Systematic Reviews
Copyright ©The Author(s) 2024.
World J Stem Cells. May 26, 2024; 16(5): 604-614
Published online May 26, 2024. doi: 10.4252/wjsc.v16.i5.604
Table 1 Summary of the studies included in the systematic literature review
Ref.GCLsGSCs pathwayTherapeutic targetTherapeutic agentEffects
Molecular
Adjuvant treatments response
Eller et al[9], 2005Ros57, Jon52, Mor56RAS/RAF/MAPKEGFRCetuximabEGFR inhibitionRTR reduction
Bao et al[1], 2006A172ATR/Chk1/p53, ATM/Chk2/p53Chk1, Chk2DBHChk1/2 inhibitionRTR reduction
Clement et al[10], 2007U87HH-GLIGLI1, GLI2, GLI3RCyclopamineGLI1,2 inhibition and GLI3R activationCTR to TMZ reduction
Bleau et al[11], 2009U87PI3K/AKT/mTORPI3Kα/δ, Akt PHDLY294002, perifosineABCG2 inhibitionCTR to TMZ reduction
Li et al[12], 2009U373MGNF-κBLRRFIP1miR-21LRRFIP1 inhibitionCTR to VM-26 reduction
Wang et al[13], 2010T3359, T3691, T4105, T4202, T4592NotchNOTCH1, NOTCH2GSIs, Notch1/2-specific shRNANOTCH1/2 inhibitionRTR reduction
Facchino et al[14], 2010Not specifiedPRC1BMI1RNAi (shBMI1)BMI1 inhibitionRTR reduction
Li et al[15], 2010Not specifiedPI3K/Akt/mTORABCG2miRNA-328ABCG2 inhibitionCTR to TMZ reduction
Ulasov et al[16], 2011U87MGNotch, SHHNOTCH1, SMOGSI-1, cyclopamineNotch and SHH inhibitionCTR to TMZ reduction
Wu et al[17], 2010Not specifiedATR/CHK1/p53CHK1RNAi (shCHK1)CHK1 inhibitionRTR reduction
Squatrito et al[18], 2012Not applicableATM/CHK2/p53CHK2RCAS/PDGFCHK2 inhibitionRTR reduction
Zhu et al[19], 2011HSR-GBM1/2/3NotchJAG1, DLL4RNAi (shJAG1, shDLL4)JAG1 and DLL4 inhibitionCTR to TMZ and RTR reduction
Nadkarni et al[20], 2012U251, U87PIKKATMKU-55933ATM inhibitionCTR to TMZ reduction
Nabissi et al[21], 2013U87MGPI3K/Akt/mTORTRPV2CBDTRPV2 inhibitionCTR to TMZ, BCNU and DOXO reduction
Wang et al[22], 2013SU-2PI3K/Akt/mTORmTORC1/2NVP-BEZ235mTORC1/2 inhibitionRTR reduction
Martín et al[23], 2013A172, U87, U373ABCABCG2/BCRPMelatoninABCG2/BCRP inhibitionCTR to TMZ reduction
Bhat et al[24], 2013Not specifiedTNF-α/NF-κBNF-κBIkB-SRNF-κB inhibitionRTR reduction
Aldea et al[25], 2014Not specifiedPI3K/AKT/mTOR RAS/RAF/MAPKmTOR, RAFMetformin, sorafenibmTOR and RAF, inhibitionCTR to TMZ reduction
Nabissi et al[26], 2015Not specifiedPI3K/AKT/mTOR TRPV2Aml-1aCBDAml-1a inhibitionCTR to BCNU reduction
Yu et al[27], 2015U87, U251, T98G, SHG44PI3K/AKT/mTORmTORC1/2NVP-BEZ235mTORC1/2 inhibitionCTR to TMZ reduction
Natsumeda et al[28], 2016HSR-GBM1, JHH520NotchHES1, HES5, HEY1, autophagyMRK003 + CQNotch inhibitionCTR reduction
Venugopal et al[29], 2015Not specifiedWnt/β-cateninCK1αPyrviniumCK1α inhibitionCTR to TMZ and RTR reduction
Yi et al[30], 2016U87Autophagic PCDAutophagy, Bcl-2, Caspase-3CQBcl-2 inhibition and Caspase-3 activationRTR reduction
Marampon et al[31], 2017U87MG, U251MGHDACHDAC4, HDAC6shRNAs (HDAC4-shRNA, HDAC6-shRNA)HDAC4/6 inhibitionRTR reduction
Huang et al[32], 2017Not specifiedMST4/ATG4BATG4BNSC185058ATG4B inhibitionRTR reduction
Dai et al[33], 2017T98G, U87, U251, U343, MGR2, Hs683AKT/GSK3β/β-cateninSCD1siRNA (SCD1-siRNA)SCD1 inhibitionCTR to TMZ reduction
Minata et al[34], 2019U87, TS528PTEN/PI3K/AKTpY240-PTENPD173074FGFR2 inhibitionCTR to TMZ and RTR reduction
Yuan et al[35], 2019T98G-R, U118-RFUS/MDM2FUS domains (RRM, Znf_BP2)ADAMTS9-AS2FUS domains inhibitionCTR to TMZ reduction
Moon et al[36], 2020T98G, LN229, U118MG, U87MG, U251MGCK1A/BTRCP/MBD3/NuRDCK1APyr-PamMBD3 pathway inhibition by activating CK1ACTR to TMZ reduction
Huang et al[37], 2021Not specifiedCK2α/PRMT6/RCC1PRMT6EPZ020411PRMT6 inhibitionRTR reduction
Chen et al[38], 2022T98G, LN229PI3K/AKT/mTOR, NF-κBEPHB3, TNFAIP3YTHDF2EPHB3 and TNFAIP3, inhibitionCTR to TMZ reduction
Chang et al[39], 2023Not specifiedUSP36/ALKBH5USP36shRNAChk1 inhibitionRTR reduction
ABCG2/BCRP: ATP binding cassette G2/breast cancer resistance protein; ADAMTS9-AS2: Antisense RNA 2 to ADAMTS9; Aml-1a: Acute myeloid leukemia; ATR/Chk1/p53: Ataxia telangiectasia and Rad3-related/checkpoint kinase 1/protein 53; ATM: Ataxia telangiectasia mutated; Bcl-2: B-cell lymphoma 2; BTRCP/MBD3/NuRD: Beta transducin repeat-containing protein/methyl-CpG binding domain protein 3/nucleosome remodeling and deacetylase; BCNU: Carmustine; BER: Base excision repair; BMI1: B lymphoma Mo-MLV insertion region 1; CBD: Cannabidiol; CQ: Chloroquine; CTR: Chemotherapy resistance; DBH: Debromohymenialdisine; DLL4: Delta-like 4; DOXO: Doxorubicin; EGFR: Epidermal growth factor receptor; EPHB3: Eph receptor B3; FGFR2: Fibroblast growth receptor 2; FUS/MDM2: Fused in sarcoma/mouse double minute 2; GCL: Glioma cell line; GLI3R: Glioma associated oncogene homolog 3 repressor; GSI: Gamma secretase inhibitor; GSK3β: Glycogen synthase kinase 3 beta; HES: Hairy and enhancer of split; HDAC: Histone deacetylase; HH-GLI: Hedgehog-glioma-associated oncogene; IkB-SR: IkB super repressor; JAG1: Jagged 1; LRRFIP1: Leucin rich repeat flightless-interacting protein 1; miRNA: MicroRNA; miR-21: MicroRNA 21; MST4/ATG4B: Macrophage stimulation 1/autophagy related protein 4B; NF-κB: Nuclear factor κB; PARPi: Poly(ADP-ribose) polimerase; PHD: Prolyl hydroxylase; PI3K/AKT/mTOR: Phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin; PIKK: Phosphoinositide 3-kinase related kinase; PCD: Programmed cell death; PRC1: Polycomb repressive complex 1; PRMT6/RCC1: Protein arginine methyltransferase 6/regulator of chromosome condensation 1; pY240-PTEN: Phosphorylated tyrosine 240 in the phosphatase and tensin homolog; Pyr-Pam: Pyrvinium pamoate; RAS/RAF/MAPK: Rat sarcoma/rapidly accelerated fibrosarcoma/mitogen activated protein kinase; RCAS/PDGF: Replication-competent avian sarcoma-leukosis virus/platelet derived growth factor; RNAi: RNA inhibitors; RRM: RNA recognition motif; RTR: Radiotherapy resistance; SHH: Sonic hedgehog; shRNA: Short hairpin RNA; SCD1: Stearoyl-CoA desaturase 1; SMO: Smoothened protein; TNFAIP3: Tumor necrosis factor alpha-induced protein 3; TNF-α: Tumor necrosis factor α; TMZ: Temozolomide; TRPV2: Transient receptor potential cation channel subfamily V member 2; USP36/ALKBH5: Ubiquitin-specific protease 36/AlkB homolog 5, RNA demethylase; VM-26: Teniposide; YTHDF2: YTH N(6)-methyladenosine RNA binding protein 2; ZNF_BP2: Zinc finger domain binding protein 2.
Table 2 Summary of the ongoing clinical trials focusing on targeted therapies against the molecular mechanism of glioma stem cell-mediated resistance to adjuvant treatments
Trial name
Year
Title
Trial phase
Therapeutic agent
NCT009164092014A prospective, multicenter trial of NovoTTF-100 A together with TMZ compared to TMZ alone in patients with newly diagnosed GBMIIINovoTTF-100A device
NCT014742392016Randomized noncomparative phase II trial with bevacizumab and FOT in the treatment of recurrent GBMIIBevacizumab
NCT026982802018Phase II study of bevacizumab and ACNU in patients with recurrent high-grade gliomaIIBevacizumab
NCT043968602020Randomized noncomparative phase II trial with bevacizumab and FOT in the treatment of recurrent GBMII/IIIIpilimumab, nivolumab, NovoTTF-100 A device
NCT013108682021An evaluation of the tolerability and feasibility of combining 5-ALA with BCNU wafers (Gliadel®) in the surgical management of primary GBMII5-ALA Gliadel® wafers
NCT01290939OngoingPhase III trial exploring the combination of bvacizumab and CCNU in patients with first recurrence of a GBMIIIBevacizumab
NCT00884741OngoingPhase III double-blind placebo-controlled trial of conventional concurrent chemoradiation and adjuvant TMZ plus bevacizumab versus conventional concurrent chemoradiation and adjuvant TMZ in patients with newly diagnosed GBMIIIBevacizumab
NCT02017717OngoingA randomized phase III open-label study of nivolumab versus bevacizumab and multiple phase I safety cohorts of nivolumab or nivolumab in combination with ipilimumab across different lines of GBMIIINivolumab, bevacizumab, ipilimumab
NCT00753246OngoingPhase III study of standard radiotherapy plus concomitant and adjuvant OSAG 101 (Theraloc®) plus TMZ versus standard radiotherapy plus concomitant and adjuvant TMZ patient with newly diagnosed, histologically confirmed GBM multiforme grade IVIIINimotuzumab
GBM: Glioblastoma; TMZ: Temozolomide.