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Current Advances in Osteosarcoma - Eugenie S. Kleinerman

Year 2014


Historical Perspective on the Introduction and Use of Chemotherapy for the Treatment of OsteosarcomaIntroductionRationale for the Application of ChemotherapyEffective Chemotherapeutic AgentsConpadri and Compadri RegimensHistorical PerspectiveDoxorubicinHistorical PerspectiveCurrent PracticeHigh-Dose MethotrexateHistorical PerspectiveHigh-Dose Methotrexate “Rescue” in OsteosarcomaClinical Application of High-Dose Methotrexate in OsteosarcomaCurrent PracticeCis-DiamminodichloroplatinumHistorical PerspectiveCurrent PracticeOxazaphosphorinesHistorical PerspectiveCurrent PracticeImmunostimulatory Compounds and ChemotherapyNew Chemotherapeutic AgentsInhalation ChemotherapyNeoadjuvant (Preoperative or Presurgical) ChemotherapyTreatment of Pulmonary MetastasesLimb SalvageTherapeutic Regimens and StrategiesDrawbacks of ChemotherapyAncillary DiscoveriesCommentConclusionReferencesPart I Novel Therapeutic TargetsWnt Signaling in OsteosarcomaIntroductionOverview of Wnt/β-Catenin Signaling Pathway and CancerOverview of Wnt/β-Catenin Signaling Pathway and OsteosarcomaRole of Wnt Antagonists in OsteosarcomaControversy of Inactivity of Wnt/β-Catenin Pathway in High-Grade OSTargeting Noncanonical Wnt Pathways (β-Catenin-Independent Pathways)Wnt/B-Catenin Signaling and Stem CellsTherapy Against Wnt Target Genes in OsteosarcomaConclusionReferencesReceptor Tyrosine Kinases in Osteosarcoma: Not Just the Usual SuspectsReceptor Tyrosine KinasesRegulation of RTKsRTK Dysregulation in CancerTargeting RTKS in CancerRTKs in OsteosarcomaScreening and Validation StudyIGF-1RAxlEphB2FGFR2RetOther RTKsSummaryReferencesUnderstanding the Role of Notch in OsteosarcomaIntroduction: The Notch Signaling PathwayRole of Notch Signaling in Normal Osteoblast DevelopmentNotch and the VasculatureRole of Notch Signaling in Normal Vascular DevelopmentNotch and Arterial/Venous SpecificationNotch and Sprouting AngiogenesisNotch and Vascular Mural FunctionsNotch and Macrophage-Mediated AngiogenesisRole of Notch Signaling in Tumor VascularNotch Signaling at the Primary TumorNotch Signaling at the Metastatic SiteNotch Signaling in OsteosarcomaConclusionsReferencesDevelopmental Pathways Hijacked by OsteosarcomaIntroductionRunx2Wnt/β-CateninFGFMMPIGFRBMPOsterixTWISTHippo/YAP Pathway in Osteoblast DifferentiationHippo/YAP Pathway in OsteosarcomaERBB4 Signaling in Osteoblast DifferentiationERBB4 in OsteosarcomaConclusionsReferencesMicroRNAs in OsteosarcomagenesisProfiles and Patterns of MicroRNAs in OsteosarcomaPronostic MicroRNAs in OsteosarcomaGeneral AggressivenessMetastasisChemoresistancePathways of Influence for MicroRNAsProliferationApoptosisDNA Damage RepairInvasionAngiogenesisDriving MicroRNA DysregulationFuture DirectionsReferencesRECQ DNA Helicases and OsteosarcomaIntroductionRECQ Family of DNA Helicases and Cancer PredispositionFunctions of the RECQL4 DNA HelicaseRothmund–Thomson Syndrome: Nature's Model of OsteosarcomaUnderstanding the Role of RECQL4 in Osteosarcoma DevelopmentPrevious Recql4 Mouse ModelsGeneration of a Conditional (Bone-Specific) Mouse Model of RTSImplications for Understanding and Potentially Targeting RECQ-Related Pathways for Cancer TherapyReferencesAutophagy in OsteosarcomaIntroductionRegulation of Autophagy in OSAutophagy and Tumorigenesis: Cell Survival vs. Cell DeathAutophagy as a Cell Death MechanismAutophagy as a Cell Survival MechanismImplications of Autophagy in OSModulation of AutophagySummaryReferencesHER-2 Involvement in OsteosarcomaIntroductionHER-2 BiologyHER-2 in Breast CancerHER-2 in Osteosarcoma Cell LinesHER-2 Is a Negative Prognostic Indicator in OsteosarcomaHER-2 Is Not Prognostic in OsteosarcomaHER-2 Is a Positive Prognostic Indicator in OsteosarcomaSummary of HER-2 StudiesTrastuzumab in OsteosarcomaLessons LearnedConclusionReferencesPart II Tumor MicroenvironmentRole of Ezrin in Osteosarcoma MetastasisEzrin, Radixin, and Moesin ProteinsFunctional Relationship and Structure Organization in Normal TissuesConformational Regulation: PhysiologyCellular FunctionsEzrin Expression in CancerMelanomaHead and Neck CancerNon Small Cell Lung Cancer (NSCLC)Brain CancerEzrin in Sarcomas/OsteosarcomaExpressionEzrin Expression Predicts Outcome in OS PatientsA Biological Understanding of Ezrin in OS MetastasisEzrin Increases Survival of OS Cells Early After Their Arrival in the LungDynamic Regulation During MetastasisEarly Metastatic Stress and PKC InhibitionAlteration of Cellular MetabolismRegulation of Protein TranslationLinkage to mTOR PathwayInhibition of Ezrin Functions as Therapeutic Target in OS MetastasisConclusion and Future DirectionsReferencesParticipation of the Fas/FasL Signaling Pathway and the Lung Microenvironment in the Development of Osteosarcoma Lung MetastasesIntroductionThe Death Receptor Fas and the Fas Signaling PathwayFas Expression Inversely Correlates with the Metastatic Potential of Osteosarcoma CellsAn Intact Fas/FasL Signaling Pathway is Essential for the Elimination of Fas+ Osteosarcoma CellsFas Regulation in OsteosarcomaFas Expression in Osteosarcoma Is Not Regulated by MethylationmiR-20a Encoded by MicroRNA 17-92 Cluster Regulates Fas ExpressionHarnessing the Lung Microenvironment as Part of the Therapy Aimed at Eradicating Osteosarcoma Lung MetastasesGemcitabine Upregulates Fas ExpressionSummaryReferencesPart III Unique Osteosarcoma ModelsZebrafish as a Model for Human OsteosarcomaGeneral IntroductionIntroduction to Zebrafish as a Cancer ModelMiniature LaboratoryBackgroundCell Lines Versus Primary Tumor and Niche SupportImmune ResponseHigh-Throughput Injection and ImagingDrug ScreensSingle DrugsCombined TherapiesMimicking Human OsteosarcomaConclusionReferencesUsing Canine Osteosarcoma as a Model to Assess Efficacy of Novel Therapies: Can Old Dogs Teach Us New Tricks?TherapiesLiposome-Encapsulated Muramyl TripeptidePhosphatidylethanolamine (L-MTP-PE)TetrathiomolybdateAerosol TherapyGemcitabineInterleukin 2ReferencesPart IV Novel Therapeutic Approaches Based on Biology: Tumor Targeted TherapyOncolytic Viruses for Potential Osteosarcoma TherapyIntroductionOncolytic DNA Viruses in OsteosarcomaAdenovirusHerpes Simplex VirusVaccinia VirusOncolytic RNA Viruses in OsteosarcomaReovirusSemliki Forest VirusVesicular Stomatitis VirusMeasles VirusPoliovirusNewcastle Disease VirusGeneral Challenges and Novel Approaches of Virotherapy in HumansTumor SpecificityNeutralizing AntibodiesCombination TherapyRisks of VirotherapySpecific Challenges of Virotherapy in OsteosarcomaFuture DirectionsReferencesIL-11Rα: A Novel Target for the Treatment of OsteosarcomaIntroductionIL-11Rα in OsteosarcomaTherapeutic ActivityConclusionReferencesBone-Seeking Radiopharmaceuticals as Targeted Agents of Osteosarcoma: Samarium-153-EDTMP and Radium-223Osteosarcoma Biology Favors Use of Bone-Seeking RadiopharmaceuticalsRadiation for Osteosarcoma Cancer ControlThe Problem of Multiple Bone and/or Metastatic Sites of OsteosarcomaProperties of Samarium-153-EDTMP, a Beta-Emitting RadiopharmaceuticalPreclinical Studies of Samarium-153-EDTMP in Relation to OsteosarcomaSamarium-153-EDTMP Experience Against Cancer in HumansHigh-Dose Samarium-153-EDTMPAdvantages of Radium-223, an Alpha Particle Emitting Bone-Seeking Radiopharmaceutical Compared to the Beta Emitter, Samarium-153-EDTMPPossible Roles of Bone-Seeking Radiopharmaceuticals in Osteosarcoma TherapyWould Low Marrow Toxicity of Radium-223 Allow Concurrent Use with Osteosarcoma Chemotherapy?ConclusionReferencesPart V Novel Therapeutic Approaches Based on Biology: ImmunotherapyMuramyl Tripeptide-Phosphatidyl Ethanolamine Encapsulated in Liposomes (L-MTP-PE) in the Treatment of OsteosarcomaIntroductionBackgroundEarly Clinical InvestigationProspective Randomized Phase III TrialPhase III Randomized Trial for Patients with Metastatic Disease at Initial PresentationCompassionate Access TrialsRegulatory Status of L-MTP-PEReferencesGenetically Modified T-Cell Therapy for OsteosarcomaIntroductionT-Cell Therapy Targets for OsteosarcomaGenetic Approaches to Render T Cells Specific for Osteosarcomaα/β TCR Modified T-CellsCAR-Modified T CellsGenetic Approaches to Enhance the Effector Function of Osteosarcoma-Specific T CellsEnhancing T-Cell Expansion and Persistence In VivoGenetic Modifications to Overcome Tumor-Mediated ImmunosuppressionGenetic Modification of T Cells to Improve Homing to Tumor SitesImproving Safety of T-Cell TherapyCombinatorial T-Cell TherapyConclusionsReferencesNatural Killer Cells for OsteosarcomaBrief Overview of NK Cell BiologyActivating and Inhibitory ReceptorsMechanisms of NK Cell-Mediated KillingEvidence for NK Cell Activity in OsteosarcomaNK Cell Function in Osteosarcoma PatientsExpression of NK LigandsMechanisms of KillingMechanisms of Immune EscapeIndirect Activation of NK Cell FunctionMonoclonal AntibodiesCytokinesChemotherapyImmunomodulatorsNK Cell Adoptive ImmunotherapyClinical NK Cell Sources and TrialsFuture ApproachesReferences
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