Current Combinatorial Therapeutic Aspects: The Future Prospect for Glioblastoma Treatment

Abstract

There are several types of brain tumors but glioblastoma (GBM) is one of the highly malignant tumors. A primary concern with GBM is that the treatment is inadequate. Even after giving many multi-stacked combinations of therapies to patients, inclusive of chemotherapy, radiation, and surgery, the median survival rate remains poor. Due to its heterogeneous nature, the use of selective therapy for specific targeting of tumor cells is of particular importance. Although many treatment alternatives which include surgery with adjuvant chemotherapy and radiotherapy are available, the prognosis of the disease is very poor. Combination therapy is becoming the foundation of modern antitumor therapy and it is continuously evolving and developing innovative drug regimens as evidenced by ongoing preclinical and clinical trials. In this review, we discuss the current treatment options and emerging therapeutic approaches for the treatment of GBM. The prospects for alternative glioblastoma therapy are also discussed.

References

[1] TanAC, AshleyDM, LopezGY, et al. . Management of glioblastoma: State of the art and future directions. CA Cancer J Clin, 2020, 70(4): 299-312

[2] FisherJP, AdamsonDC. Current FDA-Approved Therapies for High-Grade Malignant Gliomas. Biomedicines, 2021, 9(3): 324

[3] GesundheitB, Ben-DavidE, PosenY, et al. . Effective Treatment of Glioblastoma Multiforme With Oncolytic Virotherapy: A Case-Series. Front Oncol, 2020, 10: 702

[4] TaylorOG, BrzozowskiJS, SkeldingKA. Glioblastoma Multiforme: An Overview of Emerging Therapeutic Targets. Front Oncol, 2019, 9: 963

[5] LouisDN, PerryA, WesselingP, et al. . The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol, 2021, 23(8): 1231-1251

[6] ShergalisA, BankheadA 3, LuesakulU, et al. . Current Challenges and Opportunities in Treating Glioblastoma. Pharmacol Rev, 2018, 70(3): 412-445

[7] RongL, LiN, ZhangZ. Emerging therapies for glioblastoma: current state and future directions. J Exp Clin Cancer Res, 2022, 41(1): 142

[8] ZhaoY, YueP, PengY, et al. . Recent advances in drug delivery systems for targeting brain tumors. Drug Deliv, 2023, 30(1): 1-18

[9] MalikS, MuhammadK, WaheedY. Emerging Applications of Nanotechnology in Healthcare and Medicine. Molecules, 2023, 28(18): 6624

[10] Mosleh-ShiraziS, AbbasiM, MoaddeliMR, et al. . Nanotechnology Advances in the Detection and Treatment of Cancer: An Overview. Nanotheranostics, 2022, 6(4): 400-423

[11] PatraJK, DasG, FracetoLF, et al. . Nano based drug delivery systems: recent developments and future prospects. J Nanobiotechnol, 2018, 16(1): 71

[12] GraczykA, PawlowskaR, JedrzejczykD, et al. . Gold Nanoparticles in Conjunction with Nucleic Acids as a Modern Molecular System for Cellular Delivery. Molecules, 2020, 25(1): 204

[13] DesfrançoisC, AuzélyR, TexierI. Lipid Nanoparticles and Their Hydrogel Composites for Drug Delivery: A Review. Pharmaceuticals (Basel), 2018, 11(4): 118

[14] Barzegar BehroozA, TalaieZ, SyahirA. Nanotechnology-Based Combinatorial Anti-Glioblastoma Therapies: Moving from Terminal to Treatable. Pharmaceutics, 2022, 14(8): 1697

[15] BegagićE, PugonjaR, BečulićH, et al. . Molecular Targeted Therapies in Glioblastoma Multiforme: A Systematic Overview of Global Trends and Findings. Brain Sci, 2023, 13(11): 1602

[16] BhowmikA, KhanR, GhoshMK. Blood brain barrier: a challenge for effectual therapy of brain tumors. Biomed Res Int, 2015, 2015: 320941

[17] MitusovaK, PeltekOO, KarpovTE, et al. . Overcoming the blood-brain barrier for the therapy of malignant brain tumor: current status and prospects of drug delivery approaches. J Nanobiotechnol, 2022, 20(1): 412

[18] GerritsenJKW, BroekmanMLD, De VleeschouwerS, et al. . Safe surgery for glioblastoma: Recent advances and modern challenges. Neurooncol Pract, 2022, 9(5): 364-379

[19] HanifF, MuzaffarK, PerveenK, et al. . Glioblastoma Multiforme: A Review of its Epidemiology and Pathogenesis through Clinical Presentation and Treatment. Asian Pac J Cancer Prev, 2017, 18(1): 3-9

[20] RominiyiO, VanderlindenA, ClentonSJ, et al. . Tumour treating fields therapy for glioblastoma: current advances and future directions. Br J Cancer, 2021, 124(4): 697-709

[21] StrobelH, BaischT, FitzelR, et al. . Temozolomide and Other Alkylating Agents in Glioblastoma Therapy. Biomedicines, 2019, 7(3): 69

[22] OrtizR, PerazzoliG, CabezaL, et al. . Temozolomide: An Updated Overview of Resistance Mechanisms, Nanotechnology Advances and Clinical Applications. Curr Neuropharmacol, 2021, 19(4): 513-537

[23] ChienCH, HsuehWT, ChuangJY, et al. . Dissecting the mechanism of temozolomide resistance and its association with the regulatory roles of intracellular reactive oxygen species in glioblastoma. J Biomed Sci, 2021, 28(1): 18

[24] JovanovićN, MitrovićT, CvetkovićVJ, et al. . The Impact of MGMT Promoter Methylation and Temozolomide Treatment in Serbian Patients with Primary Glioblastoma. Medicina (Kaunas), 2019, 55(2): 34

[25] RiveraAL, PelloskiCE, GilbertMR, et al. . MGMT promoter methylation is predictive of response to radiotherapy and prognostic in the absence of adjuvant alkylating chemotherapy for glioblastoma. Neuro Oncol, 2010, 12(2): 116-121

[26] ColardoM, SegattoM, Di BartolomeoS. Targeting RTK-PI3K-mTOR Axis in Gliomas: An Update. Int J Mol Sci, 2021, 22(9): 4899

[27] Di NunnoV, FranceschiE, TosoniA, et al. . Glioblastoma: Emerging Treatments and Novel Trial Designs. Cancers (Basel), 2021, 13(15): 3750

[28] KumarAR, DevanAR, NairB, et al. . Harnessing the immune system against cancer: current immunotherapy approaches and therapeutic targets. Mol Biol Rep, 2021, 48(12): 8075-8095

[29] BuonaguroL, TagliamonteM. Selecting Target Antigens for Cancer Vaccine Development. Vaccines (Basel), 2020, 8(4): 615

[30] GedeonPC, ChoiBD, SampsonJH, et al. . Rindopepimut: anti-EGFRvIII peptide vaccine, oncolytic. Drugs Future, 2013, 38(3): 147-155

[31] ReardonDA, DesjardinsA, VredenburghJJ, et al. . Rindopepimut with Bevacizumab for Patients with Relapsed EGFRvIII-Expressing Glioblastoma (ReACT): Results of a Double-Blind Randomized Phase II Trial. Clin Cancer Res, 2020, 26(7): 1586-1594

[32] WellerM, ButowskiN, TranDD, et al. . Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial. Lancet Oncol, 2017, 18(10): 1373-1385

[33] SchijnsVEJC, PrettoC, StrikAM, et al. . Therapeutic Immunization against Glioblastoma. Int J Mol Sci, 2018, 19(9): 2540

[34] ZhaoT, LiC, GeH, et al. . Glioblastoma vaccine tumor therapy research progress. Chin Neurosurg J, 2022, 8(1): 2

[35] YaoY, LuoF, TangC, et al. . Molecular subgroups and B7-H4 expression levels predict responses to dendritic cell vaccines in glioblastoma: an exploratory randomized phase II clinical trial. Cancer Immunol Immunother, 2018, 67(11): 1777-1788

[36] Van GoolSW, MakalowskiJ, KampersLFC, et al. . Dendritic cell vaccination for glioblastoma multiforme patients: has a new milestone been reached?. Transl Cancer Res, 2023, 12(8): 2224-2228

[37] BanerjeeK, NúñezFJ, HaaseS, et al. . Current Approaches for Glioma Gene Therapy and Virotherapy. Front Mol Neurosci, 2021, 14: 621831

[38] MozheiO, TeschemacherAG, KasparovS. Viral Vectors as Gene Therapy Agents for Treatment of Glioblastoma. Cancers (Basel), 2020, 12(12): 3724

[39] WakabayashiT, NatsumeA, HashizumeY, et al. . A phase I clinical trial of interferon-beta gene therapy for high-grade glioma: novel findings from gene expression profiling and autopsy. J Gene Med, 2008, 10(4): 329-339

[40] JainKK. A Critical Overview of Targeted Therapies for Glioblastoma. Front Oncol, 2018, 8: 419

[41] RobertsJW, PowlovichL, SheybaniN, et al. . Focused ultrasound for the treatment of glioblastoma. J Neurooncol, 2022, 157(2): 237-247

[42] HershAM, BhimreddyM, Weber-LevineC, et al. . Applications of Focused Ultrasound for the Treatment of Glioblastoma: A New Frontier. Cancers (Basel), 2022, 14(19): 4920

[43] HershDS, WadajkarAS, RobertsN, et al. . Evolving Drug Delivery Strategies to Overcome the Blood Brain Barrier. Curr Pharm Des, 2016, 22(9): 1177-1193

[44] IdbaihA, CanneyM, BelinL, et al. . Safety and Feasibility of Repeated and Transient Blood-Brain Barrier Disruption by Pulsed Ultrasound in Patients with Recurrent Glioblastoma. Clin Cancer Res, 2019, 25(13): 3793-3801

[45] MaJ, Motsinger-ReifA. Current Methods for Quantifying Drug Synergism. Proteom Bioinform, 2019, 1(2): 43-48

[46] ChengYS, WilliamsonPR, ZhengW. Improving therapy of severe infections through drug repurposing of synergistic combinations. Curr Opin Pharmacol, 2019, 48: 92-98

[47] PazhouhiM, SaririR, RabziaA, et al. . Thymoquinone synergistically potentiates temozolomide cytotoxicity through the inhibition of autophagy in U87MG cell line. Iran J Basic Med Sci, 2016, 19(8): 890-898

[48] SurarakT, ChantreeP, SangpairojK. Synergistic Effects of Taurine and Temozolomide Via Cell Proliferation Inhibition and Apoptotic Induction on U-251 MG Human Glioblastoma Cells. Asian Pac J Cancer Prev, 2021, 22(12): 4001-4009

[49] NaeemA, HuP, YangM, et al. . Natural Products as Anticancer Agents: Current Status and Future Perspectives. Molecules, 2022, 27(23): 8367

[50] Da RosM, IorioAL, De GregorioV, et al. . Aldoxorubicin and Temozolomide combination in a xenograft mice model of human glioblastoma. Oncotarget, 2018, 9(79): 34935-34944

[51] WangD, WangZ, DaiX, et al. . Apigenin and Temozolomide Synergistically Inhibit Glioma Growth Through the PI3K/AKT Pathway. Cancer Biother Radiopharm, 2021, 39(2): 125-132

[52] XiongJ, GuoG, GuoL, et al. . Amlexanox Enhances Temozolomide-Induced Antitumor Effects in Human Glioblastoma Cells by Inhibiting IKBKE and the Akt-mTOR Signaling Pathway. ACS Omega, 2021, 6(6): 4289-4299

[53] VengojiR, MachaMA, NimmakayalaRK, et al. . Afatinib and Temozolomide combination inhibits tumorigenesis by targeting EGFRvIII-cMet signaling in glioblastoma cells. J Exp Clin Cancer Res, 2019, 38(1): 266

[54] ZhangX, NiQ, WangY, et al. . Synergistic Anticancer Effects of Formononetin and Temozolomide on Glioma C6 Cells. Biol Pharm Bull, 2018, 41(8): 1194-1202

[55] KaramiA, HossienpourM, Mohammadi NooriE, et al. . Synergistic Effect of Gefitinib and Temozolomide on U87MG Glioblastoma Angiogenesis. Nutr Cancer, 2022, 74(4): 1299-1307

[56] GautamM, GabraniR. Combinatorial Effect of Temozolomide and Naringenin in Human Glioblastoma Multiforme Cell Lines. Nutr Cancer, 2022, 74(3): 1071-1078

[57] OhHC, ShimJK, ParkJ, et al. . Combined effects of niclosamide and temozolomide against human glioblastoma tumorspheres. J Cancer Res Clin Oncol, 2020, 146(11): 2817-2828

[58] LiuY, SongX, WuM, et al. . Synergistic Effects of Resveratrol and Temozolomide Against Glioblastoma Cells: Underlying Mechanism and Therapeutic Implications. Cancer Manag Res, 2020, 12: 8341-8354

[59] YamadaT, TsujiS, NakamuraS, et al. . Riluzole enhances the antitumor effects of temozolomide via suppression of MGMT expression in glioblastoma. J Neurosurg, 2020, 134(3): 701-710

[60] KhazaeiM, PazhouhiM, KhazaeiS. Temozolomide and tranilast synergistic antiproliferative effect on human glioblastoma multiforme cell line (U87MG). Med J Islam Repub Iran, 2019, 33: 39

[61] KumthekarP, GrimmS, ChandlerJ, et al. . A phase II trial of arsenic trioxide and temozolomide in combination with radiation therapy for patients with malignant gliomas. J Neurooncol, 2017, 133(3): 589-594

[62] CzabankaM, BruennerJ, ParmaksizG, et al. . Combined temozolomide and sunitinib treatment leads to better tumour control but increased vascular resistance in O6-methylguanine methyltransferase-methylated gliomas. Eur J Cancer, 2013, 49(9): 2243-2252

[63] TownerRA, HockerJ, SmithN, et al. . OKN-007 Alters Protein Expression Profiles in High-Grade Gliomas: Mass Spectral Analysis of Blood Sera. Brain Sci, 2022, 12(1): 100

[64] QinS, LiA, YiM, et al. . Recent advances on anti-angiogenesis receptor tyrosine kinase inhibitors in cancer therapy. J Hematol Oncol, 2019, 12(1): 27

[65] ShrihastiniV, MuthuramalingamP, AdarshanS, et al. . Plant Derived Bioactive Compounds, Their Anti-Cancer Effects and In Silico Approaches as an Alternative Target Treatment Strategy for Breast Cancer: An Updated Overview. Cancers (Basel), 2021, 13(24): 6222

[66] WuW, KlockowJL, ZhangM, et al. . Glioblastoma multiforme (GBM): An overview of current therapies and mechanisms of resistance. Pharmacol Res, 2021, 171: 105780

[67] GreenwellM, RahmanPK. Medicinal Plants: Their Use in Anticancer Treatment. Int J Pharm Sci Res, 2015, 6(10): 4103-4112

[68] MaoQQ, XuXY, CaoSY, et al. . Bioactive Compounds and Bioactivities of Ginger (Zingiber officinale Roscoe). Foods, 2019, 8(6): 185

[69] ElhagR, MazzioEA, SolimanKF. The effect of silibinin in enhancing toxicity of temozolomide and etoposide in p53 and PTEN-mutated resistant glioma cell lines. Anticancer Res, 2015, 35(3): 1263-1269

[70] SainiRK, RanjitA, SharmaK, et al. . Bioactive Compounds of Citrus Fruits: A Review of Composition and Health Benefits of Carotenoids, Flavonoids, Limonoids, and Terpenes. Antioxidants (Basel), 2022, 11(2): 239

[71] ZhaiK, SiddiquiM, AbdellatifB, et al. . Natural Compounds in Glioblastoma Therapy: Preclinical Insights, Mechanistic Pathways, and Outlook. Cancers (Basel), 2021, 13(10): 2317

[72] KhanT, AliM, KhanA, et al. . Anticancer Plants: A Review of the Active Phytochemicals, Applications in Animal Models, and Regulatory Aspects. Biomolecules, 2019, 10(1): 47

[73] SunJ. D-Limonene: safety and clinical applications. Altern Med Rev, 2007, 12(3): 259-264

[74] JiaSS, XiGP, ZhangM, et al. . Induction of apoptosis by D-limonene is mediated by inactivation of Akt in LS174T human colon cancer cells. Oncol Rep, 2013, 29(1): 349-354

[75] HaagJD, GouldMN. Mammary carcinoma regression induced by perillyl alcohol, a hydroxylated analog of limonene. Cancer Chemother Pharmacol, 1994, 34(6): 477-483

[76] GautamM, GabraniR. Synergism of d-limonene and temozolomide on migratory and apoptotic behaviors of human glioblastoma cell lines. Bioimpacts, 2024, 14(5): 27681

[77] GautamM, GabraniR. Evaluation of bromelain and temozolomide synergistic combination in human glioblastoma cells. Adv Tradit Med (Adtm), 2024, 24: 507-518

[78] DeheleanCA, MarcoviciI, SoicaC, et al. . Plant-Derived Anticancer Compounds as New Perspectives in Drug Discovery and Alternative Therapy. Molecules, 2021, 26(4): 1109

[79] PereiraEWM, HeimfarthL, SantosTK, et al. . Limonene, a citrus monoterpene, non-complexed and complexed with hydroxypropyl-β-cyclodextrin attenuates acute and chronic orofacial nociception in rodents: Evidence for involvement of the PKA and PKC pathway. Phytomedicine, 2022, 96: 153893

[80] ChenTC, da FonsecaCO, LevinD, et al. . The Monoterpenoid Perillyl Alcohol: Anticancer Agent and Medium to Overcome Biological Barriers. Pharmaceutics, 2021, 13(12): 2167

[81] NehraG, AndrewsS, RettigJ, et al. . Intranasal administration of the chemotherapeutic perillyl alcohol results in selective delivery to the cerebrospinal fluid in rats. Sci Rep, 2021, 11(1): 6351

[82] FariaGM, SoaresIDP, D’Alincourt SalazarM, et al. . Intranasal perillyl alcohol therapy improves survival of patients with recurrent glioblastoma harboring mutant variant for MTHFR rs1801133 polymorphism. BMC Cancer, 2020, 20(1): 294

[83] Sharifi-RadJ, RayessYE, RizkAA, et al. . Turmeric and Its Major Compound Curcumin on Health: Bioactive Effects and Safety Profiles for Food, Pharmaceutical, Biotechnological and Medicinal Applications. Front Pharmacol, 2020, 11: 01021

[84] GiordanoA, TommonaroG. Curcumin and Cancer. Nutrients, 2019, 11(10): 2376

[85] SminiaP, van den BergJ, van KootwijkA, et al. . Experimental and clinical studies on radiation and curcumin in human glioma. J Cancer Res Clin Oncol, 2021, 147(2): 403-409

[86] GerseyZC, RodriguezGA, BarbariteE, et al. . Curcumin decreases malignant characteristics of glioblastoma stem cells via induction of reactive oxygen species. BMC Cancer, 2017, 17(1): 99

[87] HeinrichM, MahJ, AmirkiaV. Alkaloids Used as Medicines: Structural Phytochemistry Meets Biodiversity-An Update and Forward Look. Molecules, 2021, 26(7): 1836

[88] MoudiM, GoR, YienCY, et al. . Vinca alkaloids. Int J Prev Med, 2013, 4(11): 1231-1235

[89] LiY, ZhaoY, ZhouX, et al. . Cytotoxic Indole Alkaloid 3α-Acetonyltabersonine Induces Glioblastoma Apoptosis via Inhibition of DNA Damage Repair. Toxins (Basel), 2017, 9(5): 150

[90] PancheAN, DiwanAD, ChandraSR. Flavonoids: an overview. J Nutr Sci, 2016, 5: e47

[91] ZhaiK, MazurakovaA, KoklesovaL, et al. . Flavonoids Synergistically Enhance the Anti-Glioblastoma Effects of Chemotherapeutic Drugs. Biomolecules, 2021, 11(12): 1841

[92] KongY, FengZ, ChenA, et al. . The Natural Flavonoid Galangin Elicits Apoptosis, Pyroptosis, and Autophagy in Glioblastoma. Front Oncol, 2019, 9: 942

[93] GautamM, GabraniR. Evaluation of the vanillin treatment on migration and anchorage-independent growth of glioblastoma cell line. J App Biol Biotech, 2024, 12(1): 106-110

[94] BonaNP, PedraNS, AzambujaJH, et al. . Tannic acid elicits selective antitumoral activity in vitro and inhibits cancer cell growth in a preclinical model of glioblastoma multiforme. Metab Brain Dis, 2020, 35(2): 283-293

[95] MasucciMT, MinopoliM, CarrieroMV. Tumor Associated Neutrophils. Their Role in Tumorigenesis, Metastasis, Prognosis and Therapy. Front Oncol, 2019, 9: 1146

[96] ZhangJ, ChenD, HanDM, et al. . Tannic acid mediated induction of apoptosis in human glioma Hs 683 cells. Oncol Lett, 2018, 15(5): 6845-6850

[97] MaokaT. Carotenoids as natural functional pigments. J Nat Med, 2020, 74(1): 1-16

[98] SiP, ZhuC. Biological and neurological activities of astaxanthin (Review). Mol Med Rep, 2022, 26(4): 300

[99] TsujiS, NakamuraS, MaokaT, et al. . Antitumour Effects of Astaxanthin and Adonixanthin on Glioblastoma. Mar Drugs, 2020, 18(9): 474

[100] LopesFG, OliveiraKA, LopesRG, et al. . Anti-cancer Effects of Fucoxanthin on Human Glioblastoma Cell Line. Anticancer Res, 2020, 40(12): 6799-6815

[101] PartridgeB, EardleyA, MoralesBE, et al. . Advancements in drug delivery methods for the treatment of brain disease. Front Vet Sci, 2022, 9: 1039745

[102] TiekD, ChengSY. DNA damage and metabolic mechanisms of cancer drug resistance. Cancer Drug Resist, 2022, 5(2): 368-379

RIGHTS & PERMISSIONS

Huazhong University of Science and Technology