0000000000154663

AUTHOR

Francis J. Giles

showing 8 related works from this author

9-ING-41, a small-molecule glycogen synthase kinase-3 inhibitor, is active in neuroblastoma.

2018

Advanced stage neuroblastoma is a very aggressive pediatric cancer with limited treatment options and a high mortality rate. Glycogen Synthase Kinase-3β (GSK-3β) is a potential therapeutic target in neuroblastoma. Using immunohistochemical staining, we observed positive GSK-3β expression in 67% of human neuroblastomas (34 out of 51 cases). Chemically distinct GSK-3 inhibitors (AR-A014418, TDZD8 and 9-ING-41), suppressed the growth of neuroblastoma cells whereas 9-ING-41, a clinically relevant small molecule GSK-3β inhibitor with broad spectrum pre-clinical antitumor activity, being the most potent. Inhibition of GSK-3 resulted in a decreased expression of the antiapoptotic molecule XIAP and…

0301 basic medicineCancer ResearchIndolesMice NudeCell Growth ProcessesIrinotecanArticleMaleimides03 medical and health sciencesMiceNeuroblastoma0302 clinical medicineGSK-3NeuroblastomaCell Line TumorAntineoplastic Combined Chemotherapy ProtocolsmedicineAnimalsHumansPharmacology (medical)Enzyme InhibitorsGlycogen synthasePharmacologyGlycogen Synthase Kinase 3 betabiologyChemistryDrug Synergismmedicine.diseasePediatric cancerXenograft Model Antitumor AssaysXIAP030104 developmental biologyOncologyCell cultureApoptosis030220 oncology & carcinogenesisCancer researchbiology.proteinImmunohistochemistryFemaleAnti-cancer drugs
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Identification of a novel activating mutation (Y842C) within the activation loop of FLT3 in patients with acute myeloid leukemia (AML).

2004

Fms-like tyrosine kinase 3 (FLT3) receptor mutations as internal tandem duplication (ITD) or within the kinase domain are detected in up to 35% of patients with acute myeloid leukemia (AML). N-benzoyl staurosporine (PKC412), a highly effective inhibitor of mutated FLT3 receptors, has significant antileukemic efficacy in patients with FLT3-mutated AML. Mutation screening of FLT3 exon 20 in AML patients (n = 110) revealed 2 patients with a novel mutation (Y842C) within the highly conserved activation loop of FLT3. FLT3-Y842C-transfected 32D cells showed constitutive FLT3 tyrosine phosphorylation and interleukin 3 (IL-3)-independent growth. Treatment with PKC412 led to inhibition of proliferat…

Models MolecularImmunologyBiologymedicine.disease_causeBiochemistryCell Linechemistry.chemical_compoundMicefluids and secretionshemic and lymphatic diseasesProto-Oncogene ProteinsmedicineSTAT5 Transcription FactorAnimalsHumansTyrosinePhosphotyrosineMutationCell CycleMyeloid leukemiaReceptor Protein-Tyrosine Kinaseshemic and immune systemsTyrosine phosphorylationCell BiologyHematologymedicine.diseaseMilk ProteinsProtein Structure TertiaryDNA-Binding ProteinsEnzyme ActivationLeukemiaLeukemia Myeloid AcutechemistryGene Expression Regulationfms-Like Tyrosine Kinase 3embryonic structuresFms-Like Tyrosine Kinase 3MutationCancer researchTrans-ActivatorsTyrosineSignal transductionTyrosine kinaseSignal TransductionBlood
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Clinical Course and Significance of the Novel FLT3-Y842C Mutation in a Patient with AML Treated with PKC412 Monotherapy.

2004

Abstract We recently identified a novel mutation (Y842C) within the tyrosine kinase domain of FLT3 in a patient treated with PKC410 monotherapy (ASH 2003, # 4681). Here, we present follow up studies including the clinical course of the patient and frequency analysis in 110 patients with AML. In addition, we characterized the novel mutation using overexpression of FLT3-Y842C in 32D cells. AML M2 was diagnosed in a 63 year old, male patient in 1993. After having experienced his second relapse upon standard therapy the patient was refractory to alemtuzumab treatment. Due to reduced performance status the patient was not eligible to standard chemotherapy and was enrolled into a phase II trial i…

ChemotherapyPerformance statusbusiness.industryPoint mutationmedicine.medical_treatmentImmunologyhemic and immune systemsCell BiologyHematologyBioinformaticsBiochemistryExonfluids and secretionshemic and lymphatic diseasesembryonic structuresCancer researchmedicineAlemtuzumabClinical significancebusinessTyrosine kinaseEx vivomedicine.drugBlood
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Mechanisms of Resistance to the FLT3-Tyrosine Kinase Inhibitor PKC412 in Patients with AML.

2004

Abstract The FLT3 receptor tyrosine kinase is expressed in 70-90% of cases of AML. Up to 35% of patients with AML show mutations in the JM-region or kinase domain of FLT3. These lead to autophosphorylation promoting ligand-independent cell proliferation and inhibition of apoptosis. Treatment with FLT3 tyrosine kinase inhibitors (TKI) is a promising tool in therapy of AML. Preliminary results investigating the FLT3-TKI PKC412 in patients with relapsed/refractory AML revealed that 11/15 patients (73%) with mutated FLT3 and 16/46 patients (35%) with WT FLT3 showed a >50% blast response in peripheral blood (Estey E et al. Blood.2003; 102:919a). Despite its remarkable efficacy in reducing…

biologymedicine.drug_classKinaseCell growthImmunologyAutophosphorylationClone (cell biology)Cell BiologyHematologyBiochemistryTyrosine-kinase inhibitorReceptor tyrosine kinasehemic and lymphatic diseasesImmunologymedicinebiology.proteinCancer researchPhosphorylationTyrosine kinaseBlood
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Phase IA/II Study of Oral LBH589, a Novel Deacetylase Inhibitor (DACi), Administered on 2 Schedules, in Patients with Advanced Hematologic Malignanci…

2007

Abstract LBH589 is a novel cinnamic acid hydroxamate DACi which induces apoptosis in multiple hematologic tumor cell lines in vitro at nanomolar levels. LBH589 has been administered orally, once-a-day, on Monday/Wednesday/Friday, every week (Arm 1) or every other week (Arm 2), in cycles of 28 days, to adult pts with advanced hematologic malignancies. A 3-parameter Bayesian logistic regression model guided dose escalation. To date, 61 pts, median age 67 yrs (range 16–87), 40 male, 21 female, have been enrolled: 33 pts in Arm 1 at dose levels (mg/dose) of 20 (9 pts), 30 (12 pts), 40 (10 pts), and 60 (2 pts); 28 pts in Arm 2 at dose levels (mg/dose) of 30 (7 pts), 45 (12 pts), and 60 (9 pts). …

medicine.medical_specialtybusiness.industryNauseaImmunologyPeripheral edemaCell BiologyHematologyNeutropeniamedicine.diseaseBiochemistryGastroenterologySurgeryEvery other weekInternal medicineVomitingmedicineIn patientmedicine.symptombusinessAdverse effectFebrile neutropeniaBlood
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Phase ia/ii, two-arm, open-label, dose-escalation study of oral panobinostat administered via two dosing schedules in patients with advanced hematolo…

2013

Panobinostat is a potent oral pandeacetylase inhibitor that leads to acetylation of intracellular proteins, inhibits cellular proliferation and induces apoptosis in leukemic cell lines. A phase Ia/II study was designed to determine the maximum-tolerated dose (MTD) of daily panobinostat, administered on two schedules: three times a week every week or every other week on a 28-day treatment cycle in patients with advanced hematologic malignancies. The criteria for hematologic dose-limiting toxicities differed between patients with indications associated with severe cytopenias at baseline (leukemia and myeloid disorders) and those less commonly associated with baseline cytopenias (lymphoma and …

MaleOncologyCancer ResearchIndolesMyeloidhodgkin lymphomahydroxamic acidAdministration Oralresponse criteriaPharmacologyHydroxamic Acidst-cell lymphomaHistoneschemistry.chemical_compoundhemic and lymphatic diseasesAged 80 and overHematologyMiddle AgedLeukemiaTreatment Outcomemedicine.anatomical_structuremyelomaOncologyvorinostatHematologic NeoplasmsFemaleAdultmedicine.medical_specialtypanobinostatrefractory multiple-myelomaMaximum Tolerated DoseAntineoplastic AgentsmyelofibrosisNeutropeniahistone deacetylase inhibitorsmyelodysplastic disordersDrug Administration ScheduleYoung AdultInternal medicinePanobinostatmedicineHumansIn patientAdverse effectMyelofibrosisAgedNeoplasm Staginginternational-working-groupacetylationbusiness.industrymedicine.diseaseLymphomachemistryhistone deacetylasehypoxia-inducible factor-1-alphalbh589business
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A Phase I Study of Intravenous LBH589, a Novel Cinnamic Hydroxamic Acid Analogue Histone Deacetylase Inhibitor, in Patients with Refractory Hematolog…

2006

Abstract Purpose: LBH589 is a novel histone deacetylase inhibitor that inhibits proliferation and induces apoptosis in tumor cell lines. In this phase I study, LBH589 was administered i.v. as a 30-minute infusion on days 1 to 7 of a 21-day cycle. Experimental Design: Fifteen patients (median age, 63 years; range, 42-87 years) with acute myeloid leukemia (13 patients), acute lymphocytic leukemia (1 patient), or myelodysplastic syndrome (1 patient) were treated with LBH589 at the following dose levels (mg/m2): 4.8 (3 patients), 7.2 (3 patients), 9.0 (1 patient), 11.5 (3 patient), and 14.0 (5 patients). The levels of histone acetylation were measured using quantitative flow cytometry and plasm…

AdultCancer ResearchIndolesMaximum Tolerated Dosemedicine.drug_classApoptosisPharmacologyHydroxamic AcidsDrug Administration ScheduleHistonesStructure-Activity Relationshipchemistry.chemical_compoundPredictive Value of TestsPanobinostatAcute lymphocytic leukemiaPanobinostatBiomarkers TumormedicineHumansEnzyme InhibitorsAgedCell ProliferationAged 80 and overDose-Response Relationship Drugbusiness.industryHistone deacetylase inhibitorArea under the curveQTcF ProlongationMyeloid leukemiaMiddle AgedPrecursor Cell Lymphoblastic Leukemia-Lymphomamedicine.diseaseHypokalemiaHistone Deacetylase InhibitorsLeukemiaTreatment OutcomeOncologychemistryCinnamatesLeukemia MyeloidMyelodysplastic SyndromesAcute DiseaseInjections IntravenousImmunologymedicine.symptombusinessFollow-Up StudiesClinical Cancer Research
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Clinical resistance to the kinase inhibitor PKC412 in acute myeloid leukemia by mutation of Asn-676 in the FLT3 tyrosine kinase domain.

2005

Activating mutations in the FLT3 tyrosine kinase (TK) occur in approximately 35% of patients with acute myeloid leukemia (AML). Therefore, targeting mutated FLT3 is an attractive therapeutic strategy, and early clinical trials testing FLT3 TK inhibitors (TKI) showed measurable clinical responses. Most of these responses were transient; however, in a subset of patients blast recurrence was preceded by an interval of prolonged remission. The etiology of clinical resistance to FLT3-TKI in AML is unclear but is of major significance for the development of future therapeutic strategies. We searched for mechanisms of resistance in 6 patients with AML who had relapses upon PKC412 treatment. In an …

ImmunologyMutation MissenseBiologyBiochemistrychemistry.chemical_compoundIn vivoRecurrencehemic and lymphatic diseasesHumansProtein Kinase InhibitorsProtein Kinase CQuizartinibKinaseMyeloid leukemiaCell BiologyHematologyProtein-Tyrosine KinasesStaurosporineEnzyme ActivationProtein kinase domainchemistryfms-Like Tyrosine Kinase 3Drug Resistance NeoplasmLeukemia MyeloidFms-Like Tyrosine Kinase 3Acute DiseaseCancer researchTyrosine kinaseCrenolanibBlood
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