2024
The novel DNA cross-linking agent KL-50 is active against patient-derived models of new and recurrent post-temozolomide mismatch repair-deficient glioblastoma
McCord M, Sears T, Wang W, Chaliparambil R, An S, Sarkaria J, James C, Ruggeri B, Gueble S, Bindra R, Horbinski C. The novel DNA cross-linking agent KL-50 is active against patient-derived models of new and recurrent post-temozolomide mismatch repair-deficient glioblastoma. Neuro-Oncology 2024, 27: 644-651. PMID: 39658092, PMCID: PMC11889708, DOI: 10.1093/neuonc/noae257.Peer-Reviewed Original ResearchMedian survival of miceSurvival of miceMedian survivalIDH wild-type glioblastomaO-6-methylguanine-DNA methyltransferaseExposure to temozolomideAcquired resistance to TMZWild-type glioblastomaPatient-derived xenograftsSensitivity to temozolomidePatient-derived modelsResistance to temozolomideLN229 glioma cellsPatient-derived glioblastomaRecurrent tumorsMGMT deficiencyFractionated RTTemozolomideLow dosesImprove outcomesGlioblastomaEnzyme deficiencyMismatch repairGlioma cellsGBM12EXTH-23. NEW DNA-CROSSLINKING CHEMOTHERAPY IS EFFECTIVE AGAINST POST-TEMOZOLOMIDE MISMATCH REPAIR-DEFICIENT PATIENT-DERIVED HYPERMUTANT GLIOMAS
McCord M, Wang W, An S, Sears T, Sarkaria J, James C, Ruggieri B, Bindra R, Horbinski C. EXTH-23. NEW DNA-CROSSLINKING CHEMOTHERAPY IS EFFECTIVE AGAINST POST-TEMOZOLOMIDE MISMATCH REPAIR-DEFICIENT PATIENT-DERIVED HYPERMUTANT GLIOMAS. Neuro-Oncology 2024, 26: viii241-viii241. PMCID: PMC11553709, DOI: 10.1093/neuonc/noae165.0954.Peer-Reviewed Original ResearchPatient-derived xenograftsDNA inter-strand cross-linksMismatch repairDNA mismatch repairGlioblastoma cell linesBase mismatchesShRNA knockdownGlioblastoma patient-derived xenograftsMGMT deficiencyMGMT-deficient cellsDNA damageInter-strand cross-linksDNAMMR-deficient tumor cellsCell linesPatient-derived xenograft modelsComplementary in vitro studiesAlkylating agent temozolomideMMR genesVehicle control miceDays post-engraftmentApoptosisMismatch repair mutationsDNA basesResistance to temozolomidePKCδ-Mediated Phosphorylation of CD25 Initiates Feedback Control of Oncogenic Tyrosine Kinases in Acute Lymphoblastic Leukemia
Sun R, Lee J, Artadji D, Robinson M, Kume K, Cheng Z, Cosgun K, Chan L, Leveille E, Ma N, Geng H, Paietta E, Vaidehi N, Müschen M. PKCδ-Mediated Phosphorylation of CD25 Initiates Feedback Control of Oncogenic Tyrosine Kinases in Acute Lymphoblastic Leukemia. Blood 2024, 144: 632-632. DOI: 10.1182/blood-2024-211038.Peer-Reviewed Original ResearchB-ALL cellsPatient-derived xenograftsPh+ B-ALLPh-like B-ALLAntibody-drug conjugatesB-ALL casesB-ALLCre-mediated deletionOncogenic tyrosine kinasesBCR-ABL1Tyrosine kinase signalingSurface expressionColony formation capacityCD25 mRNACell surface expression of CD25Tyrosine kinaseGenetic deletionSurface expression of CD25Oncogenic tyrosine kinase signalingKinase signalingOncogene BCR-ABL1Transplant recipient miceControl ADCNegative feedback regulationExpression of CD25Using Structure-Based Modeling to Identify Effective Drug Combinations in RAS-Mutant Acute Myeloid Leukemia
Jones L, Rukhlenko O, Dias T, Carmody C, Wynne K, Kholodenko B, Bond J. Using Structure-Based Modeling to Identify Effective Drug Combinations in RAS-Mutant Acute Myeloid Leukemia. Blood 2024, 144: 4161-4161. DOI: 10.1182/blood-2024-207308.Peer-Reviewed Original ResearchAcute myeloid leukemiaPatient-derived xenograftsCombination-treated miceInhibitor combinationsPeripheral bloodPhosphorylated ERKBone marrowRAS pathway activationSpleen weightMyeloid leukemiaAML patient-derived xenograftDrug combinationsVehicle controlSingle agentHuman CD45+ cellsPre-clinical mouse modelPediatric acute myeloid leukemiaAssociated with poor outcomesHigh-risk patient groupsMedian spleen weightSB-treated micePreclinical in vivo modelsCD45+ cellsLateral tail veinPathway activationTargeting TREX1 induces innate immune response in drug-resistant Small Cell Lung Cancer
Murayama T, Mahadevan N, Meador C, Ivanova E, Pan Y, Knelson E, Tani T, Nakayama J, Ma X, Thai T, Hung Y, Kim W, Watanabe H, Cai K, Hata A, Paweletz C, Barbie D, Cañadas I. Targeting TREX1 induces innate immune response in drug-resistant Small Cell Lung Cancer. Cancer Research Communications 2024, 4: 2399-2414. PMID: 39177280, PMCID: PMC11391691, DOI: 10.1158/2767-9764.crc-24-0360.Peer-Reviewed Original ResearchConceptsSmall-cell lung cancerPatient-derived xenograftsCells to chemotherapyLung cancerInnate immune responseImmune responseSmall cell lung cancerHuman SCLC tumorsSurvival of resistant cellsResponse to chemotherapyCell lung cancerEfficacy of chemotherapyRepair exonuclease 1Postchemotherapy samplesAntitumor immunitySCLC tumorsCold tumorsAvailable therapiesChromatin immunoprecipitation sequencingTransposase-accessible chromatinInduce immunogenicityChemotherapyResistant cellsTherapeutic strategiesTREX1 expressionDetecting small cell transformation in patients with advanced EGFR mutant lung adenocarcinoma through epigenomic cfDNA profiling
Zarif T, Meador C, Qiu X, Seo J, Davidsohn M, Savignano H, Lakshminarayanan G, McClure H, Canniff J, Fortunato B, Li R, Banwait M, Semaan K, Eid M, Long H, Hung Y, Mahadevan N, Barbie D, Oser M, Piotrowska Z, Choueiri T, Baca S, Hata A, Freedman M, Berchuck J. Detecting small cell transformation in patients with advanced EGFR mutant lung adenocarcinoma through epigenomic cfDNA profiling. Clinical Cancer Research 2024, 30: 3798-3811. PMID: 38912901, PMCID: PMC11369616, DOI: 10.1158/1078-0432.ccr-24-0466.Peer-Reviewed Original ResearchConceptsEGFR mutant lung adenocarcinomaSmall cell lung cancerSmall cell transformationLung cancer patient-derived xenograftPatient-derived xenograftsLung adenocarcinomaEGFR mutantsChIP-seqEpigenomic featuresMeDIP-seqImmunoprecipitation sequencingCell transformationHistological transformation to small cell lung cancerTransformation to small cell lung cancerMethylated DNA immunoprecipitation sequencingTransposase-accessible chromatin sequencingH3K27ac ChIP-seqMechanisms of treatment resistanceChromatin immunoprecipitation sequencingHistone modification H3K27acMutant lung adenocarcinomaCell lung cancerChromatin accessibilityChromatin sequencingEpigenomic landscapeA first-in-human, phase 1, dose escalation study of SGR-2921 as monotherapy in patients with relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome.
Weiss D, Dinardo C, Strickland S, Skikne B, Zeidan A, Traer E, Carraway H, Carraway H, Frankel S, Wang J, Pirie-Shepherd S, Piccotti J, Wright D, Akinsanya K. A first-in-human, phase 1, dose escalation study of SGR-2921 as monotherapy in patients with relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome. Journal Of Clinical Oncology 2024, 42: tps6590-tps6590. DOI: 10.1200/jco.2024.42.16_suppl.tps6590.Peer-Reviewed Original ResearchEastern Cooperative Oncology GroupCell line-derived xenograftsDose-escalation studyMaximum tolerated dosePatient-derived xenograftsHigh riskEscalation studyTreatment armsEffects of CYP3A4 inhibitionRecommended phase 2 doseRelapsed/refractory acute myeloid leukemiaPhase 2 doseAccelerated titration designMinichromosome maintenance protein 2Preliminary antitumor activityCooperative Oncology GroupFirst-in-humanAcute myeloid leukemiaGrade 2 eventsTreated patient populationTolerated dose levelsAML cell linesAnti-tumor activityInhibition of Cdc7Cancer cell deathASCL1 Drives Tolerance to Osimertinib in EGFR Mutant Lung Cancer in Permissive Cellular Contexts.
Hu B, Wiesehöfer M, de Miguel F, Liu Z, Chan L, Choi J, Melnick M, Arnal Estape A, Walther Z, Zhao D, Lopez-Giraldez F, Wurtz A, Cai G, Fan R, Gettinger S, Xiao A, Yan Q, Homer R, Nguyen D, Politi K. ASCL1 Drives Tolerance to Osimertinib in EGFR Mutant Lung Cancer in Permissive Cellular Contexts. Cancer Research 2024, 84: 1303-1319. PMID: 38359163, DOI: 10.1158/0008-5472.can-23-0438.Peer-Reviewed Original ResearchTyrosine kinase inhibitorsPatient-derived xenograftsEGFR mutant lung cancerMutant lung cancerPre-treatment tumorsResidual diseaseDrug toleranceLung cancerResidual tumor cells in vivoEGFR mutant lung adenocarcinomaTyrosine kinase inhibitor osimertinibEGFR tyrosine kinase inhibitorsTyrosine kinase inhibitor treatmentTumor cells in vivoMutant lung adenocarcinomaMaximal tumor regressionTranscription factor Ascl1Drug-tolerant cellsTime of maximal responseEvidence of cellsCells in vivoOsimertinib treatmentTumor regressionSingle cell transcriptional profilingTumor cellsAntitumor efficacy of a sequence-specific DNA-targeted γPNA-based c-Myc inhibitor
Malik S, Pradeep S, Kumar V, Xiao Y, Deng Y, Fan R, Vasquez J, Singh V, Bahal R. Antitumor efficacy of a sequence-specific DNA-targeted γPNA-based c-Myc inhibitor. Cell Reports Medicine 2024, 5: 101354. PMID: 38183981, PMCID: PMC10829792, DOI: 10.1016/j.xcrm.2023.101354.Peer-Reviewed Original ResearchConceptsTarget genomic DNAGenomic DNASequencing of genomic DNAGenomic DNA levelInhibit c-myc transcriptionC-myc transcriptionGenomic DNA targetsTarget oncogenesMultiple cell linesC-Myc inhibitorCancer therapyHistone deacetylase inhibitorsRNA targetsDNA targetsPatient-derived xenograftsPre-clinical modelsDNADeacetylase inhibitorsCell linesOncogeneInhibiting oncogenesDNA levelsAntitumor efficacyPrecision medicineChemotherapeutic drugs
2023
Elimusertib has anti-tumor activity in preclinical patient-derived pediatric solid tumor models
Pusch F, García H, Xu R, Gürgen D, Bei Y, Brückner L, Röefzaad C, von Stebut J, Bardinet V, Gonzalez R, Eggert A, Schulte J, Hundsdörfer P, Seifert G, Haase K, Schäfer B, Wachtel M, Kühl A, Ortiz M, Wengner A, Scheer M, Henssen A. Elimusertib has anti-tumor activity in preclinical patient-derived pediatric solid tumor models. Molecular Cancer Therapeutics 2023, 23: 507-519. PMID: 38159110, PMCID: PMC10985474, DOI: 10.1158/1535-7163.mct-23-0094.Peer-Reviewed Original ResearchConceptsPatient-derived xenograftsPediatric solid tumor modelsPreclinical antitumor activitySolid tumor modelsTumor modelStandard-of-care chemotherapyAntitumor activityInhibitor of ataxia telangiectasiaSolid tumor entitiesClinically meaningful responseAnti-tumor activityPreclinical activityRad3-related proteinTumor entitiesPediatric malignanciesAntitumor effectCancer entitiesResponse biomarkersSmall molecule inhibitorsClinical trialsElimusertibMeaningful responseAtaxia telangiectasiaResponse rateCell linesDynamic Recruitment of Inhibitory Complexes Controls Oncogenic Signaling in B-Cell Malignancies
Sun R, Lee J, Robinson M, Kume K, Ma N, Cosgun K, Chan L, Antoshkina I, Khanduja D, Leveille E, Katz S, Chen J, Paietta E, Vaidehi N, Müschen M. Dynamic Recruitment of Inhibitory Complexes Controls Oncogenic Signaling in B-Cell Malignancies. Blood 2023, 142: 719. DOI: 10.1182/blood-2023-189742.Peer-Reviewed Original ResearchB-cell malignanciesB-cell lymphomaHigher serum levelsMature B-cell lymphomasSoluble CD25Serum levelsOncogenic signalingMouse modelB cellsAggressive B-cell lymphomasAcceleration of diseaseActivation of inhibitoryPoor clinical outcomeCD25 surface expressionB cell subsetsRole of CD25Patient-derived xenograftsB cell populationsB-cell receptor signalingB-cell leukemiaGenetic mouse modelsKnockin mouse modelCell deathMature B cell populationClinical outcomesE7820, an Anti-Cancer Sulfonamide, in Combination with Venetoclax in Patients with Splicing Factor Mutant Myeloid Malignancies: A Phase II Clinical Trial
Bewersdorf J, Chandhok N, Watts J, Derkach A, Abdel-Wahab O, Stein E, Taylor J. E7820, an Anti-Cancer Sulfonamide, in Combination with Venetoclax in Patients with Splicing Factor Mutant Myeloid Malignancies: A Phase II Clinical Trial. Blood 2023, 142: 1547. DOI: 10.1182/blood-2023-182369.Peer-Reviewed Original ResearchAcute myeloid leukemiaEastern Cooperative Oncology GroupPhase II clinical trialChronic myelomonocytic leukemiaMyelodysplastic syndromePatient-derived xenograftsII clinical trialsPreclinical dataSplicing factor genesMyeloid malignanciesClinical trialsAdequate end-organ functionContext of combination therapyDay 1Safety run-in phaseRefractory acute myeloid leukemiaSimon 2-stage designResponse rateDynamic BH3 profilingCycles of therapyNegative prognostic impactEvent-free survivalMyelodysplastic syndrome patientsHuman acute myeloid leukemiaPhase II trialMultiomics identifies metabolic subtypes based on fatty acid degradation allocating personalized treatment in hepatocellular carcinoma
Li B, Li Y, Zhou H, Xu Y, Cao Y, Cheng C, Peng J, Li H, Zhang L, Su K, Xu Z, Hu Y, Lu J, Lu Y, Qian L, Wang Y, Zhang Y, Liu Q, Xie Y, Guo S, Mehal W, Yu D. Multiomics identifies metabolic subtypes based on fatty acid degradation allocating personalized treatment in hepatocellular carcinoma. Hepatology 2023, 79: 289-306. PMID: 37540187, PMCID: PMC10789383, DOI: 10.1097/hep.0000000000000553.Peer-Reviewed Original ResearchImmune checkpoint inhibitorsPatient-derived xenograftsTransarterial chemoembolizationF1 subtypeMolecular classificationAnti-programmed cell death-1 therapyNovel molecular classificationCancer patient therapyCheckpoint inhibitorsBevacizumab treatmentPD-L1Immunosuppressive microenvironmentRNA sequencingPatient cohortHepatocellular carcinomaImmunological characteristicsTherapeutic strategiesPotential respondersPatient therapyYM-155Prognosis predictionPrecision therapySingle-cell RNA sequencingMetabolic subtypesTumor microenvironmentExportin 1 inhibition prevents neuroendocrine transformation through SOX2 down-regulation in lung and prostate cancers
Quintanal-Villalonga A, Durani V, Sabet A, Redin E, Kawasaki K, Shafer M, Karthaus W, Zaidi S, Zhan Y, Manoj P, Sridhar H, Shah N, Chow A, Bhanot U, Linkov I, Asher M, Yu H, Qiu J, de Stanchina E, Patel R, Morrissey C, Haffner M, Koche R, Sawyers C, Rudin C. Exportin 1 inhibition prevents neuroendocrine transformation through SOX2 down-regulation in lung and prostate cancers. Science Translational Medicine 2023, 15: eadf7006. PMID: 37531417, PMCID: PMC10777207, DOI: 10.1126/scitranslmed.adf7006.Peer-Reviewed Original ResearchConceptsPatient-derived xenograftsProstatic adenocarcinomaNE transformationXenograft modelExportin 1Associated with poor prognosisProstate adenocarcinoma cell lineInactivation of TP53Adenocarcinoma xenograft modelEctopic SOX2 expressionEGFR inhibitor osimertinibAdenocarcinoma cell lineNE phenotypeNeuroendocrine transformationSelinexor treatmentStandard cytotoxicsProstate cancerLineage plasticityPotential therapeutic targetNE featuresPoor prognosisProstateSOX2 expressionAdenocarcinomaLung
2022
Elimusertib (BAY1895344), a novel ATR inhibitor, demonstrates in vivo activity in ATRX mutated models of uterine leiomyosarcoma
Harold J, Bellone S, Manavella D, Mutlu L, McNamara B, Hartwich T, Zipponi M, Yang-Hartwich Y, Demirkiran C, Verzosa M, Choi J, Dong W, Buza N, Hui P, Altwerger G, Huang G, Andikyan V, Clark M, Ratner E, Azodi M, Schwartz P, Santin A. Elimusertib (BAY1895344), a novel ATR inhibitor, demonstrates in vivo activity in ATRX mutated models of uterine leiomyosarcoma. Gynecologic Oncology 2022, 168: 157-165. PMID: 36442427, PMCID: PMC9797429, DOI: 10.1016/j.ygyno.2022.11.014.Peer-Reviewed Original ResearchConceptsPatient-derived xenograftsUterine leiomyosarcomaVivo activityVehicle control treatmentMedian overall survivalTumor volume differencesOral scheduleWestern blot analysisOverall survivalOral gavageAggressive malignancyPDX modelsClinical trialsSCID miceTumor measurementsULMS patientsSignificant growth inhibitionNovel ATR inhibitorTumor samplesSignificant toxicityWestern blotKinase inhibitorsATRX mutationsGene mutationsControl vehiclePreclinical and clinical efficacy of trastuzumab deruxtecan in breast cancer brain metastases
Kabraji S, Ni J, Sammons S, Li T, Van Swearingen AED, Wang Y, Pereslete A, Hsu L, DiPiro PJ, Lascola C, Moore H, Hughes M, Raghavendra AS, Gule-Monroe M, Murthy RK, Winer EP, Anders CK, Zhao JJ, Lin NU. Preclinical and clinical efficacy of trastuzumab deruxtecan in breast cancer brain metastases. Clinical Cancer Research 2022, 29: 174-182. PMID: 36074155, PMCID: PMC9811155, DOI: 10.1158/1078-0432.ccr-22-1138.Peer-Reviewed Original ResearchConceptsBreast cancer brain metastasesActive brain metastasesObjective response rateCNS objective response rateCancer brain metastasesBrain metastasesT-DXdPatient-derived xenograftsPDX modelsCohort studyTrastuzumab deruxtecanClinical efficacyClinical trialsHER2-positive breast cancer brain metastasesMetastatic HER2-positive breast cancerResponse rateMulti-institutional cohort studyHER2-positive breast cancerRetrospective multi-institutional cohort studyOrthotopic patient-derived xenograftsRetrospective cohort studyProspective clinical trialsSubset of patientsCentral nervous system activityPivotal clinical trialsYES1 Is a Druggable Oncogenic Target in SCLC
Redin E, Garrido-Martin EM, Valencia K, Redrado M, Solorzano JL, Carias R, Echepare M, Exposito F, Serrano D, Ferrer I, Nunez-Buiza A, Garmendia I, García-Pedrero JM, Gurpide A, Paz-Ares L, Politi K, Montuenga LM, Calvo A. YES1 Is a Druggable Oncogenic Target in SCLC. Journal Of Thoracic Oncology 2022, 17: 1387-1403. PMID: 35988891, DOI: 10.1016/j.jtho.2022.08.002.Peer-Reviewed Original ResearchConceptsSubpopulation of patientsOncogenic targetsPatient-derived xenograftsMarked antitumor activityGain/amplificationPlasma-derived exosomesDistant metastasisIndependent predictorsTargetable oncogenesPoor prognosisAggressive subtypeClinical managementLung cancerPharmacologic blockadeTumor regressionMouse modelTumor growthPlasma exosomesMolecular subgroupsPharmacologic inhibitionMetastasisAntitumor activityFunctional experimentsOrganoid modelsClinical samplesA phase Ia/Ib, dose-escalation/expansion study of the MDM2–p53 antagonist BI 907828 in patients with solid tumors, including advanced/metastatic liposarcoma (LPS).
Gounder M, Yamamoto N, Patel M, Bauer T, Schöffski P, Grempler R, Durland-Busbice S, Geng J, Maerten A, LoRusso P. A phase Ia/Ib, dose-escalation/expansion study of the MDM2–p53 antagonist BI 907828 in patients with solid tumors, including advanced/metastatic liposarcoma (LPS). Journal Of Clinical Oncology 2022, 40: 3004-3004. DOI: 10.1200/jco.2022.40.16_suppl.3004.Peer-Reviewed Original ResearchAdvanced liposarcomaDay 1Solid tumorsECOG PS 0/1Manageable safety profileObjective response rateOverall safety dataPrior systemic therapyTreatment-related AEsGDF-15 levelsAdvanced solid tumorsSubgroup of patientsNumber of patientsPatient-derived xenograftsHigher plasma exposureTarget engagement markerPart AEvaluable patientsIA/IBPS 0/1Dose expansionPrimary endpointMetastatic liposarcomaOverall survivalArm Bp16INK4A-deficiency predicts response to combined HER2 and CDK4/6 inhibition in HER2+ breast cancer brain metastases
Ni J, Kabraji S, Xie S, Wang Y, Pan P, He X, Liu Z, Leone JP, Long HW, Brown MA, Winer EP, Dillon DAR, Lin NU, Zhao JJ. p16INK4A-deficiency predicts response to combined HER2 and CDK4/6 inhibition in HER2+ breast cancer brain metastases. Nature Communications 2022, 13: 1473. PMID: 35304445, PMCID: PMC8933392, DOI: 10.1038/s41467-022-29081-2.Peer-Reviewed Original ResearchConceptsPatient-derived xenograftsBrain metastasesMetastatic HER2-positive breast cancerBiomarker-driven clinical trialsBreast cancer brain metastasesHER2-positive breast cancerOrthotopic patient-derived xenograftsMajority of HER2Cancer brain metastasesCDK4/6 inhibitionProtein immunohistochemistryClinical trialsBreast cancerHER2Tumor suppressor p16INK4aPatientsMetastasisBCBMAbemaciclibTucatinibXenograftsImmunohistochemistryCancerCDK4/6TrialsComprehensive Analysis of Metabolic Isozyme Targets in Cancer
Marczyk M, Gunasekharan V, Casadevall D, Qing T, Foldi J, Sehgal R, Shan NL, Blenman KRM, O'Meara TA, Umlauf S, Surovtseva YV, Muthusamy V, Rinehart J, Perry RJ, Kibbey R, Hatzis C, Pusztai L. Comprehensive Analysis of Metabolic Isozyme Targets in Cancer. Cancer Research 2022, 82: 1698-1711. PMID: 35247885, PMCID: PMC10883296, DOI: 10.1158/0008-5472.can-21-3983.Peer-Reviewed Original ResearchConceptsPotential therapeutic targetAcetyl-CoA carboxylase 1Therapeutic targetCancer typesCell linesBreast cancer viabilityPatient-derived xenograftsNovel metabolic targetsCorresponding cell linesExpression patternsDrug treatmentMatching normal tissuesRelated commentaryTumor growthMalignant transformationSmall molecule inhibitionCancer viabilityCancer Cell Line EncyclopediaNormal tissuesMetabolic vulnerabilitiesCarboxylase 1Anticancer therapyCellular changesCell proliferationMetabolic reprogramming
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