2017
Phase I Dose-Escalation Study of Taselisib, an Oral PI3K Inhibitor, in Patients with Advanced Solid Tumors
Juric D, Krop I, Ramanathan RK, Wilson TR, Ware JA, Bohorquez S, Savage HM, Sampath D, Salphati L, Lin RS, Jin H, Parmar H, Hsu JY, Von Hoff DD, Baselga J. Phase I Dose-Escalation Study of Taselisib, an Oral PI3K Inhibitor, in Patients with Advanced Solid Tumors. Cancer Discovery 2017, 7: 704-715. PMID: 28331003, PMCID: PMC5501742, DOI: 10.1158/2159-8290.cd-16-1080.Peer-Reviewed Original ResearchConceptsDose-limiting toxicityAdverse eventsMutant tumorsHigh-grade adverse eventsTreatment-related adverse eventsConfirmed response rateMetastatic solid tumorsTumor xenograft modelPatient tumor samplesMeasurable diseasePharmacodynamic findingsPreclinical dataTumor patientsTumor growth inhibitorLow doseXenograft modelDose levelsResponse rateSolid tumorsPathway inhibitionPatientsPathway suppressionTumor samplesTumorsHotspot mutations
2016
Combination inhibition of PI3K and mTORC1 yields durable remissions in mice bearing orthotopic patient-derived xenografts of HER2-positive breast cancer brain metastases
Ni J, Ramkissoon SH, Xie S, Goel S, Stover DG, Guo H, Luu V, Marco E, Ramkissoon LA, Kang YJ, Hayashi M, Nguyen QD, Ligon AH, Du R, Claus EB, Alexander BM, Yuan GC, Wang ZC, Iglehart JD, Krop IE, Roberts TM, Winer EP, Lin NU, Ligon KL, Zhao JJ. Combination inhibition of PI3K and mTORC1 yields durable remissions in mice bearing orthotopic patient-derived xenografts of HER2-positive breast cancer brain metastases. Nature Medicine 2016, 22: 723-726. PMID: 27270588, PMCID: PMC4938731, DOI: 10.1038/nm.4120.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAminopyridinesAnimalsAntineoplastic AgentsApoptosisBrain NeoplasmsBreast NeoplasmsCarrier ProteinsCaspase 3Cell Cycle ProteinsDNA RepairDrug Resistance, NeoplasmDrug Therapy, CombinationEukaryotic Initiation FactorsEverolimusFemaleGene Expression ProfilingGenomic InstabilityHumansImmunohistochemistryKi-67 AntigenMagnetic Resonance ImagingMechanistic Target of Rapamycin Complex 1MiceMice, SCIDMolecular Targeted TherapyMorpholinesMultiprotein ComplexesNeoplasm TransplantationPhosphoinositide-3 Kinase InhibitorsPhosphoproteinsPhosphorylationReceptor, ErbB-2Remission InductionTOR Serine-Threonine KinasesXenograft Model Antitumor AssaysConceptsBreast cancer brain metastasesCancer brain metastasesBrain metastasesHER2-positive breast cancer brain metastasesOrthotopic patient-derived xenograftsPI3KPatient-derived xenograftsDurable remissionsTherapeutic responseMouse modelCombined inhibitionCombination inhibitionMetastasisInhibitionRemissionXenograftsMiceResponse and resistance to BET bromodomain inhibitors in triple-negative breast cancer
Shu S, Lin CY, He HH, Witwicki RM, Tabassum DP, Roberts JM, Janiszewska M, Jin Huh S, Liang Y, Ryan J, Doherty E, Mohammed H, Guo H, Stover DG, Ekram MB, Peluffo G, Brown J, D’Santos C, Krop I, Dillon D, McKeown M, Ott C, Qi J, Ni M, Rao P, Duarte M, Wu S, Chiang C, Anders L, Young R, Winer E, Letai A, Barry W, Carroll J, Long H, Brown M, Shirley Liu X, Meyer C, Bradner J, Polyak K. Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer. Nature 2016, 529: 413-417. PMID: 26735014, PMCID: PMC4854653, DOI: 10.1038/nature16508.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAzepinesBinding, CompetitiveCasein Kinase IICell Cycle ProteinsCell Line, TumorCell ProliferationChromatinDrug Resistance, NeoplasmEpigenesis, GeneticFemaleGene Expression Regulation, NeoplasticGenome, HumanHumansMediator Complex Subunit 1MiceNuclear ProteinsPhosphorylationPhosphoserineProtein BindingProtein Phosphatase 2Protein Structure, TertiaryProteomicsTranscription FactorsTranscription, GeneticTriazolesTriple Negative Breast NeoplasmsXenograft Model Antitumor Assays
2015
PI3K-p110α mediates resistance to HER2-targeted therapy in HER2+, PTEN-deficient breast cancers
Wang Q, Liu P, Spangle JM, Von T, Roberts TM, Lin NU, Krop IE, Winer EP, Zhao JJ. PI3K-p110α mediates resistance to HER2-targeted therapy in HER2+, PTEN-deficient breast cancers. Oncogene 2015, 35: 3607-3612. PMID: 26500061, PMCID: PMC4846581, DOI: 10.1038/onc.2015.406.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBreast NeoplasmsCell Line, TumorCell SurvivalClass I Phosphatidylinositol 3-KinasesDrug Resistance, NeoplasmFemaleHumansLapatinibMammary Neoplasms, ExperimentalMice, KnockoutMolecular Targeted TherapyPhosphatidylinositol 3-KinasesPhosphoinositide-3 Kinase InhibitorsProtein Kinase InhibitorsProto-Oncogene Proteins c-aktPTEN PhosphohydrolaseQuinazolinesReceptor, ErbB-2Signal TransductionThiazolesTumor BurdenXenograft Model Antitumor AssaysConceptsBreast tumorsP110β inhibitorsHuman epidermal growth factor receptor 2 (HER2) amplificationP110α inhibitionPTEN lossInhibition of HER2Treatment of HER2Human cancersPI3K pathway activationPTEN-deficient breast cancersGenetic mouse modelsPI3K/Akt signalingPTEN-deficient tumorsPI3K/AktDual HER2Therapeutic regimenHER2 inhibitionPIK3CA mutationsTumor regressionBreast cancerMouse modelXenograft modelHER2Null tumorsHER2 activation
2013
Preclinical and Clinical Studies of Gamma Secretase Inhibitors with Docetaxel on Human Breast Tumors
Schott AF, Landis MD, Dontu G, Griffith KA, Layman RM, Krop I, Paskett LA, Wong H, Dobrolecki LE, Lewis MT, Froehlich AM, Paranilam J, Hayes DF, Wicha MS, Chang JC. Preclinical and Clinical Studies of Gamma Secretase Inhibitors with Docetaxel on Human Breast Tumors. Clinical Cancer Research 2013, 19: 1512-1524. PMID: 23340294, PMCID: PMC3602220, DOI: 10.1158/1078-0432.ccr-11-3326.Peer-Reviewed Original ResearchConceptsBreast cancer stem cellsGamma-secretase inhibitorsAdvanced breast cancerClinical trialsBreast cancerSecretase inhibitorsMaximum-tolerated doseEfficacy of docetaxelSerial tumor biopsiesNotch pathwayTumors of patientsDoses of MKConcurrent clinical trialsHuman breast tumorsNotch pathway inhibitorsCancer stem cellsManageable toxicityTumorgraft modelsDocetaxel treatmentBCSC markersSerial biopsiesConventional therapyPreclinical dataClinical studiesExperimental therapies
2008
Short Preoperative Treatment With Erlotinib Inhibits Tumor Cell Proliferation in Hormone Receptor–Positive Breast Cancers
Guix M, de Matos Granja N, Meszoely I, Adkins TB, Wieman BM, Frierson KE, Sanchez V, Sanders ME, Grau AM, Mayer IA, Pestano G, Shyr Y, Muthuswamy S, Calvo B, Krontiras H, Krop IE, Kelley MC, Arteaga CL. Short Preoperative Treatment With Erlotinib Inhibits Tumor Cell Proliferation in Hormone Receptor–Positive Breast Cancers. Journal Of Clinical Oncology 2008, 26: 897-906. PMID: 18180460, DOI: 10.1200/jco.2007.13.5939.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAnimalsAntineoplastic AgentsBiomarkers, TumorBreast NeoplasmsCell ProliferationChemotherapy, AdjuvantErbB ReceptorsErlotinib HydrochlorideFemaleHumansImmunohistochemistryIn Situ Nick-End LabelingKi-67 AntigenMiceMice, NudeMiddle AgedNeoadjuvant TherapyNeoplasm StagingNeoplasms, Hormone-DependentProtein Kinase InhibitorsProtein-Tyrosine KinasesQuinazolinesReceptor, ErbB-2Receptors, EstrogenReceptors, ProgesteroneSignal TransductionTandem Mass SpectrometryTreatment OutcomeXenograft Model Antitumor AssaysConceptsTumor cell proliferationBreast cancerPreoperative treatmentCell proliferationHormone receptor-positive breast cancerP-S6P-AktEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinibHormone receptor-positive cancersReceptor-positive breast cancerHuman epidermal growth factor receptor 2Epidermal growth factor receptor 2ER-positive breast cancerP-EGFRTyrosine kinase inhibitor erlotinibTriple-negative breast cancerP-MAPKImmediate preoperative periodUntreated breast cancerGrowth factor receptor 2Day of surgeryInvasive breast cancerReceptor-positive cancersTriple-negative cancersKinase inhibitor erlotinib