مقاومت گلیوبلاستوما در برابر شیمی‌درمانی: مکانیسم‌های مولکولی و استراتژی‌های نوآورانه معکوس‌سازی (جلد ۱۵)

Cover Front-Ma_2021_Glioblastoma-Resistance-to-Chemotherapy--Molecular-Mechanisms- Front Matter Copyri_2021_Glioblastoma-Resistance-to-Chemotherapy--Molecular-Mechanisms-an Copyright Aims-and-Scope-for-Series--Can_2021_Glioblastoma-Resistance-to-Chemotherapy- Aims and Scope for Series ``Cancer Sensitizing Agents for Chemotherapy´´ Aims-and-Scope-o_2021_Glioblastoma-Resistance-to-Chemotherapy--Molecular-Mec Aims and Scope of the Volume About-the-Seri_2021_Glioblastoma-Resistance-to-Chemotherapy--Molecular-Mecha About the Series Editor About-the-Volu_2021_Glioblastoma-Resistance-to-Chemotherapy--Molecular-Mecha About the Volume Editors Contribu_2021_Glioblastoma-Resistance-to-Chemotherapy--Molecular-Mechanisms- Contributors Contents Prefa_2021_Glioblastoma-Resistance-to-Chemotherapy--Molecular-Mechanisms-and Preface Chapter-1---Overview-of-glioblast_2021_Glioblastoma-Resistance-to-Chemothera Overview of glioblastoma biological hallmarks and molecular pathology Introduction Biological hallmarks Pseudopalisading necrosis Microvascular hyperplasia and angiogenesis Local invasion Altered metabolism Immunosuppressive microenvironment Heterogeneity and cancer stem-like cells Molecular pathology Molecular markers 1p/19q codeletion Isocitrate dehydrogenase EGFR p53 pathway PTEN and PI3K-AKT pathway Rb pathway Ras/Raf/MAPK pathway Extrachromosomal DNA Epigenetic markers MGMT methylation Telomerase reverse transcriptase ATRX Conclusions and future perspectives References Chapter-2---Past-and-present_2021_Glioblastoma-Resistance-to-Chemotherapy--M Past and present drug treatments for glioblastoma Introduction Brief history of glioblastoma Pre-Stupp era Standard of care for glioblastoma (2005 to now) Chemotherapy Tyrosine kinase pathway EGFR pathway VEGF Pl3K/mTOR pathway Met Immunotherapy Conclusion References Chapter-3---Investigational_2021_Glioblastoma-Resistance-to-Chemotherapy--Mo Investigational new drugs against glioblastoma Introduction Special challenges Concepts to explain failure Temozolomide, the prototype of antiglioma drugs Agents that target DNA integrity Agents that induce direct DNA damage Agents that impair DNA repair DNA protein kinase inhibitors Telomerase inhibition Agents that target epigenetic determinants of chromosome structure and gene transcription Modulators of chromatin organization Histone deacetylase inhibitors Histone methylase inhibitors Agents that directly alter cell cycle or cell death regulation Targeting cell cycle regulation CDK4/6 inhibitors Drugs that interfere with the mitotic spindle Targeting the apoptotic circuitry Direct proapoptotic agents Agents that directly alter protein homeostasis Inhibition of the ubiquitin-proteasome pathway Inhibition of the neddylation pathway Targeting upstream molecular pathways EGFR inhibition Inhibitors of the PI3K/AKT/mTOR pathway Pan-PI3K inhibitors AKT inhibitors mTORC1/2 inhibitors Multitarget inhibitors if the PI3K pathway Inhibition of the RAS/MEK/ERK pathway Synthetic lethality and drug delivery Conclusions Acknowledgments References Chapter-4---Molecular-mechanis_2021_Glioblastoma-Resistance-to-Chemotherapy- Molecular mechanisms in temozolomide-resistant glioblastoma Introduction What is glioblastoma? Treatments for GBM Chemotherapy for GBM Molecular events in GBM cells after TMZ treatment Molecular events in TMZ-resistant GBM cells after TMZ treatment Innate TMZ-resistant GBM cells Research models (in vitro, in vivo) for innate TMZ-resistant GBM Molecular events of innate TMZ-resistant GBMs/PDXs Acquired TMZ-resistant GBM cells Research models (in vitro, in vivo) for acquired TMZ-resistant GBMs/PDXs TMZ-resistance mechanisms in acquired TMZ-resistant GBM/PDX cells Therapeutic approaches Therapeutic approaches for GBM treatment Therapeutic approaches for TMZ-resistant GBM cells to overcome TMZ resistance: Single-agent approach Targeting DNA repair and DNA damage response enzymes Signaling pathway inhibitors Targeting transcription factor and transcriptional regulator DNA synthesis inhibition Gene therapy Ligand and receptor Metabolism inhibition miRNA modulation Therapeutic approaches for TMZ-resistant GBM cells to overcome TMZ resistance: Multitarget approach with TMZ Therapeutic approaches for TMZ-resistant GBM cells to overcome TMZ resistance: Multitarget approach without TMZ Clinical trial Methods for identification of novel targets for sensitizing TMZ Models for studying modulators of TMZ response in GBM In vitro models of TMZ resistance In vivo models of TMZ resistance Methods used for identifying modulators of TMZ response Methods for evaluation of a single modulator of TMZ resistance Methods for genome-wide screening modulators of TMZ resistance Conclusions and future directions Acknowledgment References Chapter-5---Glioma-stem-cells-and-as_2021_Glioblastoma-Resistance-to-Chemoth Glioma stem cells and associated molecular mechanisms in Glioblastoma Chemoresistance Introduction Glioblastoma Glioma stem-like cells Current therapies and the role of GSCs Surgical resection Bioavailability of temozolomide Glioma stem-like cell biology aiding survival GSC identification GSC role in resistance to hypoxia GSC role in angiogenesis GSC role in immune evasion The impact of GSC heterogeneity and plasticity on chemoresistance Specific molecular pathways of GSC resistance to chemotherapy ATP-binding cassette transporter channel Methylguanine-DNA-methyltransferase Mismatch and base excision repair mechanisms Cell cycle checkpoints Conclusion References Chapter-6---Signaling-in-the-tumo_2021_Glioblastoma-Resistance-to-Chemothera Signaling in the tumor microenvironment of therapy-resistant glioblastoma Introduction TME Signals from the ECM Hypoxia Tumor/stroma interactions Immune infiltrates-modulators-microglia and macrophages Self-renewal pathways: WNT Self-renewal pathways: Notch Self-renewal pathways: Sonic Hedgehog Receptor tyrosine kinases EGFR RAS/MAPK/ERK PI3K/AKT/MTOR JAK/STAT Phospholipase C (PLC/PKC) Therapeutic resistance to EGFR inhibition PDGFR VEGF Secreted factors: TGF-β Secreted factors: BMP Transcription factors: NF-κB Effects of therapy on the TME Radiotherapy Chemotherapy Targeting the TME Conclusion References Chapter-7---Intratumoral-heterogene_2021_Glioblastoma-Resistance-to-Chemothe Intratumoral heterogeneity associated with glioblastoma drug response and resistance Introduction Genetic and transcriptomic ITH Cellular and functional ITH Molecular mechanisms of treatment resistance O6-methylguanine-DNA methyltransferase (MGMT) status Drug efflux pumps DNA checkpoints Apoptosis Cell-intrinsic and -extrinsic mechanisms of resistance Cell state and the proneural-to-mesenchymal transition Immune cell and niche interactions Conclusions References Chapter-8---Role-of-apoptosis--autoph_2021_Glioblastoma-Resistance-to-Chemot Role of apoptosis, autophagy, and the unfolded protein response in glioblastoma chemoresistance Introduction Apoptosis Intrinsic pathway of apoptosis Extrinsic pathway of apoptosis Apoptosis mediators Poly (ADP-ribose) polymerases (PARPs) family protein Bcl-2 family proteins Inhibitors of apoptosis proteins (IAPs) P53 Apoptosis and chemoresistance Chemoresistance in glioblastoma Role of Bcl-2 family proteins in chemoresistance of glioma cells Hypoxia and chemoresistance in glioma cells Role of p53 in alkylating agent chemoresistance Role of miRNAs in alkylating agent chemoresistance Role of defective DNA repair systems in alkylating agent chemoresistance Autophagy pathway Autophagy and apoptosis cross talk: self-eating and self-killing processes The dual roles of autophagy in glioblastoma promotion and suppression Autophagy involvement in the initiation and overcome chemoresistance in GBM Autophagy involvement in mechanisms of anticancer activity of alkylating agents Autophagy involvement in chemoresistance to alkylating drugs in GBM Endoplasmic reticulum stress, and unfolded protein response (UPR) Cross talk between UPR, autophagy, and apoptosis Role of UPR in glioblastoma chemoresistance Role of UPR branches in GBM-induced chemoresistant to TMZ GRP78 IRE1 PERK ATF6 UPR affects chemotherapy-induced cell death in GBM How simvastatin/TMZ affect GBM chemoresistance Tissue-engineered tumor models Bioengineered glioblastoma and neuroblastoma in vitro models Brain tumor tissue-engineered models for chemotherapeutic evaluations Conclusion References Chapter-9---Role-of-multidrug-resist_2021_Glioblastoma-Resistance-to-Chemoth Role of multidrug resistance in glioblastoma chemoresistance: Focus on ABC transporters Introduction Structure and functions of ABC proteins Structure of ABC proteins Functions of ABC proteins Mechanisms of action of ABC transporters ABC transporters in glioblastoma ABCB1 (MDR1, P-glycoprotein) ABCC1 (MRP1) ABCG2, breast cancer resistance protein (BCRP) Clinical value Conclusion Acknowledgments References Chapter-10---Role-of-mitochondrial-reacti_2021_Glioblastoma-Resistance-to-Ch Role of mitochondrial reactive oxygen species in glioblastoma drug resistance and strategies for therapeutic ... Introduction Glioblastoma TMZ: Mechanism of action and resistance Additional TMZ mechanism of action Reactive oxygen species in GBM GBM and ROS Metabolism and mitochondrial dysfunction modulate ROS production Direct and indirect ROS effects Modulation of ROS scavenging ROS therapeutic activity in GBM GBM and HIF-1α activity Reactive oxygen species and chaperone-mediated autophagy ROS-CMA axis as a therapeutic target for GBM Conclusions Acknowledgments References Chapter-11---Glioblastoma-cell-i_2021_Glioblastoma-Resistance-to-Chemotherap Glioblastoma cell-induced immunosuppression causing chemoresistance Introduction The glioblastoma secretome Cytokine-induced immunosuppression in glioblastoma Interleukin-6 (IL-6) and STAT3 signaling Interleukin-1β (IL-1β) and the sphingolipid rheostat Transforming growth factor-β (TGF-β) and T cell paralysis Interleukin-8 (IL-8) and other cytokines Indoleamine 2,3-dioxygenase and the kynurenine pathway Programmed death-ligand 1 (PD-L1) (cluster of differentiation, CD 274) References Chapter-12---Role-of-cell-quiescence-in_2021_Glioblastoma-Resistance-to-Chem Role of cell quiescence in glioblastoma cytotoxic resistance and strategies for therapeutic intervention Introduction Resistance mechanisms in GBM Resistance to radiation Chemotherapy resistance Cell quiescence Quiescence and treatment resistance Molecular drivers of quiescence Targeting quiescent GBM tumor cells Methods to identify and isolate quiescent cells Vital dye retention, proliferative potential, and cytotoxic sensitivity in glioblastoma cells Conclusions Acknowledgments References Chapter-13---The-molecular-and-cellular-ef_2021_Glioblastoma-Resistance-to-C The molecular and cellular effects of radiotherapy-induced microenvironment changes on potential chemoresista ... Introduction Extracellular microenvironment of the brain in glioblastoma Brain extracellular matrix Brain extracellular matrix in development and homeostasis Microglia: The guards in brain parenchyma Microglial activation and brain matrix regulation Extracellular matrix in glioblastoma Radiation-induced changes in the brain and GBM microenvironment Radiation therapy Molecular and cellular adaptations to RT Radiation effects on ECM remodeling and invasiveness Radiation-induced redox dynamics and modulation of inflammation Radiation-induced cell senescence and bystander effects Therapeutic implications and future directions Conclusions References Chapter-14---Molecular-and-cellula_2021_Glioblastoma-Resistance-to-Chemother Molecular and cellular mechanisms in recurrent glioblastoma chemoresistance Introduction Recurrent glioblastoma Glioblastoma stem cells Main mechanisms of chemoresistance in GSCs Aberrant DNA repair Cell cycle checkpoints deregulation Deregulation of GSC symmetric/asymmetric division in GBM recurrence Efflux pumps Other intrinsic and extrinsic mechanisms involved in the recurrence of GBM Phenotypic plasticity and trans-differentiation Apoptosis escape Autophagy Cell metabolism Extracellular signaling pathways Exosome secretion Receptor tyrosine kinase Changes in the TME The perivascular niche The blood-brain barrier Conclusion Acknowledgment References Chapter-15---Role-of-long-noncod_2021_Glioblastoma-Resistance-to-Chemotherap Role of long noncoding RNAs in temozolomide-resistant glioblastoma Introduction GBM cancer Long noncoding RNA TP73-AS1 lncRNA PAXIP1-AS1 LncRNA SOX2OT MIR-155 HG LINC00021 SNHG12 SNHG15 EPIC1 MALAT1 NEAT1 Cancer susceptibility candidate 2 Lnc-TALC HOTAIR XIST LncRNA 003092.1 Key cellular components in therapy resistance Long noncoding RNA (lncRNA)-mediated gene silencing through polycomb mechanisms Noncoding RNA epigenetics lncRNA classification Functions of LncRNA in the nucleus Functions of LncRNAs in regulating gene expression in the cytoplasm Mechanisms of actions of lncRNA LncRNA classification based on region implicated by the lncRNA Conclusions Acknowledgments References Chapter-16---Mechanisms-of-glioblast_2021_Glioblastoma-Resistance-to-Chemoth Mechanisms of glioblastoma resistance to antiangiogenic agents and reversal approaches Conflict of interest Introduction Tumor neovascularization through angiogenesis, vasculogenesis, and vascular mimicry Angiogenesis and vasculogenesis Vascular mimicry Antiangiogenic therapies and development of resistance Receptor tyrosine kinase inhibitors and anti-VEGF antibodies Mechanisms of AAT resistance and possible intervention Endothelial cells, bone marrow-derived progenitor cells, and angiogenic myeloid and vasculogenic cells following AAT Transdifferentiation of GSCs and evolution of neovascular channels by VM The emergence of IL-CXCR2 pathway as a potential therapeutic target References Chapter-17---Treatment-and-resist_2021_Glioblastoma-Resistance-to-Chemothera Treatment and resistance of glioblastoma to CAR T-cell immunotherapies Introduction to CAR T-cell therapy CAR T-cell therapy in GBM: Recent clinical advances IL13Rα2 CAR T cells EGFRvIII CAR T cells HER2 CAR T cells Challenges and mechanisms of resistance to CAR T-cell therapy in GBM Paucity of tumor-specific targets and tumor heterogeneity Impaired trafficking to tumor T-cell intrinsic dysfunction Immune checkpoints and other immunosuppressive microenvironment factors Future directions to overcome resistance Optimizing antigen selection and addressing heterogeneity Increased trafficking to tumor Improving intrinsic T-cell fitness CAR T cells in combination with other therapies Conclusions References Chapter-18---On-chip-analysis_2021_Glioblastoma-Resistance-to-Chemotherapy-- On-chip analysis of glioblastoma cell chemoresistance Introduction Glioblastoma and chemotherapy monitoring Exosomes as biomarkers for chemotherapy monitoring Exosomal RNA analysis for monitoring chemoresistance in GBM Overview of iMER Microfluidic chip operation iMER exosome enrichment and RNA analysis Exosome mRNA profiles reflect parent cellular status Exosomal mRNA as a biomarker for treatment efficacy Exosomal mRNA reflects TMZ treatment efficacy in clinical samples Outlook References Chapter-19---Three-dimensional-in-vit_2021_Glioblastoma-Resistance-to-Chemot Three-dimensional in vitro models to study potentiation of glioblastoma resistance by hypoxia Introduction Hypoxia as a tumor microenvironment component in glioblastoma Hypoxia and cancer stem cell Hypoxia and cancer stem cell marker In vitro 3D model for glioblastoma Conclusion References Chapter-20---Chemoresistance-m_2021_Glioblastoma-Resistance-to-Chemotherapy- Chemoresistance mechanisms in mouse models of glioblastoma Introduction Factors involved in GBM chemoresistance O6-methylguanine-DNA methyltransferase (MGMT) Mismatch repair (MMR) pathway Factors related to the regulation of apoptosis Other factors Mouse models Transplantation models Genetically engineered mouse models (GEMMs) Conclusion Acknowledgment References Chapter-21---Therapeutic-approache_2021_Glioblastoma-Resistance-to-Chemother Therapeutic approaches to overcome temozolomide resistance in glioblastoma Introduction Targeting DNA repair mechanisms MGMT-targeted therapies Basic excision repair (BER)-targeted therapies Epigenetic targeting Targeting receptor tyrosine kinases and cellular pathways Epidermal growth factor receptor (EGFR) Vascular endothelial growth factor receptor (VEGFR) Fibroblast growth factor receptor (FGFR) Tumor suppressor p53 Tumor suppressor NFκB Tumor suppressor pRb Autophagy pathways Antiangiogenic therapies VEGF-inhibitors and VEGF-trap FGF-inhibitors and combinations Integrase and matrix metalloproteinases inhibitors Current and future therapies Targeting cancer stem cells Drug efflux transporters Cell survival signals Notch signaling Sonic Hedgehog signaling (SHH) WNT-PI3K-AKT signaling Intercellular communication among GBM cells Tumor treating fields Clinical trials Adverse effects and limitations Quality of life Alternative delivery methods Cell drug delivery methods Nanotherapeutics Other approaches Immune-checkpoint (IC) inhibitors Viral delivery Conclusion References Chapter-22---Understanding-signal-tran_2021_Glioblastoma-Resistance-to-Chemo Understanding signal transduction pathways to overcome targeted therapy resistance in glioblastoma Introduction Current status of chemotherapy in GBM treatment Molecular mechanisms of TMZ resistance in GBM cells TMZ-induced DNA replication stress and double-strand breaks TMZ-induced DMR after replication stress and DSBs in the DNA Ataxia-telangiectasia mutated (ATM) and ATM and RAD3-related-mediated (ATR) pathways Regulation of p53 and its related molecules and pathways in TMZ-induced DMR in GBMs TMZ-induced ATM and ATR-dependent regulation of p53 TMZ-induced MDM2-dependent regulation of p53 Regulation of TMZ-induced intrinsic and extrinsic cell death signaling downstream of p53 TMZ-induced regulation of p21 downstream of p53 TMZ-mediated regulation of MGMT expression downstream of p53 TMZ-induced endoplasmic reticulum (ER) stress responses (ERSR) in GBMs TMZ-mediated regulation of autophagy in GBMs Chemoresistance of GBM induced by plasma membrane-localizing receptor-mediated survival signaling RTK and their related signaling-mediated chemoresistance RTK Chemoresistance induced by oncogenic activation of the RTKs RTK-Ras-MAPK signaling The chemoresistance induced by the oncogenic activation of the RTK-Ras-MAPK signaling RTK-PI3K-Akt-mTORC1 (RTK-PKC-mTORC1) and RTK-PI3K-mTORC2 signaling pathways Chemoresistance induced by oncogenic activation of the RTK-Akt-mTORC1 (RTK-PKC-mTORC1) and RTK-PI3K-mTORC2 signaling RTK-JAK-STAT signaling Chemoresistance induced by oncogenic activation of the RTK-JAK-STAT signaling Integrin signaling-mediated chemoresistance of GBMs Integrin signaling Chemoresistance induced by oncogenic activation of integrin signaling TGFβ-transforming growth factor-beta receptor (TGFβR) signaling-mediated chemoresistance of GBMs TGFβ-TGFβR signaling pathway Chemoresistance induced by oncogenic activation of TGFβ-TGFβR signaling Wnt signaling-mediated chemoresistance of GBMs Wnt signaling pathway Chemoresistance induced by oncogenic activation of Wnt signaling Hedgehog signaling-mediated chemoresistance of GBMs Hedgehog signaling pathway Chemoresistance induced by the oncogenic activation of HH signaling Notch signaling-mediated chemoresistance of GBMs Notch signaling pathway Chemoresistance induced by oncogenic activation of Notch signaling Chemoresistance of GBM induced by Hippo/Yes associated-protein 1 (YAP)- mediated survival signaling Hippo/YAP1 signaling The chemoresistance induced by oncogenic activation of Hippo/YAP signaling Chemoresistance of GBMs induced by p16INK4a/p14ARF-mediated survival signaling p16INK4a/p14ARF signaling Chemoresistance induced by p16INK4a/p14ARF inactivation-mediated oncogenic activation of CDK/cyclin-RB1-E2F signaling Chemoresistance induced by cancer stem-like cells, TME, heterogeneity, and plasticity in GBMs Mechanisms regulating the chemoresistance of GBM CSCs CD133-mediated chemoresistance CD44-mediated chemoresistance Chemoresistance by ATP-binding cassette (ABC) subfamily-mediated extracellular transportation of drugs in GBMs Mechanisms of chemoresistance induced by the TME in GBMs Mechanism of chemoresistance induced by ECM components Mechanism of chemoresistance induced by hypoxia and acidosis Hypoxia-inducing factor signaling Chemoresistance induced by HIF signaling in GBMs Mechanisms of chemoresistance induced by GBM-associated cells GBM-associated astrocyte-mediated chemoresistance GBM-associated microglia-mediated chemoresistance miRNA-mediated chemoresistance Conclusions and perspectives References Chapter-23---Targeting-the-molecula_2021_Glioblastoma-Resistance-to-Chemothe Targeting the molecular mechanisms of glioma stem cell resistance to chemotherapy Introduction The adaptive microenvironment of glioma stem cells Stromal interactions Cellular interactions The immunosuppressive niche The neuronal niche The hypoxic and perivascular niche Mechanisms of glioma stem cell resistance to chemotherapy Advanced DNA repair system Limited bioavailability of chemotherapeutic agents Increased phenotypic plasticity Therapeutic strategies to overcome glioma stem cell resistance to chemotherapy Pro-differentiation therapies Targeting bone morphogenic protein signaling Role of microRNAs in differentiation Inhibiting oncogenic miRNAs Promoting tumor-suppressing miRNAs Signaling regulators of glioma stem cell differentiation Repositioning therapeutics for glioma stem cell differentiation Targeting glioma stem cell niches Targeting the immunogenic niche Targeting the neuronal niche Targeting the glioma stem cell metabolism and the hypoxic niche Targeting the angiogenic niche Targeting intracellular signaling and survival pathways Targeting the PI3K-Akt-mTOR pathway Targeting Notch signaling Targeting Shh signaling Targeting STAT3 signaling Regulating autophagy Conclusion References Chapter-24---Immunotherapy-for-gliob_2021_Glioblastoma-Resistance-to-Chemoth Immunotherapy for glioblastoma as a means to overcome resistance to standard therapy Introduction: Evolution of therapy for glioblastoma Conventional chemotherapies Targeted and antiangiogenic agents Immune surveillance and immunotherapy strategies in translation Lymphatic drainage in the CNS to secondary lymphoid organs Overcoming limited migration of DC therapies Immune checkpoint inhibitors in glioma Mechanisms of chemotherapy resistance and implications for immune activation Conclusion References Chapter-25---Role-of-microRNA-therap_2021_Glioblastoma-Resistance-to-Chemoth Role of microRNA therapy in presensitizing glioblastoma cells to temozolomide treatment Introduction Role of microRNAs in cells Regulatory role of miRNAs in cancer Regulatory role of microRNAs in GBM biology MiRNAs role in therapeutic sensitization of GBM to chemotherapy The role of miRNAs in therapeutic sensitization of GBM to TMZ Dysregulated miRNAs in GBM and response to TMZ Synthetic miRNA mimics and antisense miRNAs therapeutically modulate cellular genes and facilitate anticancer effects PLGA nanoparticles for biocompatible and clinically feasible delivery of therapeutic miRNAs for GBM therapy Antisense-microRNA-21 sensitizes GBM to TMZ Targeting miRNA-21 in combination with miRNA-10b improves GBM response to TMZ therapy Molecular treatment tailored to intracellular levels of endogenous miRNA targets for enhancing TMZ therapy MiRNAs targeting GSCs to achieve GBM therapy MicroRNAs targeting multiple cellular mechanisms as potential future therapies for GBM Conclusion and future perspectives References Chapter-26---Drug-penetration-through-the_2021_Glioblastoma-Resistance-to-Ch Drug penetration through the blood-brain barrier after radiotherapy: New approaches to bypass glioblastoma c Introduction The molecular mechanisms and genetics of chemoresistance in glioblastoma Alterations in the BBB permeability to increase the action of doxorubicin Consolidated and new treatments for glioblastoma Ionizing radiation interferes with BBB permeability by facilitating the passage of drugs Conclusion Acknowledgment References Chapter-27---Nanoparticles-beyo_2021_Glioblastoma-Resistance-to-Chemotherapy Nanoparticles beyond the blood-brain barrier for glioblastoma Introduction Barriers to delivery The BBB Exploiting endogenous transport routes across the BBB Efflux pumps Emerging delivery strategies to mitigate the BBB BBB disruption techniques Osmotic opening Disruption of BBB by FUS and microbubbles Nonthermal reversible electroporation Non BBB disruptive techniques Intranasal delivery Prodrug analogs Efflux pump inhibitors Nanoparticle-based delivery systems Liposomes Polymeric nanoparticles Metallic gold nanoparticles Magnetic particles Peptide-based particles Conclusion References Chapter-28---Small-molecules-targeting-m_2021_Glioblastoma-Resistance-to-Che Small molecules targeting misfolded mutants of p53 as a rescue strategy to improve glioblastoma chemotherapy Introduction History of the tumor suppressor p53 p53 regulation p53 structure The p53 pathway p53 mutants Distribution and frequency of p53 mutations and their clinical relevance p53 with single allele, both allele and null mutants Therapeutic strategies targeting p53 Therapeutic approaches to restore wild-type p53 function of mutant p53 protein via restoration of structural stability Considerations and principles of drugs that rescue mutant p53 structure Assay systems to identify new drugs stabilizing p53 protein structure Drugs that rescue the deleterious effect of p53 structural mutations (Tables 1 and 2) Prima-1/Prima-1MET PhiKan083, PK7088, and PK11007 SCH529074 NSC319726/ZMC1, NSC319725, and NSC328784 Stictic acid Small peptides Limitations of compounds targeting structural mutations of p53 Synergizing the effect of drugs targeting mutant p53 Conclusion References Chapter-29---p53-supplementation-_2021_Glioblastoma-Resistance-to-Chemothera p53 supplementation as a targeted cancer gene therapy for glioblastoma Role of p53 in cell cycle regulation TP53 mutation and its relevance to glioblastoma development Correlation of TP53 status to grades of gliomas TP53-based therapeutic strategies for glioblastoma Restoration of p53 function by small molecules p53-targeted cancer gene therapy Adenovirus-mediated delivery of wild-type p53 Nanoparticles as carriers for p53 gene therapy p53 with other suicide genes as combination therapy Clinical status of p53 cancer gene therapy Future perspectives and therapeutic potentials References Inde_2021_Glioblastoma-Resistance-to-Chemotherapy--Molecular-Mechanisms-and- Index Back_Cover Glioblastoma Resistance to Chemotherapy: Molecular Mechanisms and Innovative Reversal Strategies brings current knowledge from an international team of experts on the science and clinical management of glioblastoma chemoresistance. The book discusses topics such as molecular mechanisms of chemoresistance, experimental models to study chemoresistance, chemoresistance to drugs other than Temozolomide, and specific strategies to reverse chemoresistance. Additionally, it encompasses information on how to mitigate chemoresistance by targeted enhancement of p53 function. This book is a valuable resource for cancer researchers, oncologists, neuro-oncologists and other members of the biomedical field. Glioblastoma (GBM) is the most invasive and malignant primary brain tumor in humans with poor survival after diagnosis, therefore it is imperative that molecular and cellular mechanisms behind therapy resistant GBM cells, as well as the therapeutic strategies available to counter the resistance are comprehensively understood. Provides comprehensive, core knowledge related to the entire discipline of glioblastoma chemoresistance, from its many etiological mechanisms, to specific strategies to reverse resistance Presents current information from an international team of experts on the basic science, pre-clinical research, and clinical management of glioblastoma chemoresistance Discusses molecular and cellular mechanisms behind therapy resistant glioblastoma cells, as well as the therapeutic strategies available to counter this resistance