2018
First-in-Class ERK1/2 Inhibitor Ulixertinib (BVD-523) in Patients with MAPK Mutant Advanced Solid Tumors: Results of a Phase I Dose-Escalation and Expansion Study
Sullivan RJ, Infante JR, Janku F, Wong DJL, Sosman JA, Keedy V, Patel MR, Shapiro GI, Mier JW, Tolcher AW, Wang-Gillam A, Sznol M, Flaherty K, Buchbinder E, Carvajal RD, Varghese AM, Lacouture ME, Ribas A, Patel SP, DeCrescenzo GA, Emery CM, Groover AL, Saha S, Varterasian M, Welsch DJ, Hyman DM, Li BT. First-in-Class ERK1/2 Inhibitor Ulixertinib (BVD-523) in Patients with MAPK Mutant Advanced Solid Tumors: Results of a Phase I Dose-Escalation and Expansion Study. Cancer Discovery 2018, 8: 184-195. PMID: 29247021, DOI: 10.1158/2159-8290.cd-17-1119.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAminopyridinesFemaleHumansMagnetic Resonance ImagingMaleMiddle AgedMitogen-Activated Protein Kinase 1Mitogen-Activated Protein Kinase 3Mitogen-Activated Protein KinasesMutationNeoplasm StagingNeoplasmsProtein Kinase InhibitorsPyrrolesTomography, X-Ray ComputedTreatment OutcomeYoung AdultConceptsCommon treatment-related adverse eventsSolid tumorsHuman dose-escalation studyMulticenter phase I trialTreatment-related adverse eventsDose-escalation cohortsDose-expansion cohortsMutant solid tumorsPhase II doseAcceptable safety profileAdvanced solid tumorsDose-escalation studyPhase I trialPotent preclinical activityTreatment of patientsSolid tumor malignanciesERK1/2 kinase inhibitorEvaluable patientsDose expansionExpansion cohortAdverse eventsPartial responseDose escalationI trialSafety profile
2014
Combined BRAF (Dabrafenib) and MEK Inhibition (Trametinib) in Patients With BRAFV600-Mutant Melanoma Experiencing Progression With Single-Agent BRAF Inhibitor
Johnson DB, Flaherty KT, Weber JS, Infante JR, Kim KB, Kefford RF, Hamid O, Schuchter L, Cebon J, Sharfman WH, McWilliams RR, Sznol M, Lawrence DP, Gibney GT, Burris HA, Falchook GS, Algazi A, Lewis K, Long GV, Patel K, Ibrahim N, Sun P, Little S, Cunningham E, Sosman JA, Daud A, Gonzalez R. Combined BRAF (Dabrafenib) and MEK Inhibition (Trametinib) in Patients With BRAFV600-Mutant Melanoma Experiencing Progression With Single-Agent BRAF Inhibitor. Journal Of Clinical Oncology 2014, 32: 3697-3704. PMID: 25287827, PMCID: PMC4226803, DOI: 10.1200/jco.2014.57.3535.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAgedAged, 80 and overAntineoplastic Combined Chemotherapy ProtocolsDisease ProgressionDisease-Free SurvivalFemaleHumansImidazolesMaleMelanomaMiddle AgedMitogen-Activated Protein Kinase KinasesMutationOximesProtein Kinase InhibitorsProto-Oncogene Proteins B-rafPyridonesPyrimidinonesConceptsObjective response rateProgression-free survivalMedian progression-free survivalEfficacy of dabrafenibBRAF inhibitor treatmentBRAF inhibitorsOpen-label phase I/II studyInhibitor treatmentPhase I/II studySingle-agent BRAF inhibitorsMEK inhibitionBRAF inhibitor-resistant melanomaBRAF inhibitor monotherapyMedian overall survivalModest clinical efficacyBRAF inhibitor therapyEarly clinical studiesDabrafenib monotherapyInitial therapyStable diseaseII studyInhibitor monotherapyOverall survivalInhibitor therapyStudy enrollment
2013
Advances in the systemic treatment of metastatic melanoma.
Yushak M, Kluger HM, Sznol M. Advances in the systemic treatment of metastatic melanoma. Oncology 2013, 27: 374-81. PMID: 25184258, PMCID: PMC6092183.Peer-Reviewed Original ResearchMeSH KeywordsAntibodies, MonoclonalDrug Therapy, CombinationHumansImidazolesImmunologic FactorsImmunotherapy, AdoptiveIndolesIpilimumabMelanomaMutationNivolumabOximesProgrammed Cell Death 1 ReceptorProtein Kinase InhibitorsProto-Oncogene Proteins B-rafPyridonesPyrimidinonesSkin NeoplasmsSulfonamidesVemurafenibConceptsMetastatic melanomaTumor-host immune interactionsRandomized phase III trialPhase III trialsCombination of dabrafenibAdoptive cell therapyStandard of carePromising new agentPhase II dataIII trialsOverall survivalSystemic treatmentPredictive biomarkersMechanisms of resistanceTreatment outcomesIndividual patientsLimited efficacyAvailable agentsImmune interactionsNew agentsMolecular alterationsEffective agentCell therapyCurrent agentsMelanoma cells
2011
In vitro studies of dasatinib, its targets and predictors of sensitivity
Jilaveanu LB, Zito CR, Aziz SA, Chakraborty A, Davies MA, Camp RL, Rimm DL, Dudek A, Sznol M, Kluger HM. In vitro studies of dasatinib, its targets and predictors of sensitivity. Pigment Cell & Melanoma Research 2011, 24: 386-389. PMID: 21320292, PMCID: PMC4431976, DOI: 10.1111/j.1755-148x.2011.00835.x.Peer-Reviewed Original Research
2010
A phase 2 trial of dasatinib in advanced melanoma
Kluger HM, Dudek AZ, McCann C, Ritacco J, Southard N, Jilaveanu LB, Molinaro A, Sznol M. A phase 2 trial of dasatinib in advanced melanoma. Cancer 2010, 117: 2202-2208. PMID: 21523734, PMCID: PMC3116034, DOI: 10.1002/cncr.25766.Peer-Reviewed Original ResearchConceptsProgression-free survivalC-kit mutationsPhase 2 trialResponse ratePartial responseMedian progression-free survivalMelanoma cell proliferationDaily dasatinibMucosal primaryPFS ratesStarting dosageCommon toxicitiesUnresectable melanomaAdvanced melanomaPleural effusionMelanoma patientsPredictive biomarkersMinor responseCombination trialsTumor assessmentDose reductionPatientsPrespecified endpointsDasatinibMelanomaIncidence of the V600K mutation among melanoma patients with BRAF mutations, and potential therapeutic response to the specific BRAF inhibitor PLX4032
Rubinstein JC, Sznol M, Pavlick AC, Ariyan S, Cheng E, Bacchiocchi A, Kluger HM, Narayan D, Halaban R. Incidence of the V600K mutation among melanoma patients with BRAF mutations, and potential therapeutic response to the specific BRAF inhibitor PLX4032. Journal Of Translational Medicine 2010, 8: 67. PMID: 20630094, PMCID: PMC2917408, DOI: 10.1186/1479-5876-8-67.Peer-Reviewed Original ResearchConceptsV600K mutationsClinical trialsBRAF V600E/K mutationK mutationPotential therapeutic responseMutant BRAF inhibitorsBRAF inhibitor PLX4032BRAF V600K mutationMelanoma patientsTherapeutic responseBRAF mutationsPatientsV600E mutationInhibitor PLX4032BRAF kinasePLX4032TrialsCommon mutationsMutationsMelanomaIncidencePLX4032, a selective BRAFV600E kinase inhibitor, activates the ERK pathway and enhances cell migration and proliferation of BRAFWT melanoma cells
Halaban R, Zhang W, Bacchiocchi A, Cheng E, Parisi F, Ariyan S, Krauthammer M, McCusker JP, Kluger Y, Sznol M. PLX4032, a selective BRAFV600E kinase inhibitor, activates the ERK pathway and enhances cell migration and proliferation of BRAFWT melanoma cells. Pigment Cell & Melanoma Research 2010, 23: 190-200. PMID: 20149136, PMCID: PMC2848976, DOI: 10.1111/j.1755-148x.2010.00685.x.Peer-Reviewed Original ResearchConceptsMelanoma cellsTumor cellsMelanoma tumor cellsPrimary melanoma cellsMetastatic tumor cellsStatus of mutationsClinical responseRate of proliferationAdvanced lesionsInhibitor PLX4032Kinase inhibitorsPLX4032ERK pathwayCell migrationNRASDownstream effectorsCell adherenceERK1/2CellsProliferationCell cycle controlMobility of cellsActive ERK1/2Therapy
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 expression