2023
Correlation of HER2 Protein Level With mRNA Level Quantified by RNAscope in Breast Cancer
Li X, Lee J, Gao Y, Zhang J, Bates K, Rimm D, Zhang H, Smith G, Lawson D, Meisel J, Chang J, Huo L. Correlation of HER2 Protein Level With mRNA Level Quantified by RNAscope in Breast Cancer. Modern Pathology 2023, 37: 100408. PMID: 38135153, DOI: 10.1016/j.modpat.2023.100408.Peer-Reviewed Original ResearchHER2 protein levelsHER2-low breast cancerT-DXdBreast cancerRNA levelsProtein levelsHER2 expressionEarly-stage breast cancerIHC H-scoresTrastuzumab deruxtecanTissue microarray coresClinical trialsMetastatic biopsiesImmunohistochemical assaysH-scoreDrug AdministrationResponse rateUS FoodPatientsIHC assaysCancerRNAscopeRegression analysisCell linesImmunofluorescence scoresSubsets of IFN Signaling Predict Response to Immune Checkpoint Blockade in Patients with Melanoma.
Horowitch B, Lee D, Ding M, Martinez-Morilla S, Aung T, Ouerghi F, Wang X, Wei W, Damsky W, Sznol M, Kluger H, Rimm D, Ishizuka J. Subsets of IFN Signaling Predict Response to Immune Checkpoint Blockade in Patients with Melanoma. Clinical Cancer Research 2023, 29: 2908-2918. PMID: 37233452, PMCID: PMC10524955, DOI: 10.1158/1078-0432.ccr-23-0215.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitorsHuman melanoma cell linesMelanoma cell linesPD-L1Validation cohortYale-New Haven HospitalCombination of ipilimumabPD-L1 markersImmune checkpoint blockadePD-L1 biomarkerNew Haven HospitalSTAT1 levelsCell linesWestern blot analysisCheckpoint inhibitorsCheckpoint blockadeClinical responseOverall survivalImproved survivalResistance of cancersMetastatic melanomaMelanoma responsePredict responseTreatment responseDistinct patternsAssessment of the Impact of Alternative Fixatives on HER2 Detection in Breast Cancer and Gastric Cancer Tumor Specimens
Feng W, Inoue R, Kuwata T, Niikura N, Fujii S, Kumaki N, Honda K, Xu L, Goetz A, Gaule P, Cogswell J, Rimm D, McGee R. Assessment of the Impact of Alternative Fixatives on HER2 Detection in Breast Cancer and Gastric Cancer Tumor Specimens. Applied Immunohistochemistry & Molecular Morphology 2023, 31: 339-345. PMID: 37093713, PMCID: PMC10155692, DOI: 10.1097/pai.0000000000001126.Peer-Reviewed Original ResearchConceptsNeutral buffered formalinNegative percentage agreementPositive percentage agreementOverall percentage agreementBreast cancerPercentage agreementHER2 statusHuman epidermal growth factor receptor 2 (HER2) statusEpidermal growth factor receptor 2 statusTumor samplesCell linesGastric cancer tumorsGastric cancer cell linesTumor tissue samplesClinical trial sitesCancer cell linesHER2 testingTumor specimensReal-world settingTumor tissueCancer tumorsBuffered formalinSitu hybridization assaysType of fixativeCentral laboratory
2022
Quantitative measurement of HER2 expression to subclassify ERBB2 unamplified breast cancer.
Moutafi M, Robbins C, Yaghoobi V, Fernandez A, Martinez-Morilla S, Xirou V, Bai Y, Song Y, Gaule P, Krueger J, Bloom K, Hill S, Liebler D, Fulton R, Rimm D. Quantitative measurement of HER2 expression to subclassify ERBB2 unamplified breast cancer. Laboratory Investigation 2022, 102: 1101-1108. PMID: 36775350, DOI: 10.1038/s41374-022-00804-9.Peer-Reviewed Original ResearchConceptsHER2 expressionBreast cancerAttomol/HER2 proteinBreast cancer patientsBreast cancer casesOptimal patient careLevels of HER2Trastuzumab deruxtecanT-DXdCancer patientsLow HER2Cancer casesConventional assaysHER2Patient careAntibody concentrationsQuantitative immunofluorescenceAntibody drugsCancerCell linesAssaysExpressionHER2 detectionLower range
2020
Digital quantitative assessment of PD-L1 using digital spatial profiling
Gupta S, Zugazagoitia J, Martinez-Morilla S, Fuhrman K, Rimm DL. Digital quantitative assessment of PD-L1 using digital spatial profiling. Laboratory Investigation 2020, 100: 1311-1317. PMID: 32249818, PMCID: PMC7502436, DOI: 10.1038/s41374-020-0424-5.Peer-Reviewed Original ResearchConceptsTissue microarrayPD-L1Digital spatial profilingDeath 1 ligand 1 expressionPD-L1 immunohistochemistry assaysDigital quantitative assessmentDigital Spatial ProfilerLigand 1 expressionPD-L1 assaysCompanion diagnostic testingCell linesImmune therapyPredictive markerImmune cellsImmunohistochemistry assaysQuantitative immunohistochemistryUS FoodDrug AdministrationDiagnostic testingImmunohistochemistryNCounter platformTumor cellsDifferent scoring methodsMultiple studiesDifferent antibodies
2019
Quantitative assessment of PD-L1 as an analyte in immunohistochemistry diagnostic assays using a standardized cell line tissue microarray
Martinez-Morilla S, McGuire J, Gaule P, Moore L, Acs B, Cougot D, Gown AM, Yaziji H, Wang WL, Cartun RW, Hornick JL, Sholl LM, Qiu J, Mino-Kenudson M, Yi ES, Beasley MB, Merrick DT, Ambaye AB, Zhang ZJ, Walker J, Rimm DL. Quantitative assessment of PD-L1 as an analyte in immunohistochemistry diagnostic assays using a standardized cell line tissue microarray. Laboratory Investigation 2019, 100: 4-15. PMID: 31409885, PMCID: PMC6920558, DOI: 10.1038/s41374-019-0295-9.Peer-Reviewed Original ResearchConceptsTissue microarrayPD-L1Quantitative immunofluorescencePD-L1 expressionPD-L1 immunohistochemistryMulti-institutional settingRoutine clinical samplesCell linesPredictive markerClinical trialsTumor typesIHC assaysQuantitative digital image analysisImmunohistochemistryCut pointsClinical samplesAntibodiesFDAInter-assay comparisonsDiagnostic assaysIsogenic cell linesAssaysDigital image analysisSubjective assessmentLow levels
2018
Patient-derived conditionally reprogrammed cells maintain intra-tumor genetic heterogeneity
Correa BRS, Hu J, Penalva LOF, Schlegel R, Rimm DL, Galante PAF, Agarwal S. Patient-derived conditionally reprogrammed cells maintain intra-tumor genetic heterogeneity. Scientific Reports 2018, 8: 4097. PMID: 29511269, PMCID: PMC5840339, DOI: 10.1038/s41598-018-22427-1.Peer-Reviewed Original ResearchConceptsDrug target identificationNon-small cell lung cancerCancer cell biologyIntra-tumor genetic heterogeneityDrug discovery effortsMutant-allele tumor heterogeneity (MATH) scoreCell biologyWhole-exome sequencingCell heterogeneityNumber variationsPatient-derived cell culturesDiscovery effortsCR cellsCancer cell linesIntra-tumoral heterogeneityGenetic heterogeneityCell linesExome sequencingTarget identificationCell lung cancerLung cancer modelBiologyCell culturesMolecular characteristicsPrimary cultures
2017
PD-L1 Studies Across Tumor Types, Its Differential Expression and Predictive Value in Patients Treated with Immune Checkpoint Inhibitors
Kluger HM, Zito CR, Turcu G, Baine M, Zhang H, Adeniran A, Sznol M, Rimm DL, Kluger Y, Chen L, Cohen JV, Jilaveanu LB. PD-L1 Studies Across Tumor Types, Its Differential Expression and Predictive Value in Patients Treated with Immune Checkpoint Inhibitors. Clinical Cancer Research 2017, 23: 4270-4279. PMID: 28223273, PMCID: PMC5540774, DOI: 10.1158/1078-0432.ccr-16-3146.Peer-Reviewed Original ResearchConceptsNon-small cell lung cancerPD-L1 expressionRenal cell carcinomaPD-1 inhibitorsCell carcinomaImmune-infiltrating cellsMelanoma patientsPD-L1Tumor cellsTumor typesTumor-associated inflammatory cellsCTLA-4 inhibitorsCell lung cancerRenal cell carcinoma cellsHigh response rateClin Cancer ResCell linesMelanoma tumor cellsPD-1Multivariable analysisNSCLC specimensInflammatory cellsLung cancerTissue microarrayResponse rateA Quantitative Comparison of Antibodies to Programmed Cell Death 1 Ligand 1
Gaule P, Smithy JW, Toki M, Rehman J, Patell-Socha F, Cougot D, Collin P, Morrill P, Neumeister V, Rimm DL. A Quantitative Comparison of Antibodies to Programmed Cell Death 1 Ligand 1. JAMA Oncology 2017, 3: 256-259. PMID: 27541827, PMCID: PMC5491359, DOI: 10.1001/jamaoncol.2016.3015.Peer-Reviewed Original ResearchPD-L1 expressionPD-L1Tissue microarrayImmunohistochemical analysisCell death 1 ligand 1PD-1 axis inhibitorsDeath 1 ligand 1Quantitative immunofluorescenceCell linesPredictive diagnostic testsTumor tissue coresPD-L1 proteinPrediction of responseYale Pathology archivesLung cancerClinical utilityPathology archivesDiagnostic testsMonoclonal antibodiesAntibodiesTissue controlsProtein levelsTissue coresLigand 1Concordant results
2016
miR-34a Silences c-SRC to Attenuate Tumor Growth in Triple-Negative Breast Cancer
Adams BD, Wali VB, Cheng CJ, Inukai S, Booth CJ, Agarwal S, Rimm DL, Győrffy B, Santarpia L, Pusztai L, Saltzman WM, Slack FJ. miR-34a Silences c-SRC to Attenuate Tumor Growth in Triple-Negative Breast Cancer. Cancer Research 2016, 76: 927-939. PMID: 26676753, PMCID: PMC4755913, DOI: 10.1158/0008-5472.can-15-2321.Peer-Reviewed Original ResearchConceptsTriple-negative breast cancerBreast cancerTumor growthMiR-34a replacement therapyTNBC cell linesDifferent TNBC subtypesPromising therapeutic strategyAttenuates tumor growthHuman clinical trialsMiRNA-profiling studiesMiR-34a levelsCell linesPotent antitumorigenic effectsMiR-34a targetsHuman tumor specimensC-SrcReplacement therapyTNBC subtypesAggressive subtypeTreatment optionsClinical trialsDisease progressionEffective therapyPatient outcomesC-Src inhibitor
2012
Multi-Level Targeting of the Phosphatidylinositol-3-Kinase Pathway in Non-Small Cell Lung Cancer Cells
Zito CR, Jilaveanu LB, Anagnostou V, Rimm D, Bepler G, Maira SM, Hackl W, Camp R, Kluger HM, Chao HH. Multi-Level Targeting of the Phosphatidylinositol-3-Kinase Pathway in Non-Small Cell Lung Cancer Cells. PLOS ONE 2012, 7: e31331. PMID: 22355357, PMCID: PMC3280285, DOI: 10.1371/journal.pone.0031331.Peer-Reviewed Original ResearchMeSH KeywordsAdenocarcinomaAdultAgedAged, 80 and overAntineoplastic AgentsBlotting, WesternCarcinoma, Non-Small-Cell LungCarcinoma, Squamous CellCell Line, TumorCell ProliferationClass Ia Phosphatidylinositol 3-KinaseDrug SynergismFemaleFluorescent Antibody TechniqueHumansImmunoenzyme TechniquesLung NeoplasmsMaleMiddle AgedPhosphoinositide-3 Kinase InhibitorsProtein Kinase InhibitorsProto-Oncogene Proteins c-aktSignal TransductionTissue Array AnalysisTOR Serine-Threonine KinasesConceptsNon-small cell lung cancerNSCLC cell linesDual PI3K/mTOR inhibitorPI3K/AKT/mTOR pathwayPI3K/mTOR inhibitorAKT/mTOR pathwayPI3K inhibitorsNVP-BEZ235MTOR inhibitorsNVP-BKM120MTOR expressionAdvanced stageCell linesMTOR pathwayPI3K subunitsNon-small cell lung cancer cellsK inhibitorsCell lung cancer cellsCell lung cancerSquamous cell carcinomaP85 expressionSynergistic growth inhibitionRegulation of pAktExpression of p85Lung cancer cells
2010
The ERα coactivator, HER4/4ICD, regulates progesterone receptor expression in normal and malignant breast epithelium
Rokicki J, Das PM, Giltnane JM, Wansbury O, Rimm DL, Howard BA, Jones FE. The ERα coactivator, HER4/4ICD, regulates progesterone receptor expression in normal and malignant breast epithelium. Molecular Cancer 2010, 9: 150. PMID: 20550710, PMCID: PMC2894764, DOI: 10.1186/1476-4598-9-150.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBreast NeoplasmsCell Line, TumorErbB ReceptorsEstrogen Receptor alphaFemaleGene ExpressionGene Expression RegulationHumansMammary Glands, AnimalMammary Glands, HumanMiceMice, TransgenicPregnancyReceptor, ErbB-4Receptors, ProgesteroneReverse Transcriptase Polymerase Chain ReactionSignal TransductionConceptsPgR expressionExpression of PgRBreast cancerERα coactivatorMammary glandHER4 intracellular domainProgesterone receptor expressionPositive breast carcinomaMalignant breast epitheliumPrimary breast tumorsMCF-7 variantEstrogen receptor coactivatorBreast tumor cell linesCell linesBreast tumor cellsTamoxifen responseMouse mammary glandProgesterone receptorReceptor expressionBreast carcinomaMCF-7 breast tumor cell linePatient responseBreast carcinogenesisEstrogen stimulationBreast epithelium
2009
C-Raf Is Associated with Disease Progression and Cell Proliferation in a Subset of Melanomas
Jilaveanu LB, Zito CR, Aziz SA, Conrad PJ, Schmitz JC, Sznol M, Camp RL, Rimm DL, Kluger HM. C-Raf Is Associated with Disease Progression and Cell Proliferation in a Subset of Melanomas. Clinical Cancer Research 2009, 15: 5704-5713. PMID: 19737955, PMCID: PMC2763114, DOI: 10.1158/1078-0432.ccr-09-0198.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAgedAged, 80 and overBenzenesulfonatesCell Line, TumorCell ProliferationCell SurvivalCohort StudiesDisease ProgressionFemaleGene SilencingHumansIndolesMaleMelanomaMiddle AgedNevusNiacinamidePhenolsPhenylurea CompoundsProtein Kinase InhibitorsProto-Oncogene Proteins c-rafPyridinesRNA, Small InterferingSensitivity and SpecificitySkin NeoplasmsSorafenibYoung AdultConceptsExtracellular signal-regulated kinaseC-RafC-Raf expressionSubset of melanomasPhospho-c-RafSignal-regulated kinaseCell linesProtein kinase inhibitionMitogen-activated protein kinase inhibitionDecreased viabilityDecreased Bcl-2 expressionProtein kinaseCell signalingBcl-2 inhibitionRaf kinaseB-RafMelanoma cell linesPhospho-MEKSpecific siRNAsSitu protein expressionGW5074Major isoformsKinasePhospho-ERKBcl-2 expressionMolecular bases for sensitivity to figitumumab (CP-751,871) in NSCLC
Gualberto A, Dolled-Filhart M, Hixon M, Christensen J, Rimm D, Lee A, Wang Y, Pollak M, Paz-Ares L, Karp D. Molecular bases for sensitivity to figitumumab (CP-751,871) in NSCLC. Journal Of Clinical Oncology 2009, 27: 8091-8091. DOI: 10.1200/jco.2009.27.15_suppl.8091.Peer-Reviewed Original ResearchIGF-binding proteinsFree IGF-1IGF-IR overexpressionIGF-IR expressionNSCLC cell linesNSCLC ptsPlasma levelsIGF-1F trialsHigher IGF-IR expressionIGF type 1 receptorBioavailability of IGFIGF-IR pathwaySquamous cell tumorsType 1 receptorIGF-IR inhibitorCell linesLow E-cadherinE-cadherin expressionE-cadherin levelsPhase 2 activitySquamous NSCLCCell histologyClinical benefitSquamous cellsPhosphatidylinositol-3-Kinase as a Therapeutic Target in Melanoma
Aziz SA, Davies M, Pick E, Zito C, Jilaveanu L, Camp RL, Rimm DL, Kluger Y, Kluger HM. Phosphatidylinositol-3-Kinase as a Therapeutic Target in Melanoma. Clinical Cancer Research 2009, 15: 3029-3036. PMID: 19383818, PMCID: PMC4431617, DOI: 10.1158/1078-0432.ccr-08-2768.Peer-Reviewed Original ResearchMeSH KeywordsBrain NeoplasmsCell ProliferationChromonesEnzyme InhibitorsHumansImmunoblottingImmunoenzyme TechniquesMelanomaMorpholinesNevus, PigmentedPhosphatidylinositol 3-KinasesPhosphoinositide-3 Kinase InhibitorsPhosphorylationProtein Array AnalysisSkin NeoplasmsTissue Array AnalysisTumor Cells, CulturedConceptsPhosphatidylinositol-3 kinasePI3K inhibitorsExpression of p85PI3KP110alpha subunitPathway membersK inhibitorsCell linesPI3K pathway membersReverse phase protein arrayGood drug targetPhase protein arrayPI3K pathwayTargets of drugsCellular processesPhospho-Akt levelsPI3K inhibitionMelanoma cell linesDrug targetsFull activationP85K pathwayLY294002Protein arraysResistant cell linesAssociation of constitutively activated hepatocyte growth factor receptor (Met) with resistance to a dual EGFR/Her2 inhibitor in non-small-cell lung cancer cells
Agarwal S, Zerillo C, Kolmakova J, Christensen JG, Harris LN, Rimm DL, DiGiovanna MP, Stern DF. Association of constitutively activated hepatocyte growth factor receptor (Met) with resistance to a dual EGFR/Her2 inhibitor in non-small-cell lung cancer cells. British Journal Of Cancer 2009, 100: 941-949. PMID: 19240716, PMCID: PMC2661782, DOI: 10.1038/sj.bjc.6604937.Peer-Reviewed Original ResearchConceptsEpidermal growth factor receptorEGFR/HER2 inhibitorsNSCLC cell linesDual EGFR/HER2 inhibitorsGrowth factor receptorMET inhibitorsHER2 inhibitorsUse of EGFREGFR tyrosine kinase inhibitorsCell lung cancer cellsFactor receptorMajority of patientsTreatment of NSCLCCell lung carcinomaTyrosine kinase inhibitorsPotential therapeutic advantagesSubset of tumorsLung cancer cellsCell linesCurrent clinical useReceptor TKTumor cell growthHepatocyte growth factor receptorMaximal growth inhibitionImportant molecular targetActivated Wnt/ß-catenin signaling in melanoma is associated with decreased proliferation in patient tumors and a murine melanoma model
Chien AJ, Moore EC, Lonsdorf AS, Kulikauskas RM, Rothberg BG, Berger AJ, Major MB, Hwang ST, Rimm DL, Moon RT. Activated Wnt/ß-catenin signaling in melanoma is associated with decreased proliferation in patient tumors and a murine melanoma model. Proceedings Of The National Academy Of Sciences Of The United States Of America 2009, 106: 1193-1198. PMID: 19144919, PMCID: PMC2626610, DOI: 10.1073/pnas.0811902106.Peer-Reviewed Original ResearchConceptsBeta-catenin signalingNormal melanocyte developmentTranscriptional profiling revealsWnt/beta-catenin signalingMelanoma cellsUp-regulates genesWnt/ß-cateninMelanoma progressionSmall molecule activatorsRole of WntMelanocyte developmentCell fateTranscriptional changesB16 murine melanoma cellsCellular differentiationProfiling revealsMelanocyte differentiationMelanoma cell linesMurine melanoma cellsß-cateninHuman melanoma cell linesWnt3aMurine melanoma modelCell linesReduced expression
2007
High HSP90 Expression Is Associated with Decreased Survival in Breast Cancer
Pick E, Kluger Y, Giltnane JM, Moeder C, Camp RL, Rimm DL, Kluger HM. High HSP90 Expression Is Associated with Decreased Survival in Breast Cancer. Cancer Research 2007, 67: 2932-2937. PMID: 17409397, DOI: 10.1158/0008-5472.can-06-4511.Peer-Reviewed Original ResearchConceptsHigh HSP90 expressionBreast cancerHER2/neuHSP90 expressionEstrogen receptorHigh HER2/neuCell linesEarly-stage breast cancerHER2/neu expressionHuman tumorsLymph node involvementPrimary breast cancerSubset of patientsPopulation of patientsIndependent prognostic markerHigh nuclear gradeBreast cancer cell linesBreast cancer progressionCy5-conjugated antibodiesCancer cell linesNode involvementPathologic variablesPrognostic roleMultivariable analysisProspective studyLack of Extracellular Signal-Regulated Kinase Mitogen-Activated Protein Kinase Signaling Shows a New Type of Melanoma
Shields JM, Thomas NE, Cregger M, Berger AJ, Leslie M, Torrice C, Hao H, Penland S, Arbiser J, Scott G, Zhou T, Bar-Eli M, Bear JE, Der CJ, Kaufmann WK, Rimm DL, Sharpless NE. Lack of Extracellular Signal-Regulated Kinase Mitogen-Activated Protein Kinase Signaling Shows a New Type of Melanoma. Cancer Research 2007, 67: 1502-1512. PMID: 17308088, DOI: 10.1158/0008-5472.can-06-3311.Peer-Reviewed Original ResearchConceptsMitogen-activated protein kinaseERK activationB-RafERK activityMitogen-Activated Protein Kinase SignalingSignal-regulated kinase kinaseN-RASERK MAPK cascadeProtein Kinase SignalingPrimary human melanocytesRNA expression profilesCell linesEpithelial-mesenchymal transformationDistinct melanoma subtypeMAPK cascadeKinase kinaseExtracellular signalsTranscriptional targetsKinase signalingProtein kinaseExpression profilesEpithelial markersMelanoma cell linesRAS/RAFPrimary human tumorsThe X-linked inhibitor of apoptosis protein (XIAP) is up-regulated in metastatic melanoma, and XIAP cleavage by Phenoxodiol is associated with Carboplatin sensitization
Kluger HM, McCarthy MM, Alvero AB, Sznol M, Ariyan S, Camp RL, Rimm DL, Mor G. The X-linked inhibitor of apoptosis protein (XIAP) is up-regulated in metastatic melanoma, and XIAP cleavage by Phenoxodiol is associated with Carboplatin sensitization. Journal Of Translational Medicine 2007, 5: 6. PMID: 17257402, PMCID: PMC1796544, DOI: 10.1186/1479-5876-5-6.Peer-Reviewed Original ResearchConceptsMetastatic melanomaXIAP expressionCell linesCy5-conjugated antibodiesMechanism of actionMelanoma cell linesPrimary lesionOvarian cancerTherapeutic approachesTissue microarrayDisease aggressionCarboplatin sensitivityChemotherapy resistanceMalignant progressionClinical specimensBenign counterpartsCarboplatinMelanomaChemotherapy sensitizationPrimary specimensPhenoxodiolResistant cellsMelanoma cellsHigh expressionMelanoma resistance