2025
Selective STING Activation in Intratumoral Myeloid Cells via CCR2-Directed Antibody Drug Conjugate TAK-500.
Appleman V, Matsuda A, Ganno M, Zhang D, Rosentrater E, Maldonado Lopez A, Porciuncula A, Hatten T, Christensen C, Merrigan S, Lee H, Lee M, Wang C, Dong L, Huang J, Iartchouk N, Wang J, Xu H, Yoneyama T, Piatkov K, Haridas S, Harbison C, Gregory R, Parent A, Lineberry N, Arendt C, Schalper K, Abu-Yousif A. Selective STING Activation in Intratumoral Myeloid Cells via CCR2-Directed Antibody Drug Conjugate TAK-500. Cancer Immunology Research 2025 PMID: 39918395, DOI: 10.1158/2326-6066.cir-24-0103.Peer-Reviewed Original ResearchIntratumoral myeloid cellsMyeloid cellsTumor microenvironmentImmune responseCCR2+ cellsI interferonImmunosuppressive myeloid populationsImmune activation in vitroImmune cell markersLocal immune activationMurine tumor modelsAdaptive immune responsesAntibody drug conjugatesType I interferonAntitumor immunityInnate immune responseMyeloid populationsSTING agonistsSolid tumorsCCR2 proteinImmune activationTumor modelCell markersHuman tumorsAdaptive immunityProspective validation of ORACLE, a clonal expression biomarker associated with survival of patients with lung adenocarcinoma
Biswas D, Liu Y, Herrero J, Wu Y, Moore D, Karasaki T, Grigoriadis K, Lu W, Veeriah S, Naceur-Lombardelli C, Magno N, Ward S, Frankell A, Hill M, Colliver E, de Carné Trécesson S, East P, Malhi A, Snell D, O’Neill O, Leonce D, Mattsson J, Lindberg A, Micke P, Moldvay J, Megyesfalvi Z, Dome B, Fillinger J, Nicod J, Downward J, Szallasi Z, Hackshaw A, Jamal-Hanjani M, Kanu N, Birkbak N, Swanton C. Prospective validation of ORACLE, a clonal expression biomarker associated with survival of patients with lung adenocarcinoma. Nature Cancer 2025, 6: 86-101. PMID: 39789179, PMCID: PMC11779643, DOI: 10.1038/s43018-024-00883-1.Peer-Reviewed Original ResearchConceptsLung adenocarcinomaStage I diseaseClinicopathological risk factorsSurvival of patientsResponse to treatmentRNA sequencing dataI diseaseSequence dataMetastatic clonesNeedle biopsyIndividual tumorsLung expressionTranscription signalsPrognostic informationWhole exomeExpressed genesChemotherapy sensitivityProspective validationSurvival associationsTranscriptomic heterogeneityHuman tumorsEvolutionary measuresChromosomal instabilityRisk factorsNatural history
2024
Learning what keeps nanomedicines in tumours
Wang Y, Schrank B, Jiang W, Kim B. Learning what keeps nanomedicines in tumours. Nature Biomedical Engineering 2024, 8: 1330-1331. PMID: 39271934, DOI: 10.1038/s41551-024-01251-1.Peer-Reviewed Original ResearchHuman lung cancer harbors spatially organized stem-immunity hubs associated with response to immunotherapy
Chen J, Nieman L, Spurrell M, Jorgji V, Elmelech L, Richieri P, Xu K, Madhu R, Parikh M, Zamora I, Mehta A, Nabel C, Freeman S, Pirl J, Lu C, Meador C, Barth J, Sakhi M, Tang A, Sarkizova S, Price C, Fernandez N, Emanuel G, He J, Van Raay K, Reeves J, Yizhak K, Hofree M, Shih A, Sade-Feldman M, Boland G, Pelka K, Aryee M, Mino-Kenudson M, Gainor J, Korsunsky I, Hacohen N. Human lung cancer harbors spatially organized stem-immunity hubs associated with response to immunotherapy. Nature Immunology 2024, 25: 644-658. PMID: 38503922, DOI: 10.1038/s41590-024-01792-2.Peer-Reviewed Original ResearchT cellsDendritic cellsImmune hubAssociated with response to immunotherapyMature tertiary lymphoid structuresOrganization of immune cellsIntratumoral immune responsePD-1 blockadeRegulatory dendritic cellsResponse to immunotherapyAbundant T cellsRegulatory T cellsTertiary lymphoid structuresLung cancer specimensHuman lung cancerImmunogenic tumorsImmunotherapy outcomesPD-1Lymphoid structuresCancer specimensImmune cellsLung cancerHuman tumorsImmune responseTumor
2023
Epigenetic markers and therapeutic targets for metastasis
Kravitz C, Yan Q, Nguyen D. Epigenetic markers and therapeutic targets for metastasis. Cancer And Metastasis Reviews 2023, 42: 427-443. PMID: 37286865, PMCID: PMC10595046, DOI: 10.1007/s10555-023-10109-y.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsEpigenomic alterationsLineage integrityTherapeutic targetEpigenetic markersCancer cellsGenetic aberrationsCurrent knowledgeHuman tumorsMalignant cell cloneTumor progressionDNANumber of discoveriesCell clonesDisseminated diseaseCertain organsPrimary tumorTherapeutic responseMetastatic cancerEpigenomeChromatinHistonesLiquid biopsyAlterationsClonesTarget
2022
Mitochondrial fitness and cancer risk
Kossenkov AV, Milcarek A, Notta F, Jang GH, Wilson JM, Gallinger S, Zhou DC, Ding L, Ghosh JC, Perego M, Morotti A, Locatelli M, Robert ME, Vaira V, Altieri DC. Mitochondrial fitness and cancer risk. PLOS ONE 2022, 17: e0273520. PMID: 36223343, PMCID: PMC9555630, DOI: 10.1371/journal.pone.0273520.Peer-Reviewed Original ResearchConceptsPancreatic ductal adenocarcinomaSenescence-Associated Secretory PhenotypeIndependent patient cohortsPoor patient outcomesAggressive disease variantFolfirinox failureLocal inflammationPatient cohortDuctal adenocarcinomaPatient outcomesPatient riskMultiple malignanciesCancer riskMitochondrial fitnessSecretory phenotypeGene signatureHallmarks of cancerMetastatic propensityNormal tissuesHuman tumorsInterferon SignalingTumorsInner membrane mitochondrial proteinMalignancyMolecular signaturesGhost mitochondria drive metastasis through adaptive GCN2/Akt therapeutic vulnerability
Ghosh JC, Perego M, Agarwal E, Bertolini I, Wang Y, Goldman AR, Tang HY, Kossenkov AV, Landis CJ, Languino LR, Plow EF, Morotti A, Ottobrini L, Locatelli M, Speicher DW, Caino MC, Cassel J, Salvino JM, Robert ME, Vaira V, Altieri DC. Ghost mitochondria drive metastasis through adaptive GCN2/Akt therapeutic vulnerability. Proceedings Of The National Academy Of Sciences Of The United States Of America 2022, 119: e2115624119. PMID: 35177476, PMCID: PMC8872753, DOI: 10.1073/pnas.2115624119.Peer-Reviewed Original ResearchMeSH KeywordsCell DeathCell Line, TumorCell MovementCell ProliferationEpithelial-Mesenchymal TransitionHumansMitochondriaMitochondrial DynamicsMitochondrial ProteinsMuscle ProteinsNeoplasm InvasivenessNeoplasm MetastasisNeoplasmsNeoplastic ProcessesProtein Serine-Threonine KinasesProto-Oncogene Proteins c-aktReactive Oxygen SpeciesSignal TransductionConceptsEpithelial-mesenchymal transitionGene expression programsTherapeutic vulnerabilitiesTumor cell movementCytokine/chemokine signalingExpression programsTherapeutic targetCell movementMitochondrial dynamicsEssential scaffoldMitochondrial structureSurvival signalingMitochondrial integrityCancer metabolismStress responseActionable therapeutic targetsCell deathChemokine signalingMitochondriaSmall-molecule drug screensCell proliferationOxidative damageInnate immunityMetastatic disseminationHuman tumors
2021
Chromosomal instability accelerates the evolution of resistance to anti-cancer therapies
Lukow DA, Sausville EL, Suri P, Chunduri NK, Wieland A, Leu J, Smith JC, Girish V, Kumar AA, Kendall J, Wang Z, Storchova Z, Sheltzer JM. Chromosomal instability accelerates the evolution of resistance to anti-cancer therapies. Developmental Cell 2021, 56: 2427-2439.e4. PMID: 34352222, PMCID: PMC8933054, DOI: 10.1016/j.devcel.2021.07.009.Peer-Reviewed Original ResearchConceptsChromosomal instabilityAnti-cancer therapyCancer cell fitnessAcquisition of aneuploidyChromosome loss eventsSingle-cell sequencingEvolution of resistanceDifferent culture environmentsCellular fitnessPhenotypic plasticityCIN correlatesHuman tumorsCell fitnessHuman cellsStressful environmentsResistant populationsAcquisition of resistanceRecurrent aneuploidyCancer cellsPaclitaxel-resistant cellsCulture environmentAneuploidyPaclitaxel sensitivityFitnessCellsEpigenetic silencing by SETDB1 suppresses tumour intrinsic immunogenicity
Griffin GK, Wu J, Iracheta-Vellve A, Patti JC, Hsu J, Davis T, Dele-Oni D, Du PP, Halawi AG, Ishizuka JJ, Kim SY, Klaeger S, Knudsen NH, Miller BC, Nguyen TH, Olander KE, Papanastasiou M, Rachimi S, Robitschek EJ, Schneider EM, Yeary MD, Zimmer MD, Jaffe JD, Carr SA, Doench JG, Haining WN, Yates KB, Manguso RT, Bernstein BE. Epigenetic silencing by SETDB1 suppresses tumour intrinsic immunogenicity. Nature 2021, 595: 309-314. PMID: 33953401, PMCID: PMC9166167, DOI: 10.1038/s41586-021-03520-4.Peer-Reviewed Original ResearchConceptsImmune checkpoint blockadeCheckpoint blockadeCytotoxic T cell responsesT cell responsesMouse tumor modelsImmune exclusionImmune clustersRetroviral antigensImmune sensitivityImmunostimulatory genesIntrinsic immunogenicityCell responsesTumor modelCentral mechanismsHuman tumorsCancer cellsBlockadeCandidate targetsImmunogenicityAneuploidy as a promoter and suppressor of malignant growth
Vasudevan A, Schukken KM, Sausville EL, Girish V, Adebambo OA, Sheltzer JM. Aneuploidy as a promoter and suppressor of malignant growth. Nature Reviews Cancer 2021, 21: 89-103. PMID: 33432169, DOI: 10.1038/s41568-020-00321-1.Peer-Reviewed Original Research
2019
The landscape of novel and complementary targets for immunotherapy: an analysis of gene expression in the tumor microenvironment
Gaffney SG, Perry EB, Chen PM, Greenstein A, Kaech SM, Townsend JP. The landscape of novel and complementary targets for immunotherapy: an analysis of gene expression in the tumor microenvironment. Oncotarget 2019, 10: 4532-4545. PMID: 31360302, PMCID: PMC6642048, DOI: 10.18632/oncotarget.27027.Peer-Reviewed Original ResearchCediranib suppresses homology-directed DNA repair through down-regulation of BRCA1/2 and RAD51
Kaplan AR, Gueble SE, Liu Y, Oeck S, Kim H, Yun Z, Glazer PM. Cediranib suppresses homology-directed DNA repair through down-regulation of BRCA1/2 and RAD51. Science Translational Medicine 2019, 11 PMID: 31092693, PMCID: PMC6626544, DOI: 10.1126/scitranslmed.aav4508.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBRCA1 ProteinBRCA2 ProteinCell Line, TumorDNA RepairDown-RegulationE2F4 Transcription FactorFemaleGene Expression Regulation, NeoplasticHumansMice, NudePoly(ADP-ribose) Polymerase InhibitorsQuinazolinesRad51 RecombinaseReceptors, Platelet-Derived Growth FactorTumor HypoxiaVascular Endothelial Growth Factor Receptor-2Xenograft Model Antitumor AssaysConceptsHomology-directed DNA repairDNA repairE2F transcription factor 4Protein phosphatase 2ATranscription factor 4DNA repair inhibitorsPhosphatase 2ARAD51 recombinaseTranscriptional corepressorMouse tumor xenograftsSynthetic lethalityGene expressionRB2/Mouse bone marrowGrowth factor receptor inhibitionRepair inhibitorsUnknown mechanismPlatelet-derived growth factor receptor inhibitionFactor 4Human tumorsInhibitor olaparibPARP inhibitorsMutationsCombination of cediranibCancer therapyTranscriptomic Hallmarks of Tumor Plasticity and Stromal Interactions in Brain Metastasis
Wingrove E, Liu Z, Patel K, Arnal‐Estape A, Melnick M, Politi K, Monteiro C, Zhu L, Valiente M, Kluger H, Chiang V, Nguyen D. Transcriptomic Hallmarks of Tumor Plasticity and Stromal Interactions in Brain Metastasis. The FASEB Journal 2019, 33: 368.8-368.8. DOI: 10.1096/fasebj.2019.33.1_supplement.368.8.Peer-Reviewed Original ResearchBrain tumor microenvironmentBrain metastasesTumor microenvironmentTumor cellsLung adenocarcinomaTumor lesionsBrain metastatic tumor cellsBreast cancer brain metastasesHuman tumorsExpression of TIM3Cancer brain metastasesMetastatic brain tumorsExpression of astrocytesIntra-arterial injectionTumor-associated macrophagesSyngeneic model systemModels of melanomaFull-text articlesMetastatic tumor cellsCNS metastasesNeuroinflammatory responseBrain lesionsLung tumorsT cellsAthymic mice
2018
Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses
Cañadas I, Thummalapalli R, Kim J, Kitajima S, Jenkins R, Christensen C, Campisi M, Kuang Y, Zhang Y, Gjini E, Zhang G, Tian T, Sen D, Miao D, Imamura Y, Thai T, Piel B, Terai H, Aref A, Hagan T, Koyama S, Watanabe M, Baba H, Adeni A, Lydon C, Tamayo P, Wei Z, Herlyn M, Barbie T, Uppaluri R, Sholl L, Sicinska E, Sands J, Rodig S, Wong K, Paweletz C, Watanabe H, Barbie D. Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses. Nature Medicine 2018, 24: 1143-1150. PMID: 30038220, PMCID: PMC6082722, DOI: 10.1038/s41591-018-0116-5.Peer-Reviewed Original ResearchConceptsInnate immune signalingSmall cell lung cancerEndogenous retrovirusesCell lung cancerPro-tumorigenic cytokinesImmune signalingAnalysis of cell linesCancer immunotherapyMesenchymal cell stateIFN-gTumor subpopulationsLung cancerLong terminal repeatHuman tumorsSPARC expressionMesenchymal markersTumorBi-directional transcriptionChromatin-modifying enzymesSTAT1 signalingCell linesCancerInnate immunityInducible SPARCS expressionGene promoterRemarkable response to a novel ATR inhibitor in a patient with poorly differentiated neuroendocrine carcinoma.
Saito Y, Li Z, Lustberg M, Grenade C, Wesolowski R. Remarkable response to a novel ATR inhibitor in a patient with poorly differentiated neuroendocrine carcinoma. Cancer Treatment And Research Communications 2018, 16: 9-12. PMID: 31299005, DOI: 10.1016/j.ctarc.2018.04.001.Peer-Reviewed Original ResearchNeuroendocrine carcinomaExceptional responseLarge cell neuroendocrine carcinomaEarly phase clinical trialsProgression-free survivalMetastatic prostate cancerCell neuroendocrine carcinomaNumber of malignanciesPrimary human tumorsMechanism of actionCancer cell linesFree survivalCell cycle arrestClinical trialsProstate cancerDNA damaging drugsNovel ATR inhibitorPatientsHuman tumorsM6620Cytotoxic effectsCycle arrestRemarkable responseDamaging drugsClonal evolution
2017
64Cu-MM-302 Positron Emission Tomography Quantifies Variability of Enhanced Permeability and Retention of Nanoparticles in Relation to Treatment Response in Patients with Metastatic Breast Cancer
Lee H, Shields AF, Siegel BA, Miller KD, Krop I, X. C, LoRusso PM, Munster PN, Campbell K, Gaddy DF, Leonard SC, Geretti E, Blocker SJ, Kirpotin DB, Moyo V, Wickham TJ, Hendriks BS. 64Cu-MM-302 Positron Emission Tomography Quantifies Variability of Enhanced Permeability and Retention of Nanoparticles in Relation to Treatment Response in Patients with Metastatic Breast Cancer. Clinical Cancer Research 2017, 23: 4190-4202. PMID: 28298546, PMCID: PMC6790129, DOI: 10.1158/1078-0432.ccr-16-3193.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAgedBone NeoplasmsBrain NeoplasmsBreast NeoplasmsCell Membrane PermeabilityCopper RadioisotopesCyclophosphamideDoxorubicinFemaleHumansLiverMiddle AgedNanoparticlesNeoplasm MetastasisPolyethylene GlycolsPositron Emission Tomography Computed TomographyReceptor, ErbB-2SpleenTrastuzumabConceptsPET/CTHER2-positive metastatic breast cancerMetastatic breast cancerFavorable treatment outcomesRetrospective exploratory analysisClin Cancer ResHuman metastatic tumorsEPR effectMetastatic tumorsClinical trialsPatient outcomesBrain lesionsTreatment outcomesBreast cancerClinical studiesDrug levelsPreclinical studiesTumor lesionsSolid tumorsPatientsBackground uptakeTherapeutic nanoparticlesCancer ResTumorsHuman tumorsRb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance
Ku S, Rosario S, Wang Y, Mu P, Seshadri M, Goodrich Z, Goodrich M, Labbé D, Gomez E, Wang J, Long H, Xu B, Brown M, Loda M, Sawyers C, Ellis L, Goodrich D. Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance. Science 2017, 355: 78-83. PMID: 28059767, PMCID: PMC5367887, DOI: 10.1126/science.aah4199.Peer-Reviewed Original ResearchMeSH KeywordsAdenocarcinomaAndrogen AntagonistsAnimalsCell Line, TumorCell LineageCell PlasticityDrug Resistance, NeoplasmEnhancer of Zeste Homolog 2 ProteinEpigenesis, GeneticHumansMaleMiceMutationNeoplasm MetastasisNeoplasms, ExperimentalNeuroendocrine TumorsProstatic NeoplasmsPTEN PhosphohydrolaseRetinoblastoma-Like Protein p107SOXB1 Transcription FactorsTumor Suppressor Protein p53ConceptsAntiandrogen therapyLineage plasticityClinical responses to antiandrogen therapyResistance to antiandrogen therapyMouse modelMetastasis of prostatic adenocarcinomaResponse to antiandrogen therapyAndrogen receptor expressionProstate cancer progressionLoss of Trp53Lineage marker expressionVariant histologyProstatic adenocarcinomaRB1 lossProstate cancerReceptor expressionPTEN mutationsAntiandrogen resistanceTherapeutic resistanceMouse tumorsGene expression profilesNeuroendocrine variantsReprogramming factorsProstateHuman tumors
2016
Regression of Chemotherapy-Resistant Polymerase ϵ (POLE) Ultra-Mutated and MSH6 Hyper-Mutated Endometrial Tumors with Nivolumab
Santin AD, Bellone S, Buza N, Choi J, Schwartz PE, Schlessinger J, Lifton RP. Regression of Chemotherapy-Resistant Polymerase ϵ (POLE) Ultra-Mutated and MSH6 Hyper-Mutated Endometrial Tumors with Nivolumab. Clinical Cancer Research 2016, 22: 5682-5687. PMID: 27486176, PMCID: PMC5135588, DOI: 10.1158/1078-0432.ccr-16-1031.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitor nivolumabCheckpoint inhibitor nivolumabClinical responseInhibitor nivolumabAnti-PD-1 inhibitorsHyper-mutated tumorsPatient's clinical responseRemarkable clinical responsesAlternative therapeutic optionNovel treatment optionsRecurrent/metastaticHigh side effectsRecurrent diseaseEndometrial carcinomaTherapeutic optionsTreatment optionsModern chemotherapyGrade 3Side effectsPatientsHuman tumorsTumorsGene mutationsNivolumabChemotherapy
2015
Humanized Mouse Model of Myeloma Reveals Clinically Occult Genomic Changes in Primary Tumor Cells
Verma R, Strowig T, Das R, Koduru S, Hafemann A, Hopf S, Kocoglu M, Borsotti C, Zhang L, Branagan A, Eynon E, Manz M, Flavell R, Dhodapkar M. Humanized Mouse Model of Myeloma Reveals Clinically Occult Genomic Changes in Primary Tumor Cells. Blood 2015, 126: 22. DOI: 10.1182/blood.v126.23.22.22.Peer-Reviewed Original ResearchPrimary tumor cellsTumor cellsWhole-exome sequencingCopy number alterationsReliable engraftmentPrimary MM tumor cellsIndividual miceHuman tumorsGrowth factorImmune rejection mechanismsHigh-risk MMHumanized mouse modelEvaluation of tumorsMM tumor cellsPrimary human tumor cellsCytokines/growth factorsSame tumor cellsPlasma cell neoplasiaBaseline tumorMM patientsMyeloma patientsInitial tumorPatterns of LOHHuman MMPlasma cellsClostridium Perfringens Enterotoxin (CPE) and CPE-Binding Domain (c-CPE) for the Detection and Treatment of Gynecologic Cancers
Black JD, Lopez S, Cocco E, Schwab CL, English DP, Santin AD. Clostridium Perfringens Enterotoxin (CPE) and CPE-Binding Domain (c-CPE) for the Detection and Treatment of Gynecologic Cancers. Toxins 2015, 7: 1116-1125. PMID: 25835384, PMCID: PMC4417958, DOI: 10.3390/toxins7041116.Peer-Reviewed Original ResearchConceptsClostridium perfringens enterotoxinClaudin-3Claudin-4Perfringens enterotoxinAggressive human cancer cellsGynecologic malignanciesGynecologic cancerHuman cancer cellsOperative settingHuman tumorsCancer cellsPotential roleTumorsSurface proteinsEnterotoxinTreatmentHigh affinitySurgeryMalignancyCancerCytolysisReceptors
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