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Recent Advances in Glioma Cancer Treatment
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Gliomas are the brain’s most frequent and deadly tumors, accounting for roughly 30% of all brain malignancies. Glioblastoma (GBM) is characterized by changes in cell metabolism, including an increased Warburg effect, dysfunctional oxidative phosphorylation (OXPHOS), disrupted lipids metabolism, and other metabolic changes. Targeting epigenetic variables, immunotherapy, gene therapy, and different vaccine- and peptide-based treatments are some innovative approaches to improve anti-glioma treatment efficacy. Following the identification of lymphatics in the central nervous system, immunotherapy offers a potential method with the potency to permeate the blood-brain barrier.

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Update Date: 06 Sep 2022
Table of Contents

    1. Epigenetics in the Pathogenesis of Glioma

    1.1. DNA Methylation

    DNA methylation patterns in glioma cells are reported to differ from normal cells [1][2]. Most significantly, tumor cells are characterized to have widespread hypomethylation and CpG island hypermethylation. Therefore, the methylation status of glioma-related genes could be a useful diagnostic factor. Given the differences in methylation patterns and the prognostic G-CIMP index of gliomas in adults and children, adult-specific indicators of glioma must be identified. Most CpG islands are hypomethylated under normal physiological conditions [3]. However, a tumor suppressor and DNA repair genes often cause hypermethylation in tumor-related tissues [4]. These genes are associated with glioma development, due to the activity of DNA-5-hydroxymethylcytosine (5hmC). Recent evidence has revealed that 5hmC is negatively correlated with the tumor level. Moreover, p16INK4a [5], p14ARF MLH1 [6], and NDRG2 [6] are other tumor-repressor genes that are correlated with glioma. The p16INK4a gene keeps the retinoblastoma tumor-suppressor protein (pRb) in the active form (dephosphorylated) in the normal cyclinD-Rb pathway. The active form of this protein controls the cell cycle’s progress [5]. GBM tissue shows a high incidence (greater than 50%) of deletion for the p16INK4a homozygous gene. Moreover, p16INK4a is changed in 80% of glioma cell lines. Thus, restoring the p16INK4a gene could decrease growth arrest and eliminate proliferation.
    Steller et al. reported the hypermethylation of the MGMT promoter in approximately 40% of glioma tissues. The rate of methylation levels is dependent upon the zone in which the cells thereof have been cancerous [7]. Furthermore, the level of MGMT methylation is the critical index to determine TMZ susceptibility in glioma treatment. Low-adjusted MGMT can dramatically restore the in vitro and in vivo chemical sensitivity of TMZ [8]. A recurrent point mutation in isocitrate dehydrogenase 1 (IDH1) is frequently seen in adult diffuse gliomas. Mutant IDH1 gliomas are classified as mutant IDH1-1p/19q-codel or mutant IDH1-noncodel, based on the deletion of 1p/19q chromosomal regions [9][10][11]. IDH1 is the main source of NADPH in the human brain. It also can be found in other tissues of the body [12]. Most low-grade scattered astrocytomas (with a 75 percent mutation rate), anaplastic astrocytomas (with a 66 percent mutation rate), oligodendroglioma, promyelocyte, and secondary sex polymorphism include mutations in their IDH1/2 methylation regulatory protein [13]. The platelet-derived growth factor receptor alpha (PDGFRA) is a protein-coding gene that can reduce the growth of IDH mutant astrocytoma cells via the employment of demethylation medicines. This leads to the restoration of the normal function of such proteins [14][15]. Moreover, these medicines have a noticeable linkage to changes in NF1 and PDGFRA\IDH1, thus providing a practical treatment method [16].
    The MAPK pathway or its downstream effectors contribute to carcinogenesis and proliferation in many types of malignancies. They can be activated in juvenile gliomas as a result of NF1 and BRAF gene alterations [17]. In addition, BMP signaling is activated in HGG tumor cells in children [18]. Activin A receptor type I (ACVR1) encodes for the type I BMP receptor ALK2. Its *somatic mutations, which are found in about 25% of pediatric brainstem gliomas, trigger BMP pathway activation [19]. Changes in the signaling pathways caused by specific genetic abnormalities in gliomas are promising targets for developing novel targeted gene therapies [20].

    1.2. miRNAs and Glioma

    Some studies have recently revealed that miRNAs play a major role in the transcriptional control, growth, and proliferation of numerous tumor genes [21][22]. Therefore, miRNA-based personalized medicine and gene-editing techniques seem to be viable strategies in cancer therapy. Approximately half of the miRNA genes are thought to be found in glioma cancer genes or in their vulnerable locations. These miRNA genes can affect 3% of all glioma tumor genes and 30% of all coding genes [23]. A single miRNA can simultaneously alter 100 GBM-related mRNAs, and a single glioma mRNA can be controlled by one or more miRNAs [24].
    In the course of glioma disorders, miRNAs perform a number of important roles in carcinogenesis, the expression of cancer-related genes, glioma stem cell development, and regulatory pathways [25][26]. MiR-221/222 was discovered to be positively linked with the level of glioma cell invasion and infiltration. Zhang C. et al. have shown that the knockdown of MiR-221/222 could reduce cell invasion by manipulating the levels of the TIMP3 target. In a xenograft model, the knockdown of MiR-221/222 has enhanced TIMP3 expression and significantly decreased tumor growth [27]. Moreover, the overexpression of miR221/222 lowers the p27kipl levels and vice versa, which inhibits tumor proliferation [28].

    1.3. Chromatin Remodeling and Glioma

    Mutations in the critical proteins of the regeneration complex are frequently found in human diseases [29]. These mutations are caused by aberrant chromatin remodeling [30][31][32]. Deficient chromatin remodeling can result in failed chromatin regeneration, in which the nucleosomes are unable to orient themselves properly, and the primary transcription machinery is prevented from acting [33][34][35]. These changes lead to aberrant gene expression [35]. Cancer develops when these mutations cause anomalies in tumor suppressor genes or cell-cycle regulatory proteins [36][37]. Drug-resistant tumor cells can be eliminated by targeting epigenetic and evolutionary processes [38][39]. This elimination could lead to avoiding disease recurrence [40][41]. Liu et al. have reported that targeting the GBM drug resistance stem cells (GSC) by kinase inhibitors can revert them to a slow-cycling, long-lasting state [40][41]. The notch signaling pathway is active in this state, and the histone demethylase KDM6A/B is considerably up-regulated [28][42]. This condition results in the removal of H3K27 trimethylation in the cis-regulatory region of the genome and higher levels of H3K27Ac [28][39]. This cellular transition was reported to be aided by chromatin remodeling [28]. The results of this study have identified a new target to develop effective anti-GBM treatments [43]. Moreover, according to a recent study [44], the expression of the controlled transcription factors E2F1 and GSK3 in astrocytomas and GBM was linked to glioma progression and LSH expression [42][44].
    Glioma tissue also expresses the lipoprotein receptor protein (LRP6) 6, which is an upstream regulator of the GSK3 signaling cascade. LRP6 depletion decreases LSH expression by lowering the E2F1 engagement in the LSH promoter. These changes result in the suppression of cell growth. In light of these observations, the existing mechanical relationship between the activation of the LPR6/GSK3/E2F1 axis and LSH expression in glioblastoma could be interpreted as a key role in GBM. Understanding the role of LSH in the formation of gliomas adds to people's understanding of the disease and makes LSH a possible therapeutic candidate to treat these lethal brain malignancies [45][46][47].

    1.4. Histone Modification and Gliomas

    Glioma formation and progression can be accelerated by improper histone modifications [48]. These aberrant modifications could lead to transcriptional irregularities and changes in the expression of enzymes, including histone methyltransferases, histone deacetylases (HDACs), and acetyltransferases (HATs) [49][50]. Histone methyltransferases are the histone-modifying proteins that have garnered the most attention [51]. Histone methylation at the lysine and arginine residues of the N-terminal region occurs on the H3 and H4 histones and is regulated by histone methyltransferases [52][53][54]. The main role of histone methylation is that of transcriptional regulation [55][56]. It could either repress the transcription through H3K9, H3K27, and H4K20 histone methylation or activate it via H3K4 histone methylation [57]. KMTs can be categorized into two protein families, based on their catalytic domain [58][59]. The two classes of KMTs comprise the SET domain-containing family (SUV39, SET1, SET2, SMYD, SUV4-20, SET7/9, and SET8) and the DOT1 family [58][60][61].
    HATs participate in various biological processes, including cell-cycle progression, DNA damage repair, cellular senescence, and hormone signaling. HATs are among the bi-substrate enzymes that use the Ac-CoA cofactor and the histone lysine residue as substrates.
    HDAC, HDAC1, HDAC2, HDAC3, HDAC5, and HDAC9 are among the HDACs that showed substantial alterations in glioma cells [62]. The histone acetylation of lysine residues in H2A, H2B, H3, and H4 typically drives gene transcription, while histone methylation can either activate (H3K4, H3K36, and H3K79) or repress (H3K9, H3K27, and H4K20) gene transcription [63]. HDAC5 and HDAC9 expression rise in high-grade medulloblastoma, compared to low-grade medulloblastoma and abnormal tissues [64].

    2. Glioma Treatment Strategies

    2.1. Glioma Epigenetic Therapy

    2.1.1. DNA Methylation Inhibitors (DNMTi)

    The compressor tumor genes become silent by DNMT-mediated DNA methylation. Therefore, DNMT inhibition can restore the transcription of these important genes [65]. Thus, finding DNMT inhibitors could be deemed as a novel approach in glioma therapy. Aza-20-deoxycytidine 5 phosphate is the most common DNMT inhibitor, which is now in clinical trials. In tumor cells, aza-20 deoxycytidine-5 phosphate interacts with DNA and suppresses DNMT activity, which results in a favorable methylation state for anticancer activities [66].

    2.1.2. Histone Deacetylase Inhibitors (HDACi)

    HDACis have been shown to suppress transcription and end cell division in G1 and G2 phases, promote cell differentiation and apoptosis, reverse the heat shock protein-substrate protein interaction, enhance oncoprotein degradation, and limit tumor growth and angiogenesis [67]. Individually or in combination, DNMT inhibitors and HDACis can be used to treat various tumors [68]. HDACi, as a novel therapeutic agent for glioblastoma, opens up new avenues for glioma treatment. Many HDACis have now entered stage I/II clinical studies to treat various kinds of glioma, including diffuse intrinsic pontine glioma (DIPG) and progressive or recurrent GB. HDACis can be used alone or in conjunction with other chemotherapeutic drugs, such as TMZ and radiation therapy [69].
    Vorinostat and TMZ were tested in primary recurrent or refractory CNS malignancies, in a study conducted by the Department of Pediatric Oncology (COG) [70]. In children with recurrent CNS malignancies, five-day cycles of vorinostat in conjunction with TMZ were well tolerated. Vorinostat treatment resulted in the aggregation of acetylated H3 in peripheral blood mononuclear cells (PBMC). In a phase II study of verinavastat monotherapy, conducted by North Central Cancer Treatment, good tolerance in recurrent GBM patients was recorded. Moreover, an obvious increase in H2B and H4 acetylation levels was observed after treatment [71].
    A phase II research study of Panobinostat, in conjunction with bevacizumab (BEV), in anaplastic glioma and recurrent GBM patients, was conducted [72]. Treatment was acceptable in both groups prior to closure. However, adding panobinostat to BEV did not increase the 6-month progression-free survival (PFS6) rate in either group when compared to BEV monotherapy controls. According to the additional preclinical studies, Panobinostat may serve as a sensitive agent. A phase-I study of stereotactic re-irradiation in combination with panobinostat has been reported in patients with recurrent HGG [73].
    The COG has completed another phase of Valproic acid (VPA) research in children with refractory or CNS malignancies. At a steady state, half of the patients showed hyperacetylation of their histones. Krause et al. recently published a phase-II trial on simultaneous TMZ and VPA radiation therapy for GBM patients. Their findings revealed that the simultaneous administration of VPA and RT/TMZ is well tolerated in individuals with newly diagnosed GBM [74]. In general, HDACis appear to be promising therapies to improve the prognosis of malignant gliomas, when used as a monotherapy or combination therapy [75]. Improving or inventing novel epigenetic medicines or learning how to coordinate them with other treatments are viable options to reduce the damaging effect of epigenetic drug poisoning during treatment. HDAC, Vorinostat, and Valproic acid inhibitors have all had good clinical outcomes when paired with TMZ or RT in treating children with resistant or recurrent adult CNS or GBM cancers [74]. This could be a promising direction for future clinical investigations. Nonetheless, Vorinostat, in combination with erlotinib, or panobinostat in combination with BEV had no discernible effects [72]. Although these findings are not encouraging, they provide useful information for further studies.
    Contemporary immunotherapy has become a popular strategy in cancer treatment. Even though few clinical trials on the combination of HDACis and the cytotoxic-mediated immunotherapy gene have been reported, most G-MCIs are recommended to be paired with TMZ. Most G-MCIs are recommended to be paired with TMZ. This strategy dramatically improved survival rates in individuals with minimal residual disease [76]. Tumor cells employ epigenetic processes to change autoimmune genesis and impair the process of tumor cell detection by the immune system. Tumor cells can kill themselves by lowering the expression levels of critical molecules in the tumor immune response process. They exploit DNA methylation or histone modification to exert these functions [77]. Immunosuppressive medications, such as cytokines and polypeptide vaccines, are currently the most common immunosuppressive drugs that can be applied in combination with epigenetic therapies [78][79]. This approach has become an increasingly popular strategy for the treatment of malignancies such as gliomas (Table 1).
    Table 1. Treatment strategies for glioblastoma therapy.
    Standard Management
    Category Therapy Mechanisms of Action References
    Current treatments Surgical resection Removing the possible amount of tumor in almost all types of gliomas. [80]
    Radiation Using high-energy beams after surgery, mainly in high-grade gliomas. [81]
    Chemotherapy with Temozolomide (TMZ) Binding to the genome, preventing the tumor cell growth and division. [82]
    Tumor-treating fields (TTF) with bevacizumab Selectively using an electromagnetic field with bevacizumab targeting vascular endothelial growth factor (VEGF). [83]
    Future Directions
      Therapy (Study Numbers) Mechanisms of Action References
    Checkpoint inhibitors Immune checkpoint inhibitors
    Programmed cell death protein 1 (PD-1/CD279)
    • Nivolumab (NCT02335918)
    • Bevacizumab (NCT03743662)
    • Pembrolizumab (NCT03899857)
    Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4/ CD152)
    • Ipilimumab (NCT02311920)
    • Durvalumab (NCT02794883)
    Tremelimumab Indoleamine 2,3-dioxygenase (IDO)
    • Decreasing the level, and cumulation of regulatory T (Treg) cells
    • Increasing the survivorship
    • Promoting the immune-mediated tumor destruction
    [84][85][86][87][88][89][90]
    Immunostimulatory gene therapy Oncolytic viral (OV) therapy
    • G207 (NCT00028158 and NCT03911388)
    • M032 (NCT02062827)
    • sh-SirT1 lentivirus (genetically engineered Lentivirus)
    • miR-100 lentivirus (genetically engineered Lentivirus)
    • DNX-2401 (modified adenovirus) (NCT02798406, NCT02197169)
    • PVSRIPO
    • ONYX-015 (Genetically modified adenoviral vector)
    • H-1PV (wild-type parvovirus)
    • Toca 511(a retroviral OV based on the murine leukemia virus) (NCT02414165)
    • Inducing the secretion of IL-12 by tumor cells, increasing the antitumor efficiency of the therapy
    • Targeting highly expressed receptors in solid tumors (e.g., CD155 by PVSRIPO).
    • Replication in p53-deficient tumor cells (e.g., ONYX-015)
    • Improving radiotherapeutic sensitivity by silencing SirT1 (e.g., sh-SirT1 lentivirus)
    • Increasing sensitivity to chemotherapy (e.g., miR-100 lentivirus)
    • Converting the prodrug,5-fluorocytosine, into the antimetabolite by cytosine deaminase leads to tumor cell death 9, e.g., toca 511)
    • Damaging genome and attesting the cell cycle (e.g., H-1PV)
    • Reducing the number of tumor-associated macrophages
    • Increasing the survivorship
    [91][92][93]
    Suicide gene therapy
    • Ad-TK (genetically engineered Adenoviral vectors encoding HSV thymidine kinase)
    • Ad-Flt3L
    • Introducing thymidine kinase into the tumor
    • Converting ganciclovir into an active form
    • Inducing apoptosis in dividing tumor cells and releasing tumor antigens
    [94][95]
    Cytokine therapy
    • (HSVTK) genes and IL-2/ 4-encoding genes
    • of IL-4/13 and Pseudomonas exotoxin (IL-4-PE)
    • IFN-β with TMZ
    • Prolonging the survival of patients
    [96][97][98]
    Adjuvant therapy Tumor-associated macrophages (TAMs) therapy
    • Anti-CCL-2 antibody
    • BLZ945
    • PLX3397(NCT01790503)
    • Minocycline(NCT02272270, NCT01580969)
    • Cyclosporine (NCT00003625)
    • Formation and retention of tumor cell migration
    • Promoting angiogenesis
    • Increasing the survivorship
    • Inhibition of colony-stimulating factor
    • Reducing the amount of the M2 macrophage
    • Debilitating the expression of microglial secreting matrix metalloproteinases
    [99][100][101][102][103]
    Passive immunotherapy Chimeric antigen receptors (CARs) therapy
    • EGFRvIII(NCT03283631, NCT03389230)
    • IL-13Rα2 (NCT02208362)
    • HER2 (NCT01109095)
    • CD70
    • Cd147 (NCT04045847)
    • GD2 (NCT03252171)
    • EphA2(NCT02575261)
    • B7-H3(NCT04077866)
    • Inhibition of tumor growth via IFN-γ and IL-2 Secretion
    • Receding CD70+ glioblastoma in xenograft models
    [104][105][106][107][108][109]
    Antibodies
    • Daclizumab (selective antibody for the high-affinity IL-2Rα)
    • Decreasing the amount of Tregs without affecting the T cells
    [110]
    Active immunotherapy EGFRvIII-mediated vaccine
    • Rindopepimut(CDX-110) (NCT00458601)
    • MAb806 (ABT-806) (NCT01472003)
    • Targeting EGFRvIII tumor and increasing the immune response
    [111]
    Tumor cell vaccines
    • Temozolomide
    • HSPPC-96 (NCT01814813)
    • Increasing efficacy using autologous tumor lysates
    • Activating DCs (e.g., heat shock protein chaperon gp96)
    [112][113]
    Dendritic cell vaccines (DCVs)
    • ICT-107
    • DCVax-L
    • Fusions of DC and glioma cells
    • DCVax-L + GBM Pvax
    • Pp65-DCs + GM-CSF1
    • Inducing strong anti-tumor immunity by activation of NKT, CD4, and CD8 cells
    [114][115][116]
    Epigenome therapy Inhibitors of mutant IDH (mtIDHi)
    • IDH305 (NCT02381886)
    • AG-221 (NCT02273739)
    • AG-120 (Ivosidenib) (NCT02073994)
    • DS-1001b (NCT03030066)
    • etc.
    EZH2 inhibitors (EZH2i)
    • Tazemetostat (NCT03155620)
    DNA methylation inhibitors (DNMTi)
    • 5-Azacytidine (Vidaza) (NCT02223052)
    • 5-Azacytidine (Vidaza) (NCT03206021)
    Histone deacetylase inhibitors (HDACi)
    • Valproic acid (NCT03243461)
    • Vorinostat (SAHA) (NCT01189266)
    • Belinostat (NCT02137759)
    • Panobinostat(LBH589) (NCT02717455)
    • Et
    • Normalizing the function of α-ketoglutarate-dependent enzymes
    • Inhibiting polycomb repressor complex 2 (PRC2)
    • Inducing innate immune response by reactivating retroviruses
    • Modulating histone acetylation marks
    [117][118]
    Combinational therapy Combinations of multiple checkpoint inhibitors
    • Anti-CTLA4 (ipilimumab, tremelimumab) and anti-PDL1 (nivolumab, durvalumab, pembrolizumab) monoclonal antibodies
    • Nivolumab in combination with the anti-LAG3
    • Increasing the survivorship
    [119][120]
    Checkpoint inhibitors combined with other immunotherapies
    • Vaccination with GM-CSF-expressing glioma cells and treatment with anti-CTLA4 antibodies
    • Nivolumab with and without DC vaccine therapy
    • PD-1 antibody blockade in combination with CD28-targeted CAR T cell
    • Combination of a PD-1 inhibitor and VEGF inhibitor
    • Resulting in a higher antigen-specific immune response
    [121][122][123][124]
    Targeting immunosuppression in the tumor microenvironment
    • Combination therapy with the CD40 mAb and celecoxib
    • Combination of a CD200R antagonist with tumor lysate vaccination
    • Activating myeloid cells toward a tumor-killing feature
    • Inhibiting immunosuppressive functions
    [125][126]
    Combinations of multiple immunostimulatory gene therapies
    • Herpes simplex virus 1-thymidine kinase (HSV1-TK), and immune stimulation with Flt3L
    • A cytokine that recruits DCs into the tumor microenvironment
    • Killing the remained proliferating tumor cells
    • Releasing proinflammatory cytokines
    • Stimulating DCs movement toward the tumor cells
    [127]
    Immunostimulatory gene therapy combined with other immunotherapies
    • Ad-TK/Flt3L in combination with subcutaneous vaccination with DCs,
    • MDSC depletion with the anti-Gr-1 antibody following TK/Flt3L gene therapy
    • PDL1 blockade combined with TK/Flt3L gene therapy
    • CTLA-4 blockade combined with TK/Flt3L gene therapy
    • Increasing the survivorship
    [128][129]
    Vaccination combined with immune stimulatory adjuvants
    • Peptide vaccine containing 11 GBM-associated peptides, with GM-CSF
    • Peptide vaccine containing 11 GBM-associated peptides, with poly-ICLC
    • An agonist of TLR3
    • An IDH1 mutant peptide vaccine in combination with imiquimod (the TLR7 ligand)
    • mTOR inhibition with rapamycin to enhance DC vaccine
    • Stimulating DCs maturation
    [130][131]
    Vaccination combined with other immunotherapies
    • Vaccination with CEApeptide pulsed DCs
    • Anti-angiogenic therapy with immune-based therapies
    • Normalizing the tumor vasculature
    • Increasing better infiltration of immune cells into the tumor cells
    [132]
    Miscellaneous Nanoparticle formulations
    • PLGA microparticles encapsulated with nicotinamide phosphoribosyltransferase inhibitor (GMX-1778)
    • lipopolymeric NP
    • NU-0129 (NCT03020017)
    • Selectively antagonizing NAD+ biosynthesis
    • Targeting transcription factors, such as SOX2, OLIG2, SALL2, etc.
    • Targeting Bcl-2-like protein by siRNA gold nanoparticles
    [133][134]
    BBB disruptive therapies
    • SonicCould (NCT02253212)
    • Using pulsed ultrasound to open the blood-brain barrier
    [135]
    Exosomes
    • miR-21sponge construct
    • miR-199a
    • miR-34a
    • Long-noncoding RNA PTENP1
    • miR-146b
    • Inhibiting EGFR expression
    • Compelling cell apoptosis
    • Inhibiting cell proliferation and invasion
    [136][137]

    References

    1. Zheng, H.; Momeni, A.; Cedoz, P.-L.; Vogel, H.; Gevaert, O. Whole slide images reflect DNA methylation patterns of human tumors. NPJ Genom. Med. 2020, 5, 11.
    2. Chen, X.; Zhao, C.; Zhao, Z.; Wang, H.; Fang, Z. Specific glioma prognostic subtype distinctions based on DNA methylation patterns. Front. Genet. 2019, 10, 786.
    3. Malta, T.M.; de Souza, C.F.; Sabedot, T.S.; Silva, T.C.; Mosella, M.S.; Kalkanis, S.N.; Snyder, J.; Castro, A.V.B.; Noushmehr, H. Glioma CpG island methylator phenotype (G-CIMP): Biological and clinical implications. Neuro-Oncology 2018, 20, 608–620.
    4. Lövkvist, C.; Dodd, I.B.; Sneppen, K.; Haerter, J.O. DNA methylation in human epigenomes depends on local topology of CpG sites. Nucleic Acids Res. 2016, 44, 5123–5132.
    5. Lee, S.; Kim, M.; Kwon, H.; Park, I.; Park, M.; Lee, C.; Kim, Y.; Kim, C.; Hong, S. Growth inhibitory effect on glioma cells of adenovirus-mediated p16/INK4a gene transfer in vitro and in vivo. Int. J. Mol. Med. 2000, 6, 559–622.
    6. Gömöri, É.; Pál, J.; Mészáros, I.; Dóczi, T.; Matolcsy, A. Epigenetic inactivation of the hMLH1 gene in progression of gliomas. Diagn. Mol. Pathol. 2007, 16, 104–107.
    7. Mur, P.; Rodríguez de Lope, Á.; Díaz-Crespo, F.J.; Hernández-Iglesias, T.; Ribalta, T.; Fiaño, C.; García, J.F.; Rey, J.A.; Mollejo, M.; Meléndez, B. Impact on prognosis of the regional distribution of MGMT methylation with respect to the CpG island methylator phenotype and age in glioma patients. J. Neuro-Oncol. 2015, 122, 441–450.
    8. Yu, Z.; Chen, Y.; Wang, S.; Li, P.; Zhou, G.; Yuan, Y. Inhibition of NF-κB results in anti-glioma activity and reduces temozolomide-induced chemoresistance by down-regulating MGMT gene expression. Cancer Lett. 2018, 428, 77–89.
    9. Parsons, D.W.; Jones, S.; Zhang, X.; Lin, J.C.-H.; Leary, R.J.; Angenendt, P.; Mankoo, P.; Carter, H.; Siu, I.-M.; Gallia, G.L. An integrated genomic analysis of human glioblastoma multiforme. Science 2008, 321, 1807–1812.
    10. Rajaratnam, V.; Islam, M.M.; Yang, M.; Slaby, R.; Ramirez, H.M.; Mirza, S.P. Glioblastoma: Pathogenesis and current status of chemotherapy and other novel treatments. Cancers 2020, 12, 937.
    11. Venteicher, A.S.; Tirosh, I.; Hebert, C.; Yizhak, K.; Neftel, C.; Filbin, M.G.; Hovestadt, V.; Escalante, L.E.; Shaw, M.L.; Rodman, C. Decoupling genetics, lineages, and microenvironment in IDH-mutant gliomas by single-cell RNA-seq. Science 2017, 355, eaai8478.
    12. Bleeker, F.E.; Atai, N.A.; Lamba, S.; Jonker, A.; Rijkeboer, D.; Bosch, K.S.; Tigchelaar, W.; Troost, D.; Vandertop, W.P.; Bardelli, A. The prognostic IDH1 R132 mutation is associated with reduced NADP+-dependent IDH activity in glioblastoma. Acta Neuropathol. 2010, 119, 487–494.
    13. Noushmehr, H.; Weisenberger, D.J.; Diefes, K.; Phillips, H.S.; Pujara, K.; Berman, B.P.; Pan, F.; Pelloski, C.E.; Sulman, E.P.; Bhat, K.P. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 2010, 17, 510–522.
    14. Flavahan, W.A.; Drier, Y.; Liau, B.B.; Gillespie, S.M.; Venteicher, A.S.; Stemmer-Rachamimov, A.O.; Suvà, M.L.; Bernstein, B.E. Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature 2016, 529, 110–114.
    15. Chen, R.; Cohen, A.L.; Colman, H. Targeted therapeutics in patients with high-grade gliomas: Past, present, and future. Curr. Treat. Options Oncol. 2016, 17, 42.
    16. Verhaak, R. Cancer Genome Atlas Research Network: Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 2010, 17, 98–110.
    17. Vickers, N.J. Animal communication: When i’m calling you, will you answer too? Curr. Biol. 2017, 27, R713–R715.
    18. Mendez, F.; Kadiyala, P.; Nunez, F.J.; Carney, S.; Nunez, F.M.; Gauss, J.C.; Ravindran, R.; Pawar, S.; Edwards, M.; Garcia-Fabiani, M.B. Therapeutic Efficacy of Immune Stimulatory Thymidine Kinase and fms-like Tyrosine Kinase 3 Ligand (TK/Flt3L) Gene Therapy in a Mouse Model of High-Grade Brainstem GliomaImmune Stimulatory Gene Therapy in Brainstem Glioma. Clin. Cancer Res. 2020, 26, 4080–4092.
    19. Fontebasso, A.M.; Papillon-Cavanagh, S.; Schwartzentruber, J.; Nikbakht, H.; Gerges, N.; Fiset, P.-O.; Bechet, D.; Faury, D.; De Jay, N.; Ramkissoon, L.A. Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma. Nat. Genet. 2014, 46, 462–466.
    20. Kwiatkowska, A.; Nandhu, M.S.; Behera, P.; Chiocca, E.A.; Viapiano, M.S. Strategies in gene therapy for glioblastoma. Cancers 2013, 5, 1271–1305.
    21. de Menezes, M.R.; Acioli, M.E.A.; da Trindade, A.C.L.; da Silva, S.P.; de Lima, R.E.; da Silva Teixeira, V.G.; Vasconcelos, L.R.S. Potential role of microRNAs as biomarkers in human glioblastoma: A mini systematic review from 2015 to 2020. Mol. Biol. Rep. 2021, 48, 4647–4658.
    22. Katsila, T.; Kardamakis, D. The Role of microRNAs in Gliomas–Therapeutic Implications. Curr. Mol. Pharmacol. 2021, 14, 1004–1012.
    23. Berindan-Neagoe, I.; Monroig, P.d.C.; Pasculli, B.; Calin, G.A. MicroRNAome genome: A treasure for cancer diagnosis and therapy. CA Cancer J. Clin. 2014, 64, 311–336.
    24. Lakomy, R.; Sana, J.; Hankeova, S.; Fadrus, P.; Kren, L.; Lzicarova, E.; Svoboda, M.; Dolezelova, H.; Smrcka, M.; Vyzula, R. MiR-195, miR-196b, miR-181c, miR-21 expression levels and O-6-methylguanine-DNA methyltransferase methylation status are associated with clinical outcome in glioblastoma patients. Cancer Sci. 2011, 102, 2186–2190.
    25. Wang, S.; Yin, Y.; Liu, S. Roles of microRNAs during glioma tumorigenesis and progression. Histol. Histopathol. 2019, 34, 213–222.
    26. Ghaemmaghami, A.B.; Mahjoubin-Tehran, M.; Movahedpour, A.; Morshedi, K.; Sheida, A.; Taghavi, S.P.; Mirzaei, H.; Hamblin, M.R. Role of exosomes in malignant glioma: microRNAs and proteins in pathogenesis and diagnosis. Cell Commun. Signal. 2020, 18, 120.
    27. Zhang, C.; Zhang, J.; Hao, J.; Shi, Z.; Wang, Y.; Han, L.; Yu, S.; You, Y.; Jiang, T.; Wang, J. High level of miR-221/222 confers increased cell invasion and poor prognosis in glioma. J. Transl. Med. 2012, 10, 119.
    28. Zang, L.; Kondengaden, S.M.; Che, F.; Wang, L.; Heng, X. Potential epigenetic-based therapeutic targets for glioma. Front. Mol. Neurosci. 2018, 11, 408.
    29. Kondo, Y.; Katsushima, K.; Ohka, F.; Natsume, A.; Shinjo, K. Epigenetic dysregulation in glioma. Cancer Sci. 2014, 105, 363–369.
    30. Sesé, B.; Ensenyat-Mendez, M.; Iñiguez, S.; Llinàs-Arias, P.; Marzese, D.M. Chromatin insulation dynamics in glioblastoma: Challenges and future perspectives of precision oncology. Clin. Epigenet. 2021, 13, 150.
    31. Filippova, G.N.; Qi, C.-F.; Ulmer, J.E.; Moore, J.M.; Ward, M.D.; Hu, Y.J.; Loukinov, D.I.; Pugacheva, E.M.; Klenova, E.M.; Grundy, P.E. Tumor-associated zinc finger mutations in the CTCF transcription factor selectively alter its DNA-binding specificity. Cancer Res. 2002, 62, 48–52.
    32. Katainen, R.; Dave, K.; Pitkänen, E.; Palin, K.; Kivioja, T.; Välimäki, N.; Gylfe, A.E.; Ristolainen, H.; Hänninen, U.A.; Cajuso, T. CTCF/cohesin-binding sites are frequently mutated in cancer. Nat. Genet. 2015, 47, 818–821.
    33. Basta, J.; Rauchman, M. The nucleosome remodeling and deacetylase complex in development and disease. Transl. Epigenet. Clin. 2017, 37–72.
    34. Marfella, C.G.; Henninger, N.; LeBlanc, S.E.; Krishnan, N.; Garlick, D.S.; Holzman, L.B.; Imbalzano, A.N. A mutation in the mouse Chd2 chromatin remodeling enzyme results in a complex renal phenotype. Kidney Blood Press. Res. 2008, 31, 421–432.
    35. Choi, Y.J.; Yoo, N.J.; Lee, S.H. Mutation of HELLS, a chromatin remodeling gene, gastric and colorectal cancers. Pathol. Oncol. Res. 2015, 21, 851–852.
    36. Fueyo, J.; Gomez-Manzano, C.; Yung, W.A.; Kyritsis, A.P. The functional role of tumor suppressor genes in gliomas: Clues for future therapeutic strategies. Neurology 1998, 51, 1250–1255.
    37. Dahia, P. PTEN, a unique tumor suppressor gene. Endocr.-Relat. Cancer 2000, 7, 115–129.
    38. Housman, G.; Byler, S.; Heerboth, S.; Lapinska, K.; Longacre, M.; Snyder, N.; Sarkar, S. Drug resistance in cancer: An overview. Cancers 2014, 6, 1769–1792.
    39. Guo, L.; Lee, Y.-T.; Zhou, Y.; Huang, Y. Targeting epigenetic regulatory machinery to overcome cancer therapy resistance. Semin. Cancer Biol. 2022, 83, 487–502.
    40. Saini, A.; Gallo, J.M. Epigenetic instability may alter cell state transitions and anticancer drug resistance. PLoS Comput. Biol. 2021, 17, e1009307.
    41. De Angelis, M.L.; Francescangeli, F.; La Torre, F.; Zeuner, A. Stem cell plasticity and dormancy in the development of cancer therapy resistance. Front. Oncol. 2019, 9, 626.
    42. Uddin, M.S.; Al Mamun, A.; Alghamdi, B.S.; Tewari, D.; Jeandet, P.; Sarwar, M.S.; Ashraf, G.M. Epigenetics of glioblastoma multiforme: From molecular mechanisms to therapeutic approaches. Semin. Cancer Biol. 2022, 83, 100–120.
    43. Krug, B.; De Jay, N.; Harutyunyan, A.S.; Deshmukh, S.; Marchione, D.M.; Guilhamon, P.; Bertrand, K.C.; Mikael, L.G.; McConechy, M.K.; Chen, C.C. Pervasive H3K27 acetylation leads to ERV expression and a therapeutic vulnerability in H3K27M gliomas. Cancer Cell 2019, 35, 782–797.e788.
    44. Xiao, D.; Huang, J.; Pan, Y.; Li, H.; Fu, C.; Mao, C.; Cheng, Y.; Shi, Y.; Chen, L.; Jiang, Y. Chromatin remodeling factor LSH is upregulated by the LRP6-GSK3β-E2F1 axis linking reversely with survival in gliomas. Theranostics 2017, 7, 132.
    45. Zemach, A.; Kim, M.Y.; Hsieh, P.-H.; Coleman-Derr, D.; Eshed-Williams, L.; Thao, K.; Harmer, S.L.; Zilberman, D. The Arabidopsis nucleosome remodeler DDM1 allows DNA methyltransferases to access H1-containing heterochromatin. Cell 2013, 153, 193–205.
    46. Myant, K.; Termanis, A.; Sundaram, A.Y.; Boe, T.; Li, C.; Merusi, C.; Burrage, J.; Jose, I.; Stancheva, I. LSH and G9a/GLP complex are required for developmentally programmed DNA methylation. Genome Res. 2011, 21, 83–94.
    47. Von Eyss, B.; Maaskola, J.; Memczak, S.; Möllmann, K.; Schuetz, A.; Loddenkemper, C.; Tanh, M.D.; Otto, A.; Muegge, K.; Heinemann, U. The SNF2-like helicase HELLS mediates E2F3-dependent transcription and cellular transformation. EMBO J. 2012, 31, 972–985.
    48. Ruijter, A.J.d.; GENNIP, A.H.v.; Caron, H.N.; Kemp, S.; KUILENBURG, A.B.v. Histone deacetylases (HDACs): Characterization of the classical HDAC family. Biochem. J. 2003, 370, 737–749.
    49. Liu, F.; Barsyte-Lovejoy, D.; Allali-Hassani, A.; He, Y.; Herold, J.M.; Chen, X.; Yates, C.M.; Frye, S.V.; Brown, P.J.; Huang, J. Optimization of cellular activity of G9a inhibitors 7-aminoalkoxy-quinazolines. J. Med. Chem. 2011, 54, 6139–6150.
    50. Kim, Y.Z. Altered histone modifications in gliomas. Brain Tumor Res. Treat. 2014, 2, 7–21.
    51. Ciechomska, I.A.; Jayaprakash, C.; Maleszewska, M.; Kaminska, B. Histone modifying enzymes and chromatin modifiers in glioma pathobiology and therapy responses. In Glioma Signaling; Springer: Cham, Switzerland, 2020; pp. 259–279.
    52. Chang, Y.; Zhang, X.; Horton, J.R.; Upadhyay, A.K.; Spannhoff, A.; Liu, J.; Snyder, J.P.; Bedford, M.T.; Cheng, X. Structural basis for G9a-like protein lysine methyltransferase inhibition by BIX-01294. Nat. Struct. Mol. Biol. 2009, 16, 312–317.
    53. Cheung, H.C.; Yatsenko, S.A.; Kadapakkam, M.; Legay, H.; Su, J.; Lupski, J.R.; Plon, S.E. Constitutional tandem duplication of 9q34 that truncates EHMT1 in a child with ganglioglioma. Pediatr. Blood Cancer 2012, 58, 801–805.
    54. Liu, X.; Li, G.; Su, Z.; Jiang, Z.; Chen, L.; Wang, J.; Yu, S.; Liu, Z. Poly (amido amine) is an ideal carrier of miR-7 for enhancing gene silencing effects on the EGFR pathway in U251 glioma cells. Oncol. Rep. 2013, 29, 1387–1394.
    55. Heddleston, J.M.; Wu, Q.; Rivera, M.; Minhas, S.; Lathia, J.D.; Sloan, A.E.; Iliopoulos, O.; Hjelmeland, A.B.; Rich, J.N. Hypoxia-induced mixed-lineage leukemia 1 regulates glioma stem cell tumorigenic potential. Cell Death Differ. 2012, 19, 428–439.
    56. Zhou, C.; Zhang, Y.; Dai, J.; Zhou, M.; Liu, M.; Wang, Y.; Chen, X.-Z.; Tang, J. Pygo2 functions as a prognostic factor for glioma due to its up-regulation of H3K4me3 and promotion of MLL1/MLL2 complex recruitment. Sci. Rep. 2016, 6, 22066.
    57. Tao, H.; Li, H.; Su, Y.; Feng, D.; Wang, X.; Zhang, C.; Ma, H.; Hu, Q. Histone methyltransferase G9a and H3K9 dimethylation inhibit the self-renewal of glioma cancer stem cells. Mol. Cell. Biochem. 2014, 394, 23–30.
    58. Kunadis, E.; Lakiotaki, E.; Korkolopoulou, P.; Piperi, C. Targeting post-translational histone modifying enzymes in glioblastoma. Pharmacol. Ther. 2021, 220, 107721.
    59. McGrath, J.; Trojer, P. Targeting histone lysine methylation in cancer. Pharmacol. Ther. 2015, 150, 1–22.
    60. Herz, H.-M.; Garruss, A.; Shilatifard, A. SET for life: Biochemical activities and biological functions of SET domain-containing proteins. Trends Biochem. Sci. 2013, 38, 621–639.
    61. Min, J.; Feng, Q.; Li, Z.; Zhang, Y.; Xu, R.-M. Structure of the catalytic domain of human DOT1L, a non-SET domain nucleosomal histone methyltransferase. Cell 2003, 112, 711–723.
    62. Chen, C.; Duan, Z.; Yuan, Y.; Li, R.; Pang, L.; Liang, J.; Xu, X.; Wang, J. Peptide-22 and cyclic RGD functionalized liposomes for glioma targeting drug delivery overcoming BBB and BBTB. ACS Appl. Mater. Interfaces 2017, 9, 5864–5873.
    63. Berger, S.L. The complex language of chromatin regulation during transcription. Nature 2007, 447, 407–412.
    64. Ghiaseddin, A.; Reardon, D.; Massey, W.; Mannerino, A.; Lipp, E.S.; Herndon, J.E.; McSherry, F.; Desjardins, A.; Randazzo, D.; Friedman, H.S. Phase II study of bevacizumab and vorinostat for patients with recurrent World Health Organization grade 4 malignant glioma. Oncologist 2018, 23, 157-e21.
    65. Dammann, R.H.; Richter, A.M.; Jiménez, A.P.; Woods, M.; Küster, M.; Witharana, C. Impact of natural compounds on DNA methylation levels of the tumor suppressor gene RASSF1A in cancer. Int. J. Mol. Sci. 2017, 18, 2160.
    66. Chu, B.; Karpenko, M.; Liu, Z.; Aimiuwu, J.; Villalona-Calero, M.; Chan, K.; Grever, M.; Otterson, G. Phase I study of 5-aza-2′-deoxycytidine in combination with valproic acid in non-small-cell lung cancer. Cancer Chemother. Pharmacol. 2013, 71, 115–121.
    67. Hazane-Puch, F.; Arnaud, J.; Trocmé, C.; Faure, P.; Laporte, F.; Champelovier, P. Sodium selenite decreased HDAC activity, cell proliferation and induced apoptosis in three human glioblastoma cells. Anti-Cancer Agents Med. Chem. Former. Curr. Med. Chem.-Anti-Cancer Agents 2016, 16, 490–500.
    68. Pei, Y.; Liu, K.-W.; Wang, J.; Garancher, A.; Tao, R.; Esparza, L.A.; Maier, D.L.; Udaka, Y.T.; Murad, N.; Morrissy, S. HDAC and PI3K antagonists cooperate to inhibit growth of MYC-driven medulloblastoma. Cancer Cell 2016, 29, 311–323.
    69. Akasaki, Y.; Kikuchi, T.; Homma, S.; Koido, S.; Ohkusa, T.; Tasaki, T.; Hayashi, K.; Komita, H.; Watanabe, N.; Suzuki, Y.; et al. Phase I/II trial of combination of temozolomide chemotherapy and immunotherapy with fusions of dendritic and glioma cells in patients with glioblastoma. Cancer Immunol. Immunother. 2016, 65, 1499–1509.
    70. Hummel, T.R.; Wagner, L.; Ahern, C.; Fouladi, M.; Reid, J.M.; McGovern, R.M.; Ames, M.M.; Gilbertson, R.J.; Horton, T.; Ingle, A.M. A pediatric phase 1 trial of vorinostat and temozolomide in relapsed or refractory primary brain or spinal cord tumors: A Children’s Oncology Group phase 1 consortium study. Pediatr. Blood Cancer 2013, 60, 1452–1457.
    71. Galanis, E.; Jaeckle, K.A.; Maurer, M.J.; Reid, J.M.; Ames, M.M.; Hardwick, J.S.; Reilly, J.F.; Loboda, A.; Nebozhyn, M.; Fantin, V.R. Phase II trial of vorinostat in recurrent glioblastoma multiforme: A north central cancer treatment group study. J. Clin. Oncol. 2009, 27, 2052.
    72. Lee, E.Q.; Reardon, D.A.; Schiff, D.; Drappatz, J.; Muzikansky, A.; Grimm, S.A.; Norden, A.D.; Nayak, L.; Beroukhim, R.; Rinne, M.L. Phase II study of panobinostat in combination with bevacizumab for recurrent glioblastoma and anaplastic glioma. Neuro-Oncology 2015, 17, 862–867.
    73. Shi, W.; Palmer, J.D.; Werner-Wasik, M.; Andrews, D.W.; Evans, J.J.; Glass, J.; Kim, L.; Bar-Ad, V.; Judy, K.; Farrell, C. Phase I trial of panobinostat and fractionated stereotactic re-irradiation therapy for recurrent high grade gliomas. J. Neuro-Oncol. 2016, 127, 535–539.
    74. Krauze, A.V.; Myrehaug, S.D.; Chang, M.G.; Holdford, D.J.; Smith, S.; Shih, J.; Tofilon, P.J.; Fine, H.A.; Camphausen, K. A phase 2 study of concurrent radiation therapy, temozolomide, and the histone deacetylase inhibitor valproic acid for patients with glioblastoma. Int. J. Radiat. Oncol. Biol. Phys. 2015, 92, 986–992.
    75. Issa, J.-P.J.; Garcia-Manero, G.; Giles, F.J.; Mannari, R.; Thomas, D.; Faderl, S.; Bayar, E.; Lyons, J.; Rosenfeld, C.S.; Cortes, J. Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2′-deoxycytidine (decitabine) in hematopoietic malignancies. Blood 2004, 103, 1635–1640.
    76. Wheeler, L.A.; Manzanera, A.G.; Bell, S.D.; Cavaliere, R.; McGregor, J.M.; Grecula, J.C.; Newton, H.B.; Lo, S.S.; Badie, B.; Portnow, J. Phase II multicenter study of gene-mediated cytotoxic immunotherapy as adjuvant to surgical resection for newly diagnosed malignant glioma. Neuro-Oncology 2016, 18, 1137–1145.
    77. Maio, M.; Covre, A.; Fratta, E.; Di Giacomo, A.M.; Taverna, P.; Natali, P.G.; Coral, S.; Sigalotti, L. Molecular pathways: At the crossroads of cancer epigenetics and immunotherapy. Clin. Cancer Res. 2015, 21, 4040–4047.
    78. Wu, W.; Klockow, J.L.; Zhang, M.; Lafortune, F.; Chang, E.; Jin, L.; Wu, Y.; Daldrup-Link, H.E. Glioblastoma multiforme (GBM): An overview of current therapies and mechanisms of resistance. Pharmacol. Res. 2021, 171, 105780.
    79. Ohkuri, T.; Kosaka, A.; Ikeura, M.; Salazar, A.M.; Okada, H. IFN-γ-and IL-17-producing CD8+ T (Tc17-1) cells in combination with poly-ICLC and peptide vaccine exhibit antiglioma activity. J. Immunother. Cancer 2021, 9, e002426.
    80. Hervey-Jumper, S.L.; Berger, M.S. Role of surgical resection in low-and high-grade gliomas. Curr. Treat. Options Neurol. 2014, 16, 284.
    81. Chen, Z.; Hambardzumyan, D. Immune microenvironment in glioblastoma subtypes. Front. Immunol. 2018, 9, 1004.
    82. Stupp, R.; Mason, W.P.; Van Den Bent, M.J.; Weller, M.; Fisher, B.; Taphoorn, M.J.; Belanger, K.; Brandes, A.A.; Marosi, C.; Bogdahn, U. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med. 2005, 352, 987–996.
    83. Friedman, H.S.; Prados, M.D.; Wen, P.Y.; Mikkelsen, T.; Schiff, D.; Abrey, L.E.; Yung, W.A.; Paleologos, N.; Nicholas, M.K.; Jensen, R. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J. Clin. Oncol. 2009, 27, 4733–4740.
    84. Baral, A.; Ye, H.X.; Jiang, P.C.; Yao, Y.; Mao, Y. B7-H3 and B7-H1 expression in cerebral spinal fluid and tumor tissue correlates with the malignancy grade of glioma patients. Oncol. Lett. 2014, 8, 1195–1201.
    85. Zeng, J.; See, A.P.; Phallen, J.; Jackson, C.M.; Belcaid, Z.; Ruzevick, J.; Durham, N.; Meyer, C.; Harris, T.J.; Albesiano, E. Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas. Int. J. Radiat. Oncol. Biol. Phys. 2013, 86, 343–349.
    86. Jahan, N.; Talat, H.; Alonso, A.; Saha, D.; Curry, W.T. Triple combination immunotherapy with GVAX, anti-PD-1 monoclonal antibody, and agonist anti-OX40 monoclonal antibody is highly effective against murine intracranial glioma. Oncoimmunology 2019, 8, e1577108.
    87. Omuro, A.; Vlahovic, G.; Lim, M.; Sahebjam, S.; Baehring, J.; Cloughesy, T.; Voloschin, A.; Ramkissoon, S.H.; Ligon, K.L.; Latek, R. Nivolumab with or without ipilimumab in patients with recurrent glioblastoma: Results from exploratory phase I cohorts of CheckMate 143. Neuro-Oncology 2018, 20, 674–686.
    88. Hanihara, M.; Kawataki, T.; Oh-Oka, K.; Mitsuka, K.; Nakao, A.; Kinouchi, H. Synergistic antitumor effect with indoleamine 2, 3-dioxygenase inhibition and temozolomide in a murine glioma model. J. Neurosurg. 2016, 124, 1594–1601.
    89. Vom Berg, J.; Vrohlings, M.; Haller, S.; Haimovici, A.; Kulig, P.; Sledzinska, A.; Weller, M.; Becher, B. Intratumoral IL-12 combined with CTLA-4 blockade elicits T cell–mediated glioma rejection. J. Exp. Med. 2013, 210, 2803–2811.
    90. Grauer, O.M.; Nierkens, S.; Bennink, E.; Toonen, L.W.; Boon, L.; Wesseling, P.; Sutmuller, R.P.; Adema, G.J. CD4+ FoxP3+ regulatory T cells gradually accumulate in gliomas during tumor growth and efficiently suppress antiglioma immune responses in vivo. Int. J. Cancer 2007, 121, 95–105.
    91. Garber, K. China approves world’s first oncolytic virus therapy for cancer treatment. J. Natl. Cancer Inst. 2006, 98, 298–300.
    92. Andtbacka, R.H.; Kaufman, H.L.; Collichio, F.; Amatruda, T.; Senzer, N.; Chesney, J.; Delman, K.A.; Spitler, L.E.; Puzanov, I.; Agarwala, S.S. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J. Clin. Oncol. 2015, 33, 2780–2788.
    93. Bischoff, J.R.; Kirn, D.H.; Williams, A.; Heise, C.; Horn, S.; Muna, M.; Ng, L.; Nye, J.A.; Sampson-Johannes, A.; Fattaey, A. An adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Science 1996, 274, 373–376.
    94. Palu, G.; Cavaggioni, A.; Calvi, P.; Franchin, E.; Pizzato, M.; Boschetto, R.; Parolin, C.; Chilosi, M.; Ferrini, S.; Zanusso, A. Gene therapy of glioblastoma multiforme via combined expression of suicide and cytokine genes: A pilot study in humans. Gene Ther. 1999, 6, 330–337.
    95. Puntel, M.; Muhammad, A.; Candolfi, M.; Salem, A.; Yagiz, K.; Farrokhi, C.; Kroeger, K.M.; Xiong, W.; Curtin, J.F.; Liu, C. A novel bicistronic high-capacity gutless adenovirus vector that drives constitutive expression of herpes simplex virus type 1 thymidine kinase and tet-inducible expression of Flt3L for glioma therapeutics. J. Virol. 2010, 84, 6007–6017.
    96. Dranoff, G. Cytokines in cancer pathogenesis and cancer therapy. Nat. Rev. Cancer 2004, 4, 11–22.
    97. Coventry, B.J.; Ashdown, M.L. The 20th anniversary of interleukin-2 therapy: Bimodal role explaining longstanding random induction of complete clinical responses. Cancer Manag. Res. 2012, 4, 215.
    98. Okada, H.; Lieberman, F.S.; Walter, K.A.; Lunsford, L.D.; Kondziolka, D.S.; Bejjani, G.K.; Hamilton, R.L.; Torres-Trejo, A.; Kalinski, P.; Cai, Q. Autologous glioma cell vaccine admixed with interleukin-4 gene transfected fibroblasts in the treatment of patients with malignant gliomas. J. Transl. Med. 2007, 5, 67.
    99. Esiri, M.M.; Morris, C.S. Immunocytochemical study of macrophages and microglial cells and extracellular matrix components in human CNS disease: 2. Non-neoplastic diseases. J. Neurol. Sci. 1991, 101, 59–72.
    100. Mieczkowski, J.; Kocyk, M.; Nauman, P.; Gabrusiewicz, K.; Sielska, M.; Przanowski, P.; Maleszewska, M.; Rajan, W.D.; Pszczolkowska, D.; Tykocki, T. Down-regulation of IKKβ expression in glioma-infiltrating microglia/macrophages is associated with defective inflammatory/immune gene responses in glioblastoma. Oncotarget 2015, 6, 33077.
    101. Hu, F.; Ku, M.C.; Markovic, D.; Dzaye, O.; Lehnardt, S.; Synowitz, M.; Wolf, S.A.; Kettenmann, H. Glioma-associated microglial MMP9 expression is upregulated by TLR2 signaling and sensitive to minocycline. Int. J. Cancer 2014, 135, 2569–2578.
    102. Cohen, A.L.; Anker, C.J.; Salzman, K.; Jensen, R.L.; Shrieve, D.C.; Colman, H. A Phase 1 Study of Repeat Radiation, Minocycline, and Bevacizumab in Patients with Recurrent Glioma (RAMBO); American Society of Clinical Oncology: Alexandria, VA, USA, 2014.
    103. Gabrusiewicz, K.; Ellert-Miklaszewska, A.; Lipko, M.; Sielska, M.; Frankowska, M.; Kaminska, B. Characteristics of the alternative phenotype of microglia/macrophages and its modulation in experimental gliomas. PLoS ONE 2011, 6, e23902.
    104. Bagley, S.J.; Desai, A.S.; Linette, G.P.; June, C.H.; O’Rourke, D.M. CAR T-cell therapy for glioblastoma: Recent clinical advances and future challenges. Neuro-Oncology 2018, 20, 1429–1438.
    105. Nehama, D.; Di Ianni, N.; Musio, S.; Du, H.; Patané, M.; Pollo, B.; Finocchiaro, G.; Park, J.J.; Dunn, D.E.; Edwards, D.S. B7-H3-redirected chimeric antigen receptor T cells target glioblastoma and neurospheres. EBioMedicine 2019, 47, 33–43.
    106. Brown, C.E.; Alizadeh, D.; Starr, R.; Weng, L.; Wagner, J.R.; Naranjo, A.; Ostberg, J.R.; Blanchard, M.S.; Kilpatrick, J.; Simpson, J. Regression of glioblastoma after chimeric antigen receptor T-cell therapy. N. Engl. J. Med. 2016, 375, 2561–2569.
    107. Ahmed, N.; Brawley, V.; Hegde, M.; Bielamowicz, K.; Kalra, M.; Landi, D.; Robertson, C.; Gray, T.L.; Diouf, O.; Wakefield, A. HER2-specific chimeric antigen receptor–modified virus-specific T cells for progressive glioblastoma: A phase 1 dose-escalation trial. JAMA Oncol. 2017, 3, 1094–1101.
    108. Sampson, J.H.; Choi, B.D.; Sanchez-Perez, L.; Suryadevara, C.M.; Snyder, D.J.; Flores, C.T.; Schmittling, R.J.; Nair, S.K.; Reap, E.A.; Norberg, P.K. EGFRvIII mCAR-Modified T-Cell Therapy Cures Mice with Established Intracerebral Glioma and Generates Host Immunity against Tumor-Antigen LossEGFRvIII mCARs for Malignant Glioma. Clin. Cancer Res. 2014, 20, 972–984.
    109. Shen, C.-J.; Yang, Y.-X.; Han, E.Q.; Cao, N.; Wang, Y.-F.; Wang, Y.; Zhao, Y.-Y.; Zhao, L.-M.; Cui, J.; Gupta, P. Chimeric antigen receptor containing ICOS signaling domain mediates specific and efficient antitumor effect of T cells against EGFRvIII expressing glioma. J. Hematol. Oncol. 2013, 6, 33.
    110. Sampson, J.H.; Schmittling, R.J.; Archer, G.E.; Congdon, K.L.; Nair, S.K.; Reap, E.A.; Desjardins, A.; Friedman, A.H.; Friedman, H.S.; Herndon, J.E. A pilot study of IL-2Rα blockade during lymphopenia depletes regulatory T-cells and correlates with enhanced immunity in patients with glioblastoma. PLoS ONE 2012, 7, e31046.
    111. Mishima, K.; Johns, T.G.; Luwor, R.B.; Scott, A.M.; Stockert, E.; Jungbluth, A.A.; Ji, X.-D.; Suvarna, P.; Voland, J.R.; Old, L.J. Growth suppression of intracranial xenografted glioblastomas overexpressing mutant epidermal growth factor receptors by systemic administration of monoclonal antibody (mAb) 806, a novel monoclonal antibody directed to the receptor. Cancer Res. 2001, 61, 5349–5354.
    112. Crane, C.A.; Han, S.J.; Ahn, B.; Oehlke, J.; Kivett, V.; Fedoroff, A.; Butowski, N.; Chang, S.M.; Clarke, J.; Berger, M.S. Individual Patient-Specific Immunity against High-Grade Glioma after Vaccination with Autologous Tumor Derived Peptides Bound to the 96 KD Chaperone ProteinLong-term Immunity against High-Grade Glioma. Clin. Cancer Res. 2013, 19, 205–214.
    113. Ishikawa, E.; Muragaki, Y.; Yamamoto, T.; Maruyama, T.; Tsuboi, K.; Ikuta, S.; Hashimoto, K.; Uemae, Y.; Ishihara, T.; Matsuda, M. Phase I/IIa trial of fractionated radiotherapy, temozolomide, and autologous formalin-fixed tumor vaccine for newly diagnosed glioblastoma. J. Neurosurg. 2014, 121, 543–553.
    114. Kikuchi, T.; Akasaki, Y.; Irie, M.; Homma, S.; Abe, T.; Ohno, T. Results of a phase I clinical trial of vaccination of glioma patients with fusions of dendritic and glioma cells. Cancer Immunol. Immunother. 2001, 50, 337–344.
    115. Yu, J.S.; Wheeler, C.J.; Zeltzer, P.M.; Ying, H.; Finger, D.N.; Lee, P.K.; Yong, W.H.; Incardona, F.; Thompson, R.C.; Riedinger, M.S. Vaccination of malignant glioma patients with peptide-pulsed dendritic cells elicits systemic cytotoxicity and intracranial T-cell infiltration. Cancer Res. 2001, 61, 842–847.
    116. Ardon, H.; Van Gool, S.; Lopes, I.S.; Maes, W.; Sciot, R.; Wilms, G.; Demaerel, P.; Bijttebier, P.; Claes, L.; Goffin, J. Integration of autologous dendritic cell-based immunotherapy in the primary treatment for patients with newly diagnosed glioblastoma multiforme: A pilot study. J. Neuro-Oncol. 2010, 99, 261–272.
    117. Megías-Vericat, J.E.; Ballesta-Lopez, O.; Barragan, E.; Montesinos, P. IDH1-mutated relapsed or refractory AML: Current challenges and future prospects. Blood Lymphat. Cancer Targets Ther. 2019, 9, 19.
    118. Wen, P.Y.; Reardon, D.A.; Armstrong, T.S.; Phuphanich, S.; Aiken, R.D.; Landolfi, J.C.; Curry, W.T.; Zhu, J.-J.; Glantz, M.; Peereboom, D.M. A Randomized Double-Blind Placebo-Controlled Phase II Trial of Dendritic Cell Vaccine ICT-107 in Newly Diagnosed Patients with GlioblastomaICT-107 Vaccine for Newly Diagnosed Glioblastoma. Clin. Cancer Res. 2019, 25, 5799–5807.
    119. Wainwright, D.A.; Chang, A.L.; Dey, M.; Balyasnikova, I.V.; Kim, C.K.; Tobias, A.; Cheng, Y.; Kim, J.W.; Qiao, J.; Zhang, L. Durable Therapeutic Efficacy Utilizing Combinatorial Blockade against IDO, CTLA-4, and PD-L1 in Mice with Brain TumorsIDO, CTLA-4, PD-L1 Synergistic Blockade in Brain Tumors. Clin. Cancer Res. 2014, 20, 5290–5301.
    120. Wolchok, J.D.; Kluger, H.; Callahan, M.K.; Postow, M.A.; Rizvi, N.A.; Lesokhin, A.M.; Segal, N.H.; Ariyan, C.E.; Gordon, R.-A.; Reed, K. Nivolumab plus ipilimumab in advanced melanoma. N. Engl. J. Med. 2013, 369, 122–133.
    121. Agarwalla, P.; Barnard, Z.; Fecci, P.; Dranoff, G.; Curry Jr, W.T. Sequential immunotherapy by vaccination with GM-CSF expressing glioma cells and CTLA-4 blockade effectively treats established murine intracranial tumors. J. Immunother. 2012, 35, 385.
    122. Cherkassky, L.; Morello, A.; Villena-Vargas, J.; Feng, Y.; Dimitrov, D.S.; Jones, D.R.; Sadelain, M.; Adusumilli, P.S. Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. J. Clin. Investig. 2016, 126, 3130–3144.
    123. Sengupta, S.; Mao, G.; Gokaslan, Z.; Sampath, P. Chimeric antigen receptors for treatment of glioblastoma: A practical review of challenges and ways to overcome them. Cancer Gene Ther. 2017, 24, 121–129.
    124. Yasuda, S.; Sho, M.; Yamato, I.; Yoshiji, H.; Wakatsuki, K.; Nishiwada, S.; Yagita, H.; Nakajima, Y. Simultaneous blockade of programmed death 1 and vascular endothelial growth factor receptor 2 (VEGFR2) induces synergistic anti-tumour effect in vivo. Clin. Exp. Immunol. 2013, 172, 500–506.
    125. Kosaka, A.; Ohkuri, T.; Okada, H. Combination of an agonistic anti-CD40 monoclonal antibody and the COX-2 inhibitor celecoxib induces anti-glioma effects by promotion of type-1 immunity in myeloid cells and T-cells. Cancer Immunol. Immunother. 2014, 63, 847–857.
    126. Moertel, C.L.; Xia, J.; LaRue, R.; Waldron, N.N.; Andersen, B.M.; Prins, R.M.; Okada, H.; Donson, A.M.; Foreman, N.K.; Hunt, M.A. CD200 in CNS tumor-induced immunosuppression: The role for CD200 pathway blockade in targeted immunotherapy. J. Immunother. Cancer 2014, 2, 46.
    127. Candolfi, M.; Kroeger, K.M.; Muhammad, A.; Yagiz, K.; Farrokhi, C.; Pechnick, R.N.; Lowenstein, P.R.; Castro, M.G. Gene therapy for brain cancer: Combination therapies provide enhanced efficacy and safety. Curr. Gene Ther. 2009, 9, 409–421.
    128. Kamran, N.; Kadiyala, P.; Saxena, M.; Candolfi, M.; Li, Y.; Moreno-Ayala, M.A.; Raja, N.; Shah, D.; Lowenstein, P.R.; Castro, M.G. Immunosuppressive myeloid cells’ blockade in the glioma microenvironment enhances the efficacy of immune-stimulatory gene therapy. Mol. Ther. 2017, 25, 232–248.
    129. Mineharu, Y.; King, G.D.; Muhammad, A.; Bannykh, S.; Kroeger, K.M.; Liu, C.; Lowenstein, P.R.; Castro, M.G. Engineering the Brain Tumor Microenvironment Enhances the Efficacy of Dendritic Cell Vaccination: Implications for Clinical Trial DesignImmunotherapy for Brain Cancer. Clin. Cancer Res. 2011, 17, 4705–4718.
    130. Ohkuri, T.; Ghosh, A.; Kosaka, A.; Sarkar, S.N.; Okada, H. Protective role of STING against gliomagenesis: Rational use of STING agonist in anti-glioma immunotherapy. Oncoimmunology 2015, 4, e999523.
    131. Rampling, R.; Peoples, S.; Mulholland, P.J.; James, A.; Al-Salihi, O.; Twelves, C.J.; McBain, C.; Jefferies, S.; Jackson, A.; Stewart, W. A Cancer Research UK First Time in Human Phase I Trial of IMA950 (Novel Multipeptide Therapeutic Vaccine) in Patients with Newly Diagnosed GlioblastomaIMA950 Phase I Trial Final Results. Clin. Cancer Res. 2016, 22, 4776–4785.
    132. Park, M.-Y.; Kim, C.-H.; Sohn, H.-J.; Oh, S.-T.; Kim, S.-G.; Kim, T.-G. The optimal interval for dendritic cell vaccination following adoptive T cell transfer is important for boosting potent anti-tumor immunity. Vaccine 2007, 25, 7322–7330.
    133. Shankar, G.M.; Kirtane, A.R.; Miller, J.J.; Mazdiyasni, H.; Rogner, J.; Tai, T.; Williams, E.A.; Higuchi, F.; Juratli, T.A.; Tateishi, K. Genotype-targeted local therapy of glioma. Proc. Natl. Acad. Sci. USA 2018, 115, E8388–E8394.
    134. Yu, D.; Khan, O.F.; Suvà, M.L.; Dong, B.; Panek, W.K.; Xiao, T.; Wu, M.; Han, Y.; Ahmed, A.U.; Balyasnikova, I.V. Multiplexed RNAi therapy against brain tumor-initiating cells via lipopolymeric nanoparticle infusion delays glioblastoma progression. Proc. Natl. Acad. Sci. USA 2017, 114, E6147–E6156.
    135. Idbaih, A.; Canney, M.; Belin, L.; Desseaux, C.; Vignot, A.; Bouchoux, G.; Asquier, N.; Law-Ye, B.; Leclercq, D.; Bissery, A. Safety and Feasibility of Repeated and Transient Blood–Brain Barrier Disruption by Pulsed Ultrasound in Patients with Recurrent GlioblastomaBlood–Brain Barrier Disruption by Ultrasound in GBM. Clin. Cancer Res. 2019, 25, 3793–3801.
    136. Ding, X.; Xu, L.; Sun, X.; Zhao, X.; Gao, B.; Cheng, Y.; Liu, D.; Zhao, J.; Zhang, X.; Xu, L. Human bone marrow-derived mesenchymal stem cell-secreted exosomes overexpressing microrna-124-3p inhibit DLBCL progression by downregulating NFATc1. Res. Sq. 2020.
    137. Katakowski, M.; Buller, B.; Zheng, X.; Lu, Y.; Rogers, T.; Osobamiro, O.; Shu, W.; Jiang, F.; Chopp, M. Exosomes from marrow stromal cells expressing miR-146b inhibit glioma growth. Cancer Lett. 2013, 335, 201–204.
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      Fath, M.K.; Babakhaniyan, K.; Anjomrooz, M.; Jalalifar, M.; Alizadeh, S.D.; Pourghasem, Z.; Oshagh, P.A.; Azargoonjahromi, A.; Almasi, F.; Manzoor, H.Z.; et al. Recent Advances in Glioma Cancer Treatment. Encyclopedia. Available online: https://encyclopedia.pub/entry/26858 (accessed on 06 February 2023).
      Fath MK, Babakhaniyan K, Anjomrooz M, Jalalifar M, Alizadeh SD, Pourghasem Z, et al. Recent Advances in Glioma Cancer Treatment. Encyclopedia. Available at: https://encyclopedia.pub/entry/26858. Accessed February 06, 2023.
      Fath, Mohsen Karami, Kimiya Babakhaniyan, Mehran Anjomrooz, Mohammadrasoul Jalalifar, Seyed Danial Alizadeh, Zeinab Pourghasem, Parisa Abbasi Oshagh, Ali Azargoonjahromi, Faezeh Almasi, Hafza Zahira Manzoor, et al. "Recent Advances in Glioma Cancer Treatment," Encyclopedia, https://encyclopedia.pub/entry/26858 (accessed February 06, 2023).
      Fath, M.K., Babakhaniyan, K., Anjomrooz, M., Jalalifar, M., Alizadeh, S.D., Pourghasem, Z., Oshagh, P.A., Azargoonjahromi, A., Almasi, F., Manzoor, H.Z., Khalesi, B., Pourzardosht, N., Khalili, S., & Payandeh, Z. (2022, September 05). Recent Advances in Glioma Cancer Treatment. In Encyclopedia. https://encyclopedia.pub/entry/26858
      Fath, Mohsen Karami, et al. ''Recent Advances in Glioma Cancer Treatment.'' Encyclopedia. Web. 05 September, 2022.
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