2024
Passenger gene co-amplifications create collateral therapeutic vulnerabilities in cancer
Bei Y, Bramé L, Kirchner M, Fritsche-Guenther R, Kunz S, Bhattacharya A, Rusu M, Gürgen D, Dubios F, Köppke J, Proba J, Wittstruck N, Sidorova O, González R, Garcia H, Brückner L, Xu R, Giurgiu M, Rodriguez-Fos E, Yu Q, Spanjaard B, Koche R, Schmitt C, Schulte J, Eggert A, Haase K, Kirwan J, Hagemann A, Mertins P, Dörr J, Henssen A. Passenger gene co-amplifications create collateral therapeutic vulnerabilities in cancer. Cancer Discovery 2024, 14: 492-507. PMID: 38197697, PMCID: PMC10911929, DOI: 10.1158/2159-8290.cd-23-1189.Peer-Reviewed Original ResearchConceptsDEAD-box helicase 1Passenger genesTherapeutic vulnerabilitiesTricarboxylic acidCRISPR-Cas9 loss-of-function screensLoss-of-function screensCell death in vitroDisruption of mTORC1Death in vitroGene co-amplificationCancer cell linesCancer genomesHelicase 1Interaction partnersCancer dependenciesCollateral vulnerabilitiesTCA activityCo-amplificationDNA amplificationMTORC1 activityCancerPharmacological disruptionCancer biologyTarget discoveryCoamplification
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 linesParallel sequencing of extrachromosomal circular DNAs and transcriptomes in single cancer cells
Chamorro González R, Conrad T, Stöber M, Xu R, Giurgiu M, Rodriguez-Fos E, Kasack K, Brückner L, van Leen E, Helmsauer K, Dorado Garcia H, Stefanova M, Hung K, Bei Y, Schmelz K, Lodrini M, Mundlos S, Chang H, Deubzer H, Sauer S, Eggert A, Schulte J, Schwarz R, Haase K, Koche R, Henssen A. Parallel sequencing of extrachromosomal circular DNAs and transcriptomes in single cancer cells. Nature Genetics 2023, 55: 880-890. PMID: 37142849, PMCID: PMC10181933, DOI: 10.1038/s41588-023-01386-y.Peer-Reviewed Original ResearchConceptsExtrachromosomal circular DNACircular DNAParallel sequencingCancer cellsIntercellular differencesFull-length mRNADNA elementsExtrachromosomal DNATranscriptome sequencingTranscriptional impactSingle cancer cellsEcDNAExpression differencesDNATranscriptomeCellsIntratumoral heterogeneityStructural heterogeneitySequenceStructural dynamicsMRNACancerRecombination
2022
Therapeutic targeting of ATR in alveolar rhabdomyosarcoma
Dorado García H, Pusch F, Bei Y, von Stebut J, Ibáñez G, Guillan K, Imami K, Gürgen D, Rolff J, Helmsauer K, Meyer-Liesener S, Timme N, Bardinet V, Chamorro González R, MacArthur I, Chen C, Schulz J, Wengner A, Furth C, Lala B, Eggert A, Seifert G, Hundsoerfer P, Kirchner M, Mertins P, Selbach M, Lissat A, Dubois F, Horst D, Schulte J, Spuler S, You D, Dela Cruz F, Kung A, Haase K, DiVirgilio M, Scheer M, Ortiz M, Henssen A. Therapeutic targeting of ATR in alveolar rhabdomyosarcoma. Nature Communications 2022, 13: 4297. PMID: 35879366, PMCID: PMC9314382, DOI: 10.1038/s41467-022-32023-7.Peer-Reviewed Original ResearchConceptsCRISPR activation screenAlveolar rhabdomyosarcomaATR inhibitionGenome-wide CRISPR activation screenClinical outcomes of patientsMulti-modal treatment approachSensitivity to ATR inhibitionOutcomes of patientsPAX3-FOXO1Rad3 related proteinMuscle progenitor cellsDNA repair pathway activityClinical outcomesInhibition in vitroATR inhibitorsProgenitor cellsClinical trialsBRCA1 phosphorylationRas-MAPK pathwayCombined treatmentARMS cellsPARP1 inhibitorsAtaxia telangiectasiaRhabdomyosarcoma cellsTreatment approaches
2020
Enhancer hijacking determines extrachromosomal circular MYCN amplicon architecture in neuroblastoma
Helmsauer K, Valieva M, Ali S, Chamorro González R, Schöpflin R, Röefzaad C, Bei Y, Dorado Garcia H, Rodriguez-Fos E, Puiggròs M, Kasack K, Haase K, Keskeny C, Chen C, Kuschel L, Euskirchen P, Heinrich V, Robson M, Rosswog C, Toedling J, Szymansky A, Hertwig F, Fischer M, Torrents D, Eggert A, Schulte J, Mundlos S, Henssen A, Koche R. Enhancer hijacking determines extrachromosomal circular MYCN amplicon architecture in neuroblastoma. Nature Communications 2020, 11: 5823. PMID: 33199677, PMCID: PMC7669906, DOI: 10.1038/s41467-020-19452-y.Peer-Reviewed Original ResearchConceptsExtrachromosomal circular DNACore regulatory circuitEnhancer hijackingAmplicon structureDistal chromosomal fragmentsGene regulatory elementsMYCN amplificationChIP-seqShort readsHi-C.ATAC-seqChromatin landscapeNanopore sequencingRegulatory elementsRegulatory circuitsChromosome fragmentsMYCN ampliconGene copiesProximal enhancerCo-amplifiedCircular DNAAmpliconsMYCN overexpressionFunctional relevanceMYCN
2019
Extrachromosomal circular DNA drives oncogenic genome remodeling in neuroblastoma
Koche R, Rodriguez-Fos E, Helmsauer K, Burkert M, MacArthur I, Maag J, Chamorro R, Munoz-Perez N, Puiggròs M, Dorado Garcia H, Bei Y, Röefzaad C, Bardinet V, Szymansky A, Winkler A, Thole T, Timme N, Kasack K, Fuchs S, Klironomos F, Thiessen N, Blanc E, Schmelz K, Künkele A, Hundsdörfer P, Rosswog C, Theissen J, Beule D, Deubzer H, Sauer S, Toedling J, Fischer M, Hertwig F, Schwarz R, Eggert A, Torrents D, Schulte J, Henssen A. Extrachromosomal circular DNA drives oncogenic genome remodeling in neuroblastoma. Nature Genetics 2019, 52: 29-34. PMID: 31844324, PMCID: PMC7008131, DOI: 10.1038/s41588-019-0547-z.Peer-Reviewed Original ResearchProhibitin promotes de-differentiation and is a potential therapeutic target in neuroblastoma
MacArthur I, Bei Y, Garcia H, Ortiz M, Toedling J, Klironomos F, Rolff J, Eggert A, Schulte J, Kentsis A, Henssen A. Prohibitin promotes de-differentiation and is a potential therapeutic target in neuroblastoma. JCI Insight 2019, 5 PMID: 30998507, PMCID: PMC6542629, DOI: 10.1172/jci.insight.127130.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisCell Cycle CheckpointsCell DedifferentiationCell DifferentiationCell Line, TumorCell ProliferationChild, PreschoolChromosomes, Human, Pair 17HumansMAP Kinase Signaling SystemMiceNeuroblastomaProhibitinsProtein Kinase InhibitorsPyridonesPyrimidinonesRepressor ProteinsRNA-SeqRNA, MessengerSequence Analysis, RNAWhole Genome SequencingXenograft Model Antitumor AssaysConceptsLong arm of chromosome 17Neuroblastoma cellsSlow cell cycle progressionExpression of prohibitinImpaired ERK1/2 activationGene expression programsWhole genomeHigh-risk neuroblastomaChromosome 17Long armDe-differentiationPromote tumor cell proliferationTumor cell proliferationRNA sequencingAssociated with suppressionEctopic expressionProhibitinProliferation of neuroblastoma cellsCytogenetic hallmarkProhibitin expressionExpression programsAssociated with lossNeuronal developmentERK1/2 activationNeuroblastoma outcomeSynergistic activity of BET inhibitor MK-8628 and PLK inhibitor Volasertib in preclinical models of medulloblastoma
Han Y, Lindner S, Bei Y, Garcia H, Timme N, Althoff K, Odersky A, Schramm A, Lissat A, Künkele A, Deubzer H, Eggert A, Schulte J, Henssen A. Synergistic activity of BET inhibitor MK-8628 and PLK inhibitor Volasertib in preclinical models of medulloblastoma. Cancer Letters 2019, 445: 24-33. PMID: 30611741, DOI: 10.1016/j.canlet.2018.12.012.Peer-Reviewed Original ResearchConceptsModel of medulloblastomaMYC-amplified medulloblastomaMK-8628Preclinical models of medulloblastomaAnti-tumor effectsPreclinical modelsTherapeutic efficacyCentral nervous system tumorsAggressive clinical courseHigh-risk medulloblastomaTherapy-related morbidityCurrent treatment regimensNervous system tumorsTargeted treatment approachesBET protein BRD4MYC protein stabilityIn vivo modelsMYC amplificationMedulloblastoma modelApoptotic cell deathCell cycle arrestClinical courseTreatment regimensSystem tumorsTarget of Plk1
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