Squamous cell Carcinoma: Molecular Therapeutic Targets


IntroductionGenetic and Epigenetic Drivers and ControllersThe Hallmarks of CancerAccelerators, Brakes and Maintenance MenEpithelial Cell Origins: EmbryologyEmbryological Origins of HNSCCEpithelial Cell Origins: Stem Cells in Head and Neck SCCStem Cell Markers in Epithelial CancersEpithelial Cell Proliferation: Circadian Rhythms and Derangements in CancerEpithelial-Mesenchymal Transition (EMT)Energy Metabolism and Mitochondrial Function in NeoplasmsTumour Progression in Head and Neck SCCEpithelial Cell Cohesion and MovementEpithelial Cell Movement and Derangements in CancerEpithelial Cell Death: Telomerase and Apoptosis; Non-apoptotic Cell DeathPhagocytosis by Epithelial Cells: Cell SippingMicrobial Interactions: Fungal, Bacterial and ViralIntra-epithelial Cell Populations: Langerhan’s Cells, Melanocytes, Mast Cells, Merkel Cells and Their Role in the Neoplastic ProcessLangerhans Cells (LCs)MelanocytesMerkel CellsMast CellsMaintenance of Architecture of Stratified Squamous Epithelia, and Derangements in CancerThe Host Immune-Inflammatory Response to a NeoplasmGood Inflammation Versus Bad InflammationThe Development of Tumour StromaMetastasis: Local and Distant; Soil and Seed; Detection of Circulating Neoplastic CellsNerve Sheath PermeationBlood Borne MetastasisMechanisms of Bone Invasion by HNSCC“Tumour” ImmunityNutrition and CachexiaParaneoplastic Diseases: Local and SystemicDifferent Morphotypes of Squamous Cell Carcinoma: Structural and Behavioural DifferencesReferencesCancer Stem Cells—Biopathology with Reference to Head and Neck CancersIntroductionStem CellsSpatial Ordering of Stem Cells and Progeny in Oral Epithelium in Relation to Antitumor MechanismsCancer Stem CellsStochastic Model of Tumor Origin and the CSC HypothesisIdentification of Stem Cells and CSCsp-1 IntegrinTranscription Factors Oct3/4, Sox and NanogCD 133CD44E-CadherinConclusionsReferencesHypoxia in Head and Neck CancerBackgroundClassificationChronic HypoxiaAcute HypoxiaBiological ConsequencesMetabolismRegulation of Hypoxia Driven PathwaysHypoxia-Inducible Factor-1 Signalling PathwaymTOR SignallingThe Unfolded Protein Response (UPR)Micro RNAsClinical Consequences in HNSCCResistance to RadiotherapyResistance to ChemotherapyTherapeutic Approaches to Overcome Hypoxia Radioresistance in HNSCCImproving Haemoglobin (Hb) LevelsIncreasing Oxygen AvailabilityRadiosensitisersHypoxic CytotoxinsHypoxia Image-Guided RadiotherapyTargeted TherapiesTargeting Angiogenesis: VEGF ReceptorsTargeting HIF-1Methods to Detect Hypoxia in HNSCCClinical Studies Using Eppendorf polarographic Needle ElectrodesExogenous Markers of HypoxiaEndogenous Markers of HypoxiaHIF-1aGlucose Transporters (GLUT)Carbonic Anhydrase 9 (CA9)Osteopontin (OPN) in Tissue and PlasmaGene Expression Signatures of HypoxiaMagnetic Resonance Imaging (MRI)Dynamic Contrast-Enhanced MRI (DCE MRI)Blood Oxygen Level-Dependent MRI (BOLD MRI)Positron Emission Tomography (PET)F-Fluoromisonidazole (18F-FMISO)Clinical Studies of 18F-FMISO in HNSCCF-Fluoroazomycin Arabinofuranoside (18F-FAZA)Copper(II)-Diacetyl-Bis (N4-Methylthiosemicarbazone) (Cu-ATSM)Clinical Studies of Cu-ATSM in HNSCCConclusionsReferencesGenetic Aberrations and Molecular Pathways in Head and Neck CancerIntroductionEGFRmTORRASp53pRbVEGFVascular endothelial growth factor receptors (VEGFR)SurvivinNOTCH PathwayConclusionsReferencesp53 in Head and Neck Squamous Cell CarcinomaIntroductionNormal Function of p53Mutations of TP53 in HNSCC and Subsequent EffectsTP53 as a Prognostic MarkerTP53 as a Post-treatment Predictor of Outcome in HNSCCTP53 as a Druggable Target in HNSCCViral Gene TherapySelective Killing of Cells with. Non-functional p53Restoring Wild-Type Function of Mutated p53Prevention of Endogenous Inactivation ofp53p53 in HPV-Positive HNSCCConclusionsReferencesBlockage of EGFR Pathway for Anticancer Therapy in Squamous Cell Carcinoma of the Head and NeckThe Epidermal Growth Factor Receptor (EGFR)EGFR InhibitionAnti-EGFR Monoclonal AntibodiesEGFR Tyrosine Kinase Inhibitors (TKI)Strategies to Overcome Resistance to Anti-EGFR TherapyBlockage of Multiple HER ReceptorsDual targeting mAbs or mixture of mAbsCombinations of Anti-EGFR Therapy with Other Molecular Pathways InhibitorsIGF-1R InhibitorsThe c-Met PathwayInhibitors of AngiogenesisInhibitors of the PI3K/Akt/mTOR PathwayInhibitors of the Signal Transducer and Activation of Transcription (STAT) PathwayInhibitors of Heat Shock ProteinsConclusionReferencesTargeting the mTOR Signaling Circuitry in Head and Neck CancerIntroductionActivation of the EGFR-PI3K-AKT-mTOR Signaling Network in Head and Neck CancermTOR Activation in HPV-Associated HNSCCThe Emerging Genomic Landscape of Head and Neck CancerMultiple Genomic Alterations in Head and Neck Cancer Converge in the PI3K-mTOR PathwayEffectiveness of mTOR Inhibitors in Experimental HNSCC ModelsInhibiting mTOR for HNSCC Treatment in the ClinicTargeting mTOR with Metformin for Oral Cancer PreventionReferencesSurvivin as a Therapeutic Target in Squamous Cell CarcinomaIntroductionSurvivinFunctions of SurvivinRole of Survivin in Cell DivisionRole of Survivin in ApoptosisSurvivin Expression in SCC: Prognosis and DiagnosisTherapeutic Targeting of SurvivinAntisense TechnologyDominant Negative ConstructsRibozyme TechniqueHistone Deacetylase InhibitorsImmunotherapyConclusionReferencesMicroRNA: Utility as Biomarkers and Therapeutic Targets in Squamous Cell CarcinomaMicroRNA: Small but Powerful Regulators of Gene ExpressionMicroRNA Alterations in Squamous Cell CarcinomasMechanisms of Regulation of miRNA Expression in Squamous Cell CarcinomasFunctional Consequences of Aberrant MicroRNA Expression in Squamous Cell CarcinomaThe Role of miRNA in the Tumour MicroenvironmentmiRNA as Signaling Molecules in SCCClinical Utility of miRNA as Biomarkers in Squamous Cell CarcinomasmiRNA as Therapeutic Targets—A Novel Treatment Strategy in Squamous Cell Carcinomas?Concluding PerspectivesReferencesEnvoi—An Appraisal of Targeted Therapies for Head and Neck CancerIntroductionInformation from Trial RegistriesSystematic ReviewInclusion CriteriaExclusion CriteriaAssessmentsSummary of Published StudiesEGFR inhibitorsEGFR MoAb - CetuximabEGFR MoAb - ZalutumumabEGFR MoAb - PanitumumabSynchronus VEGF and EGFR blocking agentsSym 004 (anti EGFR antibody mixture)EGFR TKIDual TKI (EGFR/HER2)VEGFR TKIEGFR TKIMultikinase inhibitors (MKI)VEGFR inhibitors—MKIOther Molecular Target AgentsMammalian Target of Rapamycin (mTOR) InhibitorProteasome inhibitorMET/VEGFR inhibitorAdenovirus gene therapyAurora A kinase inhibitorSrc/Abl kinase inhibitorOutcomesResponsesSingle agents (monotherapy)Combined therapySurvivalToxicity and Side Effects of Targeted TherapyConclusionsReferences
 
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