombination Gene Mutations. Annals Of Pharmacotherapy 2023, 57: 1162-1171. PMID: 36651235, PMCID: PMC11062080, DOI: 10.1177/10600280221149136.Peer-Reviewed Original ResearchConceptsRecurrent ovarian cancer patientsOvarian cancer patientsSomatic BRCA mutationsOverall response rateCancer patientsBRCA mutationsPARP inhibitorsStable diseaseResponse rateHR mutationsDuration of therapyDuration of treatmentSomatic BRCA1/2 mutationsPoly (ADP-ribose) polymerase (PARP) inhibitorsReal-world efficacyElectronic medical recordsHomologous recombination mutationsSomatic BRCAMedian TTPTreatment interruptionChart reviewRetrospective studyEfficacy analysisEntire cohortMajor trialsCisplatin with veliparib or placebo in metastatic triple-negative breast cancer and BRCA mutation-associated breast cancer (S1416): a randomised, double-blind, placebo-controlled, phase 2 trial
Rodler E, Sharma P, Barlow W, Gralow J, Puhalla S, Anders C, Goldstein L, Tripathy D, Brown-Glaberman U, Huynh T, Szyarto C, Godwin A, Pathak H, Swisher E, Radke M, Timms K, Lew D, Miao J, Pusztai L, Hayes D, Hortobagyi G. Cisplatin with veliparib or placebo in metastatic triple-negative breast cancer and BRCA mutation-associated breast cancer (S1416): a randomised, double-blind, placebo-controlled, phase 2 trial. The Lancet Oncology 2023, 24: 162-174. PMID: 36623515, PMCID: PMC9924094, DOI: 10.1016/s1470-2045(22)00739-2.Peer-Reviewed Original ResearchConceptsTriple-negative breast cancerMedian progression-free survivalProgression-free survivalMetastatic breast cancerMetastatic triple-negative breast cancerGermline BRCA1/2Phase 2 trialVeliparib groupPlacebo groupPlatinum-based chemotherapyBreast cancerHomologous recombination deficiencyAdverse eventsPARP inhibitorsEligible patientsMetastatic diseaseEastern Cooperative Oncology Group performance statusBRCA mutation-associated breast cancerInvestigator-assessed progression-free survivalTreatment-related adverse eventsRecurrent triple-negative breast cancerAcademic clinical sitesAddition of veliparibCommon grade 3Lines of chemotherapy
2022
The Role of PARP Inhibitors in Patients with Primary Malignant Central Nervous System Tumors
Gueble SE, Vasquez JC, Bindra RS. The Role of PARP Inhibitors in Patients with Primary Malignant Central Nervous System Tumors. Current Treatment Options In Oncology 2022, 23: 1566-1589. PMID: 36242713, DOI: 10.1007/s11864-022-01024-5.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsHomologous recombination deficiencyPrimary CNS tumorsCNS tumorsClinical trialsPARP inhibitorsPreclinical evidencePrimary malignant central nervous system tumorMalignant central nervous system tumorsCentral nervous system tumorsImmune checkpoint inhibitorsStandard treatment modalityInitial clinical trialsEarly phase trialsNervous system tumorsCentral nervous tumorsExtracranial cancerCheckpoint inhibitorsDevastating malignancyStandard therapyOngoing trialsCombination therapyTreatment optionsTreatment modalitiesSystem tumorsPhase trialsMutational Signature 3 Detected from Clinical Panel Sequencing is Associated with Responses to Olaparib in Breast and Ovarian Cancers
Batalini F, Gulhan DC, Mao V, Tran A, Polak M, Xiong N, Tayob N, Tung NM, Winer EP, Mayer EL, Knappskog S, Lønning PE, Matulonis UA, Konstantinopoulos PA, Solit DB, Won H, Eikesdal HP, Park PJ, Wulf GM. Mutational Signature 3 Detected from Clinical Panel Sequencing is Associated with Responses to Olaparib in Breast and Ovarian Cancers. Clinical Cancer Research 2022, 28: of1-of10. PMID: 36048535, PMCID: PMC9623231, DOI: 10.1158/1078-0432.ccr-22-0749.Peer-Reviewed Original ResearchConceptsHomologous recombination deficiencyTriple-negative breast cancerMutational signature 3Ovarian cancerImproved progression-free survivalPARP inhibitorsPanel sequencingHigh-grade serous ovarian cancerPI3K inhibitor buparlisibPhase Ib trialProgression-free survivalIdentification of patientsRoutine clinical careSignature 3Serous ovarian cancerPARP inhibitor olaparibSame patient sampleIb trialObjective responseTNBC patientsBreast cancerBRCA1/2 mutationsClinical careInstability scoreGenomic instability scoreEmerging Role of PARP Inhibitors in Metastatic Prostate Cancer
Unlu S, Kim JW. Emerging Role of PARP Inhibitors in Metastatic Prostate Cancer. Current Oncology Reports 2022, 24: 1619-1631. PMID: 35931885, DOI: 10.1007/s11912-022-01305-0.Peer-Reviewed Original ResearchConceptsPARP inhibitorsBRCA2 mutationsProstate cancerFDA approvalMetastatic prostate cancer patientsAccelerated FDA approvalDeleterious BRCA2 mutationsHRR gene mutationsObjective response ratePhase II studyMetastatic prostate cancerProstate cancer patientsPoly (ADP-ribose) polymerase (PARP) inhibitorsUS FDA approvalSomatic mutationsMCRPC patientsCombination regimenII studyClinical benefitRadium-223Cancer patientsStandard treatmentAndrogen receptorDNA damage repair pathwaysClinical developmentA phase II study of talazoparib plus avelumab in patients with stage IV or recurrent nonsquamous non–small cell lung cancer bearing pathogenic STK11 genomic alterations (SWOG S1900C, LUNG-MAP sub-study, NCT04173507).
Skoulidis F, Redman M, Suga J, Al Baghdadi T, Villano J, Goldberg S, Villaruz L, Minichiello K, Gandara D, Herbst R, Kelly K. A phase II study of talazoparib plus avelumab in patients with stage IV or recurrent nonsquamous non–small cell lung cancer bearing pathogenic STK11 genomic alterations (SWOG S1900C, LUNG-MAP sub-study, NCT04173507). Journal Of Clinical Oncology 2022, 40: 9060-9060. DOI: 10.1200/jco.2022.40.16_suppl.9060.Peer-Reviewed Original ResearchObjective response ratePhase II studyCheckpoint inhibitorsII studyStage IVPrior linesGenomic alterationsSingle-arm phase II studyArm phase II studyBest objective response rateMedian progression-free survivalPARP inhibitorsAdequate organ functionCo-primary objectivesDurable disease stabilizationMost grade 3PD-L1 TPSDisease control rateImmune checkpoint inhibitorsMedian overall survivalNon-squamous NSCLCStage IV diseaseProgression-free survivalBest objective responseOptimal therapeutic approachMulticenter phase 2 trial of the PARP inhibitor (PARPi) olaparib in recurrent IDH1 and IDH2-mutant contrast-enhancing glioma.
Fanucci K, Pilat M, Shah R, Boerner S, Li J, Durecki D, Drappatz J, Collichio F, Puduvalli V, Lieberman F, Gonzalez J, Giglio P, Bao X, Ivy S, Bindra R, Omuro A, LoRusso P. Multicenter phase 2 trial of the PARP inhibitor (PARPi) olaparib in recurrent IDH1 and IDH2-mutant contrast-enhancing glioma. Journal Of Clinical Oncology 2022, 40: 2035-2035. DOI: 10.1200/jco.2022.40.16_suppl.2035.Peer-Reviewed Original ResearchProgression-free survivalMedian progression-free survivalStable diseaseDuration of responseOverall response ratePARP inhibitorsOverall survivalStandard therapyOlaparib monotherapyMulticenter phase 2 trialCDKN2A deletionClinical predictive markersGrade 3 lymphopeniaProlonged stable diseasePhase 2 trialGrade 4 tumorsFuture patient stratificationRecent preclinical studiesHigh-grade gliomasNovel drug combinationsContrast-enhancing gliomasEligible ptsEvaluable ptsRecent histologyPrimary endpointSTING agonism reprograms tumor-associated macrophages and overcomes resistance to PARP inhibition in BRCA1-deficient models of breast cancer
Wang Q, Bergholz JS, Ding L, Lin Z, Kabraji SK, Hughes ME, He X, Xie S, Jiang T, Wang W, Zoeller JJ, Kim HJ, Roberts TM, Konstantinopoulos PA, Matulonis UA, Dillon DA, Winer EP, Lin NU, Zhao JJ. STING agonism reprograms tumor-associated macrophages and overcomes resistance to PARP inhibition in BRCA1-deficient models of breast cancer. Nature Communications 2022, 13: 3022. PMID: 35641483, PMCID: PMC9156717, DOI: 10.1038/s41467-022-30568-1.Peer-Reviewed Original ResearchConceptsAnti-tumor immunityBreast cancerPARP inhibitorsSTING agonistsBRCA-mutant breast cancerTumor cellsAnti-tumor stateAdvanced ovarian tumorsCell-mediated suppressionType I IFN responseTumor-associated macrophagesInnate immune suppressionI IFN responseBreast tumor cellsTreatment landscapePro-tumor macrophagesImmune suppressionOvarian tumorsImmune cellsBRCA mutationsSystemic administrationT cellsMouse modelTherapeutic benefitBreast tumorsThe Pathogenic R3052W BRCA2 Variant Disrupts Homology-Directed Repair by Failing to Localize to the Nucleus
Jimenez-Sainz J, Krysztofiak A, Garbarino J, Rogers F, Jensen RB. The Pathogenic R3052W BRCA2 Variant Disrupts Homology-Directed Repair by Failing to Localize to the Nucleus. Frontiers In Genetics 2022, 13: 884210. PMID: 35711920, PMCID: PMC9197106, DOI: 10.3389/fgene.2022.884210.Peer-Reviewed Original ResearchDominant-negative alleleDNA damage responseDNA repair functionDNA strand exchangeHomology-directed repairGenome instabilityCellular functionsDamage responseDNA bindingNegative allelesStrand exchangeRepair functionGermline missense variantsCell survivalFunction mutationsMissense variantsRAD51Pathogenic allelesSimple lossPARP inhibitorsCytoplasmProteinAllelesHomologyDNAClinical utility of next-generation sequencing for prostate cancer in the context of a changing treatment landscape.
Griffin J, Jun T, Liaw B, Guin S, Tsao C, Patel V, Rossi M, Zhou X, Hantash F, Chen R, Oh W. Clinical utility of next-generation sequencing for prostate cancer in the context of a changing treatment landscape. Journal Of Clinical Oncology 2022, 40: 112-112. DOI: 10.1200/jco.2022.40.6_suppl.112.Peer-Reviewed Original ResearchProstate cancerClinical utilityPCa patientsActionable alterationsTreatment landscapeNext-generation sequencingFDA approvalPARP inhibitorsSingle-center retrospective cohortRetrospective single-center studySingle academic medical centerHomologous recombination repair genesAlternative systemic therapiesUnknown treatment statusProportion of patientsSingle-center studyMetastatic PCa patientsMetastatic prostate cancerMount Sinai HospitalSolid tumor panelAcademic medical centerElectronic medical recordsRecombination repair genesMedian TTNTMetastatic patients
2021
Matched cohort study of germline BRCA mutation carriers with triple negative breast cancer in brightness
Metzger-Filho O, Collier K, Asad S, Ansell PJ, Watson M, Bae J, Cherian M, O’Shaughnessy J, Untch M, Rugo HS, Huober JB, Golshan M, Sikov WM, von Minckwitz G, Rastogi P, Li L, Cheng L, Maag D, Wolmark N, Denkert C, Symmans WF, Geyer CE, Loibl S, Stover DG. Matched cohort study of germline BRCA mutation carriers with triple negative breast cancer in brightness. Npj Breast Cancer 2021, 7: 142. PMID: 34764307, PMCID: PMC8586340, DOI: 10.1038/s41523-021-00349-y.Peer-Reviewed Original ResearchTriple-negative breast cancerNeoadjuvant chemotherapyCohort studyBreast cancerInstability scoreGenomic instability scoreGermline BRCA mutation carriersPathologic complete response rateAddition of carboplatinComplete response rateStandard neoadjuvant chemotherapyLymph node statusBRCA mutation carriersGermline BRCA1/2 mutationsNegative breast cancerOverall cohortNode statusTreatment armsHigher oddsMutation carriersBRCA1/2 mutationsResponse rateCarboplatinPARP inhibitorsCancer
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