Glioblastoma: Pathogenesis and Current Status of Chemotherapy and Other Novel Treatments

Vilashini Rajaratnam, Mohammad Mohiminul Islam, Maixee Yang, Rachel Slaby, Hilda Martinez Ramirez, Shama Parveen Mirza, Vilashini Rajaratnam, Mohammad Mohiminul Islam, Maixee Yang, Rachel Slaby, Hilda Martinez Ramirez, Shama Parveen Mirza

Abstract

Glioblastoma is one of the most common and detrimental forms of solid brain tumor, with over 10,000 new cases reported every year in the United States. Despite aggressive multimodal treatment approaches, the overall survival period is reported to be less than 15 months after diagnosis. A widely used approach for the treatment of glioblastoma is surgical removal of the tumor, followed by radiotherapy and chemotherapy. While there are several drugs available that are approved by the Food and Drug Administration (FDA), significant efforts have been made in recent years to develop new chemotherapeutic agents for the treatment of glioblastoma. This review describes the molecular targets and pathogenesis as well as the current progress in chemotherapeutic development and other novel therapies in the clinical setting for the treatment of glioblastoma.

Keywords: chemotherapy; glioblastoma; molecular targets; novel therapy; pathogenesis.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The IDH1/2 enzyme converts isocitrate into α-ketoglutarate (shown in the blue) while the mutant IDH1/2 enzyme converts α-ketoglutarate into 2-hydroxyglutarate (shown in orange). IDH: isocitrate dehydrogenase.
Figure 2
Figure 2
Reaction of acid ceramidase (ASAH1), a lysosomal enzyme that converts ceramides into sphingosine, which is further converted to sphingosine-1-phosphate (S1P) by sphingosine kinase. Ceramide promotes apoptosis while S1P stimulates cell survival and proliferation.
Figure 3
Figure 3
Schematic representation of a simplified overview on the PI3K/AKT/mTOR pathway with the role of phosphate and tensin homolog (PTEN) and receptor tyrosine kinase (RTK).

References

    1. Ostrom Q.T., Gittleman H., Truitt G., Boscia A., Kruchko C., Barnholtz-Sloan J.S. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2011-2015. Neuro Oncol. 2018;20:iv1–iv86. doi: 10.1093/neuonc/noy131.
    1. Anjum K., Shagufta B.I., Abbas S.Q., Patel S., Khan I., Shah S.A.A., Akhter N., Hassan S.S.U. Current status and future therapeutic perspectives of glioblastoma multiforme (GBM) therapy: A review. Biomed. Pharmacother. 2017;92:681–689. doi: 10.1016/j.biopha.2017.05.125.
    1. Ferguson S., Lesniak M.S. Percival Bailey and the classification of brain tumors. Neurosurg. Focus. 2005;18:e7. doi: 10.3171/foc.2005.18.4.8.
    1. Zulch K.J., Wechsler W. Progress in Neurological Surgery. Volume 2. Karger Publisher; Basel, Switzerland: 1968. Pathology and Classification of Gliomas; pp. 1–84.
    1. Louis D.N., Perry A., Burger P., Ellison D.W., Reifenberger G., von Deimling A., Aldape K., Brat D., Collins V.P., Eberhart C., et al. International Society Of Neuropathology--Haarlem consensus guidelines for nervous system tumor classification and grading. Brain Pathol. 2014;24:429–435. doi: 10.1111/bpa.12171.
    1. Louis D.N., Perry A., Reifenberger G., von Deimling A., Figarella-Branger D., Cavenee W.K., Ohgaki H., Wiestler O.D., Kleihues P., Ellison D.W. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: A summary. Acta Neuropathol. 2016;131:803–820. doi: 10.1007/s00401-016-1545-1.
    1. Huang J., Campian J.L., Gujar A.D., Tsien C., Ansstas G., Tran D.D., DeWees T.A., Lockhart A.C., Kim A.H. Final results of a phase I dose-escalation, dose-expansion study of adding disulfiram with or without copper to adjuvant temozolomide for newly diagnosed glioblastoma. J. Neurooncol. 2018;138:105–111. doi: 10.1007/s11060-018-2775-y.
    1. Cancer I.A.f.R.o. WHO Classification of Tumours of the Central Nervous System. Volume 1 WTO; Geneva, Switzerland: 2016.
    1. Stöppler M.C., Shiel W.C., Credo Reference (Firm) WebMD (Firm) Webster’s New World Medical Dictionary. 3rd ed. redo Reference; Boston, MA, USA: Wiley; Hoboken, NJ, USA: 2014. p. 1.
    1. Dagogo-Jack I., Shaw A.T. Tumour heterogeneity and resistance to cancer therapies. Nat. Rev. Clin. Oncol. 2018;15:81–94. doi: 10.1038/nrclinonc.2017.166.
    1. Yamaguchi S., Kobayashi H., Terasaka S., Ishii N., Ikeda J., Kanno H., Nishihara H., Tanaka S., Houkin K. The impact of extent of resection and histological subtype on the outcome of adult patients with high-grade gliomas. Jpn. J. Clin. Oncol. 2012;42:270–277. doi: 10.1093/jjco/hys016.
    1. Wrensch M., Minn Y., Chew T., Bondy M., Berger M.S. Epidemiology of primary brain tumors: Current concepts and review of the literature. Neuro Oncol. 2002;4:278–299. doi: 10.1093/neuonc/4.4.278.
    1. Preusser M., de Ribaupierre S., Wohrer A., Erridge S.C., Hegi M., Weller M., Stupp R. Current concepts and management of glioblastoma. Ann. Neurol. 2011;70:9–21. doi: 10.1002/ana.22425.
    1. Aoki T., Hashimoto N., Matsutani M. Management of glioblastoma. Expert Opin. Pharmacother. 2007;8:3133–3146. doi: 10.1517/14656566.8.18.3133.
    1. Sanai N., Berger M.S. Recent surgical management of gliomas. Adv. Exp. Med. Biol. 2012;746:12–25. doi: 10.1007/978-1-4614-3146-6_2.
    1. Young R.M., Jamshidi A., Davis G., Sherman J.H. Current trends in the surgical management and treatment of adult glioblastoma. Ann. Transl. Med. 2015;3:121. doi: 10.3978/j.issn.2305-5839.2015.05.10.
    1. Ryken T.C., Frankel B., Julien T., Olson J.J. Surgical management of newly diagnosed glioblastoma in adults: Role of cytoreductive surgery. J. Neurooncol. 2008;89:271–286. doi: 10.1007/s11060-008-9614-5.
    1. Barbagallo G.M., Jenkinson M.D., Brodbelt A.R. ’Recurrent’ glioblastoma multiforme, when should we reoperate? Br. J. Neurosurg. 2008;22:452–455. doi: 10.1080/02688690802182256.
    1. Cabrera A.R., Kirkpatrick J.P., Fiveash J.B., Shih H.A., Koay E.J., Lutz S., Petit J., Chao S.T., Brown P.D., Vogelbaum M., et al. Radiation therapy for glioblastoma: Executive summary of an American Society for Radiation Oncology Evidence-Based Clinical Practice Guideline. Pract. Radiat. Oncol. 2016;6:217–225. doi: 10.1016/j.prro.2016.03.007.
    1. Minniti G., Filippi A.R., Osti M.F., Ricardi U. Radiation therapy for older patients with brain tumors. Radiat. Oncol. 2017;12:101. doi: 10.1186/s13014-017-0841-9.
    1. Mann J., Ramakrishna R., Magge R., Wernicke A.G. Advances in Radiotherapy for Glioblastoma. Front. Neurol. 2017;8:748. doi: 10.3389/fneur.2017.00748.
    1. Corso C.D., Bindra R.S., Mehta M.P. The role of radiation in treating glioblastoma: Here to stay. J. Neurooncol. 2017;134:479–485. doi: 10.1007/s11060-016-2348-x.
    1. Fedoy A.E., Yang N., Martinez A., Leiros H.K., Steen I.H. Structural and functional properties of isocitrate dehydrogenase from the psychrophilic bacterium Desulfotalea psychrophila reveal a cold-active enzyme with an unusual high thermal stability. J. Mol. Biol. 2007;372:130–149. doi: 10.1016/j.jmb.2007.06.040.
    1. Kaminska B., Czapski B., Guzik R., Krol S.K., Gielniewski B. Consequences of IDH1/2 Mutations in Gliomas and an Assessment of Inhibitors Targeting Mutated IDH Proteins. Molecules. 2019;24:968. doi: 10.3390/molecules24050968.
    1. Parsons D.W., Jones S., Zhang X., Lin J.C., Leary R.J., Angenendt P., Mankoo P., Carter H., Siu I.M., Gallia G.L., et al. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008;321:1807–1812. doi: 10.1126/science.1164382.
    1. Cohen A.L., Holmen S.L., Colman H. IDH1 and IDH2 mutations in gliomas. Curr. Neurol. Neurosci. Rep. 2013;13:345. doi: 10.1007/s11910-013-0345-4.
    1. Turkalp Z., Karamchandani J., Das S. IDH mutation in glioma: New insights and promises for the future. JAMA Neurol. 2014;71:1319–1325. doi: 10.1001/jamaneurol.2014.1205.
    1. Popovici-Muller J., Lemieux R.M., Artin E., Saunders J.O., Salituro F.G., Travins J., Cianchetta G., Cai Z., Zhou D., Cui D., et al. Discovery of AG-120 (Ivosidenib): A First-in-Class Mutant IDH1 Inhibitor for the Treatment of IDH1 Mutant Cancers. ACS Med. Chem. Lett. 2018;9:300–305. doi: 10.1021/acsmedchemlett.7b00421.
    1. Rohle D., Popovici-Muller J., Palaskas N., Turcan S., Grommes C., Campos C., Tsoi J., Clark O., Oldrini B., Komisopoulou E., et al. An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science. 2013;340:626–630. doi: 10.1126/science.1236062.
    1. Huang J., Yu J., Tu L., Huang N., Li H., Luo Y. Isocitrate Dehydrogenase Mutations in Glioma: From Basic Discovery to Therapeutics Development. Front. Oncol. 2019;9:506. doi: 10.3389/fonc.2019.00506.
    1. Lino M.M., Merlo A., Boulay J.L. Notch signaling in glioblastoma: A developmental drug target? BMC Med. 2010;8:72. doi: 10.1186/1741-7015-8-72.
    1. Yan D., Hao C., Xiao-Feng L., Yu-Chen L., Yu-Bin F., Lei Z. Molecular mechanism of Notch signaling with special emphasis on microRNAs: Implications for glioma. J. Cell. Physiol. 2018;234:158–170. doi: 10.1002/jcp.26775.
    1. Fan X., Khaki L., Zhu T.S., Soules M.E., Talsma C.E., Gul N., Koh C., Zhang J., Li Y.M., Maciaczyk J., et al. NOTCH pathway blockade depletes CD133-positive glioblastoma cells and inhibits growth of tumor neurospheres and xenografts. Stem Cells. 2010;28:5–16. doi: 10.1002/stem.254.
    1. Bazzoni R., Bentivegna A. Role of Notch Signaling Pathway in Glioblastoma Pathogenesis. Cancers (Basel) 2019;11:292. doi: 10.3390/cancers11030292.
    1. Ying M., Wang S., Sang Y., Sun P., Lal B., Goodwin C.R., Guerrero-Cazares H., Quinones-Hinojosa A., Laterra J., Xia S. Regulation of glioblastoma stem cells by retinoic acid: Role for Notch pathway inhibition. Oncogene. 2011;30:3454–3467. doi: 10.1038/onc.2011.58.
    1. Hovinga K.E., Shimizu F., Wang R., Panagiotakos G., Van Der Heijden M., Moayedpardazi H., Correia A.S., Soulet D., Major T., Menon J., et al. Inhibition of notch signaling in glioblastoma targets cancer stem cells via an endothelial cell intermediate. Stem Cells. 2010;28:1019–1029. doi: 10.1002/stem.429.
    1. Morad S.A., Cabot M.C. Ceramide-orchestrated signalling in cancer cells. Nat. Rev. Cancer. 2013;13:51–65. doi: 10.1038/nrc3398.
    1. Doan N.B., Nguyen H.S., Al-Gizawiy M.M., Mueller W.M., Sabbadini R.A., Rand S.D., Connelly J.M., Chitambar C.R., Schmainda K.M., Mirza S.P. Acid ceramidase confers radioresistance to glioblastoma cells. Oncol. Rep. 2017;38:1932–1940. doi: 10.3892/or.2017.5855.
    1. Nguyen H.S., Awad A.J., Shabani S., Doan N. Molecular Targeting of Acid Ceramidase in Glioblastoma: A Review of Its Role, Potential Treatment, and Challenges. Pharmaceutics. 2018;10:45. doi: 10.3390/pharmaceutics10020045.
    1. Doan N.B., Alhajala H., Al-Gizawiy M.M., Mueller W.M., Rand S.D., Connelly J.M., Cochran E.J., Chitambar C.R., Clark P., Kuo J., et al. Acid ceramidase and its inhibitors: A de novo drug target and a new class of drugs for killing glioblastoma cancer stem cells with high efficiency. Oncotarget. 2017;8:112662–112674. doi: 10.18632/oncotarget.22637.
    1. Doan N.B., Nguyen H.S., Montoure A., Al-Gizawiy M.M., Mueller W.M., Kurpad S., Rand S.D., Connelly J.M., Chitambar C.R., Schmainda K.M., et al. Acid ceramidase is a novel drug target for pediatric brain tumors. Oncotarget. 2017;8:24753–24761. doi: 10.18632/oncotarget.15800.
    1. Alifieris C., Trafalis D.T. Glioblastoma multiforme: Pathogenesis and treatment. Pharmacol. Ther. 2015;152:63–82. doi: 10.1016/j.pharmthera.2015.05.005.
    1. Wick W., Weller M., Weiler M., Batchelor T., Yung A.W., Platten M. Pathway inhibition: Emerging molecular targets for treating glioblastoma. Neuro Oncol. 2011;13:566–579. doi: 10.1093/neuonc/nor039.
    1. Zirlik K., Duyster J. Anti-Angiogenics: Current Situation and Future Perspectives. Oncol. Res. Treat. 2018;41:166–171. doi: 10.1159/000488087.
    1. Okuda T., Tasaki T., Nakata S., Yamashita K., Yoshioka H., Izumoto S., Kato A., Fujita M. Efficacy of Combination Therapy with MET and VEGF Inhibitors for MET-overexpressing Glioblastoma. Anticancer Res. 2017;37:3871–3876. doi: 10.21873/anticanres.11767.
    1. Weathers S.P., de Groot J. VEGF Manipulation in Glioblastoma. Oncology (Williston Park) 2015;29:720–727.
    1. Liu T., Ma W., Xu H., Huang M., Zhang D., He Z., Zhang L., Brem S., O’Rourke D.M., Gong Y., et al. PDGF-mediated mesenchymal transformation renders endothelial resistance to anti-VEGF treatment in glioblastoma. Nat. Commun. 2018;9:3439. doi: 10.1038/s41467-018-05982-z.
    1. Mischel P.S., Cloughesy T.F. Targeted molecular therapy of GBM. Brain Pathol. 2003;13:52–61. doi: 10.1111/j.1750-3639.2003.tb00006.x.
    1. Shih A.H., Holland E.C. Platelet-derived growth factor (PDGF) and glial tumorigenesis. Cancer Lett. 2006;232:139–147. doi: 10.1016/j.canlet.2005.02.002.
    1. Heldin C.H. Targeting the PDGF signaling pathway in tumor treatment. Cell Commun. Signal. 2013;11:97. doi: 10.1186/1478-811X-11-97.
    1. Cantanhede I.G., de Oliveira J.R.M. PDGF Family Expression in Glioblastoma Multiforme: Data Compilation from Ivy Glioblastoma Atlas Project Database. Sci. Rep. 2017;7:15271. doi: 10.1038/s41598-017-15045-w.
    1. Westermark B. Platelet-derived growth factor in glioblastoma-driver or biomarker? Ups. J. Med. Sci. 2014;119:298–305. doi: 10.3109/03009734.2014.970304.
    1. Popescu A.M., Alexandru O., Brindusa C., Purcaru S.O., Tache D.E., Tataranu L.G., Taisescu C., Dricu A. Targeting the VEGF and PDGF signaling pathway in glioblastoma treatment. Int. J. Clin. Exp. Pathol. 2015;8:7825–7837.
    1. Hong J.D., Wang X., Peng Y.P., Peng J.H., Wang J., Dong Y.P., He D., Peng Z.Z., Tu Q.S., Sheng L.F., et al. Silencing platelet-derived growth factor receptor-beta enhances the radiosensitivity of C6 glioma cells in vitro and in vivo. Oncol. Lett. 2017;14:329–336. doi: 10.3892/ol.2017.6143.
    1. Cenciarelli C., Marei H.E., Zonfrillo M., Pierimarchi P., Paldino E., Casalbore P., Felsani A., Vescovi A.L., Maira G., Mangiola A. PDGF receptor alpha inhibition induces apoptosis in glioblastoma cancer stem cells refractory to anti-Notch and anti-EGFR treatment. Mol. Cancer. 2014;13:247. doi: 10.1186/1476-4598-13-247.
    1. Ohgaki H., Kleihues P. Genetic pathways to primary and secondary glioblastoma. Am. J. Pathol. 2007;170:1445–1453. doi: 10.2353/ajpath.2007.070011.
    1. Watanabe K., Tachibana O., Sata K., Yonekawa Y., Kleihues P., Ohgaki H. Overexpression of the EGF receptor and p53 mutations are mutually exclusive in the evolution of primary and secondary glioblastomas. Brain Pathol. 1996;6:217–223. doi: 10.1111/j.1750-3639.1996.tb00848.x. discussion 223–214.
    1. Kraus J.A., Felsberg J., Tonn J.C., Reifenberger G., Pietsch T. Molecular genetic analysis of the TP53, PTEN, CDKN2A, EGFR, CDK4 and MDM2 tumour-associated genes in supratentorial primitive neuroectodermal tumours and glioblastomas of childhood. Neuropathol. Appl. Neurobiol. 2002;28:325–333. doi: 10.1046/j.1365-2990.2002.00413.x.
    1. Ohgaki H., Dessen P., Jourde B., Horstmann S., Nishikawa T., Di Patre P.L., Burkhard C., Schuler D., Probst-Hensch N.M., Maiorka P.C., et al. Genetic pathways to glioblastoma: A population-based study. Cancer Res. 2004;64:6892–6899. doi: 10.1158/0008-5472.CAN-04-1337.
    1. Westphal M., Maire C.L., Lamszus K. EGFR as a Target for Glioblastoma Treatment: An Unfulfilled Promise. CNS Drugs. 2017;31:723–735. doi: 10.1007/s40263-017-0456-6.
    1. Felsberg J., Hentschel B., Kaulich K., Gramatzki D., Zacher A., Malzkorn B., Kamp M., Sabel M., Simon M., Westphal M., et al. Epidermal Growth Factor Receptor Variant III (EGFRvIII) Positivity in EGFR-Amplified Glioblastomas: Prognostic Role and Comparison between Primary and Recurrent Tumors. Clin. Cancer Res. 2017;23:6846–6855. doi: 10.1158/1078-0432.CCR-17-0890.
    1. Halatsch M.E., Gehrke E.E., Vougioukas V.I., Botefur I.C., A-Borhani F., Efferth T., Gebhart E., Domhof S., Schmidt U., Buchfelder M. Inverse correlation of epidermal growth factor receptor messenger RNA induction and suppression of anchorage-independent growth by OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in glioblastoma multiforme cell lines. J. Neurosurg. 2004;100:523–533. doi: 10.3171/jns.2004.100.3.0523.
    1. Reardon D.A., Groves M.D., Wen P.Y., Nabors L., Mikkelsen T., Rosenfeld S., Raizer J., Barriuso J., McLendon R.E., Suttle A.B., et al. A phase I/II trial of pazopanib in combination with lapatinib in adult patients with relapsed malignant glioma. Clin. Cancer Res. 2013;19:900–908. doi: 10.1158/1078-0432.CCR-12-1707.
    1. Conciatori F., Bazzichetto C., Falcone I., Pilotto S., Bria E., Cognetti F., Milella M., Ciuffreda L. Role of mTOR Signaling in Tumor Microenvironment: An Overview. Int. J. Mol. Sci. 2018;19:2453. doi: 10.3390/ijms19082453.
    1. Mecca C., Giambanco I., Donato R., Arcuri C. Targeting mTOR in Glioblastoma: Rationale and Preclinical/Clinical Evidence. Dis. Markers. 2018;2018:9230479. doi: 10.1155/2018/9230479.
    1. Carballo G.B., Honorato J.R., de Lopes G.P.F., Spohr T. A highlight on Sonic hedgehog pathway. Cell Commun. Signal. 2018;16:11. doi: 10.1186/s12964-018-0220-7.
    1. Mantamadiotis T. Towards Targeting PI3K-Dependent Regulation of Gene Expression in Brain Cancer. Cancers (Basel) 2017;9:60. doi: 10.3390/cancers9060060.
    1. Lino M.M., Merlo A. PI3Kinase signaling in glioblastoma. J. Neurooncol. 2011;103:417–427. doi: 10.1007/s11060-010-0442-z.
    1. Janbazian L., Karamchandani J., Das S. Mouse models of glioblastoma: Lessons learned and questions to be answered. J. Neurooncol. 2014;118:1–8. doi: 10.1007/s11060-014-1401-x.
    1. Romano C., Schepis C. PTEN gene: A model for genetic diseases in dermatology. ScientificWorldJournal. 2012;2012:252457. doi: 10.1100/2012/252457.
    1. Lester A., Rapkins R., Nixdorf S., Khasraw M., McDonald K. Combining PARP inhibitors with radiation therapy for the treatment of glioblastoma: Is PTEN predictive of response? Clin. Transl. Oncol. 2017;19:273–278. doi: 10.1007/s12094-016-1547-4.
    1. Valdes-Rives S.A., Casique-Aguirre D., German-Castelan L., Velasco-Velazquez M.A., Gonzalez-Arenas A. Apoptotic Signaling Pathways in Glioblastoma and Therapeutic Implications. Biomed. Res. Int. 2017;2017:7403747. doi: 10.1155/2017/7403747.
    1. Hill V.K., Kim J.S., James C.D., Waldman T. Correction of PTEN mutations in glioblastoma cell lines via AAV-mediated gene editing. PLoS ONE. 2017;12:e0176683. doi: 10.1371/journal.pone.0176683.
    1. Liu Y., Liu X., Chen L., Du W., Cui Y., Piao X., Li Y., Jiang C. Targeting glioma stem cells via the Hedgehog signaling pathway. Neuroimmunol. Neuroinflammation. 2014;1:9. doi: 10.4103/2347-8659.139715.
    1. Takezaki T., Hide T., Takanaga H., Nakamura H., Kuratsu J., Kondo T. Essential role of the Hedgehog signaling pathway in human glioma-initiating cells. Cancer Sci. 2011;102:1306–1312. doi: 10.1111/j.1349-7006.2011.01943.x.
    1. Rimkus T.K., Carpenter R.L., Qasem S., Chan M., Lo H.W. Targeting the Sonic Hedgehog Signaling Pathway: Review of Smoothened and GLI Inhibitors. Cancers (Basel) 2016;8:22. doi: 10.3390/cancers8020022.
    1. Nanta R., Shrivastava A., Sharma J., Shankar S., Srivastava R.K. Inhibition of sonic hedgehog and PI3K/Akt/mTOR pathways cooperate in suppressing survival, self-renewal and tumorigenic potential of glioblastoma-initiating cells. Mol. Cell. Biochem. 2019;454:11–23. doi: 10.1007/s11010-018-3448-z.
    1. 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., et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med. 2005;352:987–996. doi: 10.1056/NEJMoa043330.
    1. Cohen M.H., Shen Y.L., Keegan P., Pazdur R. FDA drug approval summary: Bevacizumab (Avastin) as treatment of recurrent glioblastoma multiforme. Oncologist. 2009;14:1131–1138. doi: 10.1634/theoncologist.2009-0121.
    1. Stupp R., Hegi M.E., Mason W.P., van den Bent M.J., Taphoorn M.J., Janzer R.C., Ludwin S.K., Allgeier A., Fisher B., Belanger K., et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10:459–466. doi: 10.1016/S1470-2045(09)70025-7.
    1. Davis M.E. Glioblastoma: Overview of Disease and Treatment. Clin. J. Oncol. Nurs. 2016;20:S2–S8. doi: 10.1188/16.CJON.S1.2-8.
    1. Gilbert M.R., Dignam J.J., Armstrong T.S., Wefel J.S., Blumenthal D.T., Vogelbaum M.A., Colman H., Chakravarti A., Pugh S., Won M., et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N. Engl. J. Med. 2014;370:699–708. doi: 10.1056/NEJMoa1308573.
    1. Chowdhary S.A., Ryken T., Newton H.B. Survival outcomes and safety of carmustine wafers in the treatment of high-grade gliomas: A meta-analysis. J. Neurooncol. 2015;122:367–382. doi: 10.1007/s11060-015-1724-2.
    1. Song A., Andrews D.W., Werner-Wasik M., Kim L., Glass J., Bar-Ad V., Evans J.J., Farrell C.J., Judy K.D., Daskalakis C., et al. Phase I trial of alisertib with concurrent fractionated stereotactic re-irradiation for recurrent high grade gliomas. Radiother. Oncol. 2019;132:135–141. doi: 10.1016/j.radonc.2018.12.019.
    1. Herrlinger U., Tzaridis T., Mack F., Steinbach J.P., Schlegel U., Sabel M., Hau P., Kortmann R.D., Krex D., Grauer O., et al. Lomustine-temozolomide combination therapy versus standard temozolomide therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter (CeTeG/NOA-09): A randomised, open-label, phase 3 trial. Lancet. 2019;393:678–688. doi: 10.1016/S0140-6736(18)31791-4.
    1. Huang J., Chaudhary R., Cohen A.L., Fink K., Goldlust S., Boockvar J., Chinnaiyan P., Wan L., Marcus S., Campian J.L. A multicenter phase II study of temozolomide plus disulfiram and copper for recurrent temozolomide-resistant glioblastoma. J. Neurooncol. 2019;142:537–544. doi: 10.1007/s11060-019-03125-y.
    1. Silvani A., De Simone I., Fregoni V., Biagioli E., Marchioni E., Caroli M., Salmaggi A., Pace A., Torri V., Gaviani P., et al. Multicenter, single arm, phase II trial on the efficacy of ortataxel in recurrent glioblastoma. J. Neurooncol. 2019;142:455–462. doi: 10.1007/s11060-019-03116-z.
    1. Wen P.Y., Touat M., Alexander B.M., Mellinghoff I.K., Ramkissoon S., McCluskey C.S., Pelton K., Haidar S., Basu S.S., Gaffey S.C., et al. Buparlisib in Patients With Recurrent Glioblastoma Harboring Phosphatidylinositol 3-Kinase Pathway Activation: An Open-Label, Multicenter, Multi-Arm, Phase II Trial. J. Clin. Oncol. 2019;37:741–750. doi: 10.1200/JCO.18.01207.
    1. Lombardi G., De Salvo G.L., Brandes A.A., Eoli M., Ruda R., Faedi M., Lolli I., Pace A., Daniele B., Pasqualetti F., et al. Regorafenib compared with lomustine in patients with relapsed glioblastoma (REGOMA): A multicentre, open-label, randomised, controlled, phase 2 trial. Lancet Oncol. 2019;20:110–119. doi: 10.1016/S1470-2045(18)30675-2.
    1. Lieberman F.S., Wang M., Robins H.I., Tsien C.I., Curran W.J., Jr., Werner-Wasik M., Smith R.P., Schultz C., Hartford A.C., Zhang P., et al. Phase 2 Study of Radiation Therapy Plus Low-Dose Temozolomide Followed by Temozolomide and Irinotecan for Glioblastoma: NRG Oncology RTOG Trial 0420. Int. J. Radiat. Oncol. Biol. Phys. 2019;103:878–886. doi: 10.1016/j.ijrobp.2018.11.008.
    1. Krauze A.V., Mackey M., Rowe L., Chang M.G., Holdford D.J., Cooley T., Shih J., Tofilon P.J., Camphausen K. Late toxicity in long-term survivors from a phase 2 study of concurrent radiation therapy, temozolomide and valproic acid for newly diagnosed glioblastoma. Neurooncol. Pract. 2018;5:246–250. doi: 10.1093/nop/npy009.
    1. Maraka S., Groves M.D., Mammoser A.G., Melguizo-Gavilanes I., Conrad C.A., Tremont-Lukats I.W., Loghin M.E., O’Brien B.J., Puduvalli V.K., Sulman E.P., et al. Phase 1 lead-in to a phase 2 factorial study of temozolomide plus memantine, mefloquine, and metformin as postradiation adjuvant therapy for newly diagnosed glioblastoma. Cancer. 2019;125:424–433. doi: 10.1002/cncr.31811.
    1. Brandes A.A., Gil-Gil M., Saran F., Carpentier A.F., Nowak A.K., Mason W., Zagonel V., Dubois F., Finocchiaro G., Fountzilas G., et al. A Randomized Phase II Trial (TAMIGA) Evaluating the Efficacy and Safety of Continuous Bevacizumab Through Multiple Lines of Treatment for Recurrent Glioblastoma. Oncologist. 2019;24:521–528. doi: 10.1634/theoncologist.2018-0290.
    1. Bota D.A., Chung J., Dandekar M., Carrillo J.A., Kong X.T., Fu B.D., Hsu F.P., Schonthal A.H., Hofman F.M., Chen T.C., et al. Phase II study of ERC1671 plus bevacizumab versus bevacizumab plus placebo in recurrent glioblastoma: Interim results and correlations with CD4(+) T-lymphocyte counts. CNS Oncol. 2018;7:CNS22. doi: 10.2217/cns-2018-0009.
    1. Taylor J.W., Parikh M., Phillips J.J., James C.D., Molinaro A.M., Butowski N.A., Clarke J.L., Oberheim-Bush N.A., Chang S.M., Berger M.S., et al. Phase-2 trial of palbociclib in adult patients with recurrent RB1-positive glioblastoma. J. Neurooncol. 2018;140:477–483. doi: 10.1007/s11060-018-2977-3.
    1. Blakeley J.O., Grossman S.A., Chi A.S., Mikkelsen T., Rosenfeld M.R., Ahluwalia M.S., Nabors L.B., Eichler A., Ribas I.G., Desideri S., et al. Phase II Study of Iniparib with Concurrent Chemoradiation in Patients with Newly Diagnosed Glioblastoma. Clin. Cancer Res. 2019;25:73–79. doi: 10.1158/1078-0432.CCR-18-0110.
    1. Lassman A.B., van den Bent M.J., Gan H.K., Reardon D.A., Kumthekar P., Butowski N., Lwin Z., Mikkelsen T., Nabors L.B., Papadopoulos K.P., et al. Safety and efficacy of depatuxizumab mafodotin + temozolomide in patients with EGFR-amplified, recurrent glioblastoma: Results from an international phase I multicenter trial. Neuro Oncol. 2019;21:106–114. doi: 10.1093/neuonc/noy091.
    1. Marinelli A., Lamberti G., Cerbone L., Cordua N., Buonerba C., Peluso G., Di Lorenzo G., De Placido S. High-dose fotemustine in temozolomide-pretreated glioblastoma multiforme patients: A phase I/II trial. Medicine (Baltimore) 2018;97:e11254. doi: 10.1097/MD.0000000000011254.
    1. Sanai N., Li J., Boerner J., Stark K., Wu J., Kim S., Derogatis A., Mehta S., Dhruv H.D., Heilbrun L.K., et al. Phase 0 Trial of AZD1775 in First-Recurrence Glioblastoma Patients. Clin. Cancer Res. 2018;24:3820–3828. doi: 10.1158/1078-0432.CCR-17-3348.
    1. Kong X.T., Nguyen N.T., Choi Y.J., Zhang G., Nguyen H.N., Filka E., Green S., Yong W.H., Liau L.M., Green R.M., et al. Phase 2 Study of Bortezomib Combined With Temozolomide and Regional Radiation Therapy for Upfront Treatment of Patients With Newly Diagnosed Glioblastoma Multiforme: Safety and Efficacy Assessment. Int. J. Radiat. Oncol. Biol. Phys. 2018;100:1195–1203. doi: 10.1016/j.ijrobp.2018.01.001.
    1. Omuro A., Beal K., McNeill K., Young R.J., Thomas A., Lin X., Terziev R., Kaley T.J., DeAngelis L.M., Daras M., et al. Multicenter Phase IB Trial of Carboxyamidotriazole Orotate and Temozolomide for Recurrent and Newly Diagnosed Glioblastoma and Other Anaplastic Gliomas. J. Clin. Oncol. 2018;36:1702–1709. doi: 10.1200/JCO.2017.76.9992.
    1. Wirsching H.G., Tabatabai G., Roelcke U., Hottinger A.F., Jorger F., Schmid A., Plasswilm L., Schrimpf D., Mancao C., Capper D., et al. Bevacizumab plus hypofractionated radiotherapy versus radiotherapy alone in elderly patients with glioblastoma: The randomized, open-label, phase II ARTE trial. Ann. Oncol. 2018;29:1423–1430. doi: 10.1093/annonc/mdy120.
    1. Wakabayashi T., Natsume A., Mizusawa J., Katayama H., Fukuda H., Sumi M., Nishikawa R., Narita Y., Muragaki Y., Maruyama T., et al. JCOG0911 INTEGRA study: A randomized screening phase II trial of interferonbeta plus temozolomide in comparison with temozolomide alone for newly diagnosed glioblastoma. J. Neurooncol. 2018;138:627–636. doi: 10.1007/s11060-018-2831-7.
    1. Reyes-Botero G., Cartalat-Carel S., Chinot O.L., Barrie M., Taillandier L., Beauchesne P., Catry-Thomas I., Barriere J., Guillamo J.S., Fabbro M., et al. Temozolomide Plus Bevacizumab in Elderly Patients with Newly Diagnosed Glioblastoma and Poor Performance Status: An ANOCEF Phase II Trial (ATAG) Oncologist. 2018;23:524–e544. doi: 10.1634/theoncologist.2017-0689.
    1. Schiff D., Jaeckle K.A., Anderson S.K., Galanis E., Giannini C., Buckner J.C., Stella P., Flynn P.J., Erickson B.J., Schwerkoske J.F., et al. Phase 1/2 trial of temsirolimus and sorafenib in the treatment of patients with recurrent glioblastoma: North Central Cancer Treatment Group Study/Alliance N0572. Cancer. 2018;124:1455–1463. doi: 10.1002/cncr.31219.
    1. Reardon D.A., Lassman A.B., Schiff D., Yunus S.A., Gerstner E.R., Cloughesy T.F., Lee E.Q., Gaffey S.C., Barrs J., Bruno J., et al. Phase 2 and biomarker study of trebananib, an angiopoietin-blocking peptibody, with and without bevacizumab for patients with recurrent glioblastoma. Cancer. 2018;124:1438–1448. doi: 10.1002/cncr.31172.
    1. Peters K.B., Lipp E.S., Miller E., Herndon J.E., 2nd, McSherry F., Desjardins A., Reardon D.A., Friedman H.S. Phase I/II trial of vorinostat, bevacizumab, and daily temozolomide for recurrent malignant gliomas. J. Neurooncol. 2018;137:349–356. doi: 10.1007/s11060-017-2724-1.
    1. Ghiaseddin A., Reardon D., Massey W., Mannerino A., Lipp E.S., Herndon J.E., 2nd, McSherry F., Desjardins A., Randazzo D., Friedman H.S., et al. Phase II Study of Bevacizumab and Vorinostat for Patients with Recurrent World Health Organization Grade 4 Malignant Glioma. Oncologist. 2018;23:157–e121. doi: 10.1634/theoncologist.2017-0501.
    1. Chinnaiyan P., Won M., Wen P.Y., Rojiani A.M., Werner-Wasik M., Shih H.A., Ashby L.S., Michael Yu H.H., Stieber V.W., Malone S.C., et al. A randomized phase II study of everolimus in combination with chemoradiation in newly diagnosed glioblastoma: Results of NRG Oncology RTOG 0913. Neuro Oncol. 2018;20:666–673. doi: 10.1093/neuonc/nox209.
    1. Aiken R., Axelson M., Harmenberg J., Klockare M., Larsson O., Wassberg C. Phase I clinical trial of AXL1717 for treatment of relapsed malignant astrocytomas: Analysis of dose and response. Oncotarget. 2017;8:81501–81510. doi: 10.18632/oncotarget.20662.
    1. Arrillaga-Romany I., Chi A.S., Allen J.E., Oster W., Wen P.Y., Batchelor T.T. A phase 2 study of the first imipridone ONC201, a selective DRD2 antagonist for oncology, administered every three weeks in recurrent glioblastoma. Oncotarget. 2017;8:79298–79304. doi: 10.18632/oncotarget.17837.
    1. Omuro A., Vlahovic G., Lim M., Sahebjam S., Baehring J., Cloughesy T., Voloschin A., Ramkissoon S.H., Ligon K.L., Latek R., et al. Nivolumab with or without ipilimumab in patients with recurrent glioblastoma: Results from exploratory phase I cohorts of CheckMate 143. Neuro Oncol. 2018;20:674–686. doi: 10.1093/neuonc/nox208.
    1. Cloughesy T.F., Drappatz J., de Groot J., Prados M.D., Reardon D.A., Schiff D., Chamberlain M., Mikkelsen T., Desjardins A., Ping J., et al. Phase II study of cabozantinib in patients with progressive glioblastoma: Subset analysis of patients with prior antiangiogenic therapy. Neuro Oncol. 2018;20:259–267. doi: 10.1093/neuonc/nox151.
    1. Wen P.Y., Drappatz J., de Groot J., Prados M.D., Reardon D.A., Schiff D., Chamberlain M., Mikkelsen T., Desjardins A., Holland J., et al. Phase II study of cabozantinib in patients with progressive glioblastoma: Subset analysis of patients naive to antiangiogenic therapy. Neuro Oncol. 2018;20:249–258. doi: 10.1093/neuonc/nox154.
    1. Galanis E., Anderson S.K., Miller C.R., Sarkaria J.N., Jaeckle K., Buckner J.C., Ligon K.L., Ballman K.V., Moore D.F., Jr., Nebozhyn M., et al. Phase I/II trial of vorinostat combined with temozolomide and radiation therapy for newly diagnosed glioblastoma: Results of Alliance N0874/ABTC 02. Neuro Oncol. 2018;20:546–556. doi: 10.1093/neuonc/nox161.
    1. Nghiemphu P.L., Ebiana V.A., Wen P., Gilbert M., Abrey L.E., Lieberman F., DeAngelis L.M., Robins H.I., Yung W.K.A., Chang S., et al. Phase I study of sorafenib and tipifarnib for recurrent glioblastoma: NABTC 05-02. J. Neurooncol. 2018;136:79–86. doi: 10.1007/s11060-017-2624-4.
    1. Duerinck J., Du Four S., Bouttens F., Andre C., Verschaeve V., Van Fraeyenhove F., Chaskis C., D’Haene N., Le Mercier M., Rogiers A., et al. Randomized phase II trial comparing axitinib with the combination of axitinib and lomustine in patients with recurrent glioblastoma. J. Neurooncol. 2018;136:115–125. doi: 10.1007/s11060-017-2629-z.
    1. Weller M., Butowski N., Tran D.D., Recht L.D., Lim M., Hirte H., Ashby L., Mechtler L., Goldlust S.A., Iwamoto F., 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;18:1373–1385. doi: 10.1016/S1470-2045(17)30517-X.
    1. Badruddoja M.A., Pazzi M., Sanan A., Schroeder K., Kuzma K., Norton T., Scully T., Mahadevan D., Ahmadi M.M. Phase II study of bi-weekly temozolomide plus bevacizumab for adult patients with recurrent glioblastoma. Cancer Chemother. Pharmacol. 2017;80:715–721. doi: 10.1007/s00280-017-3405-7.
    1. Fariselli L., Cuppini L., Gaviani P., Marchetti M., Pinzi V., Milanesi I., Simonetti G., Tramacere I., DiMeco F., Salmaggi A., et al. Short course radiotherapy concomitant with temozolomide in GBM patients: A phase II study. Tumori. 2017;103:457–463. doi: 10.5301/tj.5000672.
    1. Yu A., Faiq N., Green S., Lai A., Green R., Hu J., Cloughesy T.F., Mellinghoff I., Nghiemphu P.L. Report of safety of pulse dosing of lapatinib with temozolomide and radiation therapy for newly-diagnosed glioblastoma in a pilot phase II study. J. Neurooncol. 2017;134:357–362. doi: 10.1007/s11060-017-2533-6.
    1. Sepulveda-Sanchez J.M., Vaz M.A., Balana C., Gil-Gil M., Reynes G., Gallego O., Martinez-Garcia M., Vicente E., Quindos M., Luque R., et al. Phase II trial of dacomitinib, a pan-human EGFR tyrosine kinase inhibitor, in recurrent glioblastoma patients with EGFR amplification. Neuro Oncol. 2017;19:1522–1531. doi: 10.1093/neuonc/nox105.
    1. Ahmed N., Brawley V., Hegde M., Bielamowicz K., Kalra M., Landi D., Robertson C., Gray T.L., Diouf O., Wakefield A., et al. 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. doi: 10.1001/jamaoncol.2017.0184.
    1. Clarke J.L., Molinaro A.M., Cabrera J.R., DeSilva A.A., Rabbitt J.E., Prey J., Drummond D.C., Kim J., Noble C., Fitzgerald J.B., et al. A phase 1 trial of intravenous liposomal irinotecan in patients with recurrent high-grade glioma. Cancer Chemother. Pharmacol. 2017;79:603–610. doi: 10.1007/s00280-017-3247-3.
    1. Ursu R., Carpentier A., Metellus P., Lubrano V., Laigle-Donadey F., Capelle L., Guyotat J., Langlois O., Bauchet L., Desseaux K., et al. Intracerebral injection of CpG oligonucleotide for patients with de novo glioblastoma-A phase II multicentric, randomised study. Eur. J. Cancer. 2017;73:30–37. doi: 10.1016/j.ejca.2016.12.003.
    1. Nayak L., de Groot J., Wefel J.S., Cloughesy T.F., Lieberman F., Chang S.M., Omuro A., Drappatz J., Batchelor T.T., DeAngelis L.M., et al. Phase I trial of aflibercept (VEGF trap) with radiation therapy and concomitant and adjuvant temozolomide in patients with high-grade gliomas. J. Neurooncol. 2017;132:181–188. doi: 10.1007/s11060-016-2357-9.
    1. Cloughesy T., Finocchiaro G., Belda-Iniesta C., Recht L., Brandes A.A., Pineda E., Mikkelsen T., Chinot O.L., Balana C., Macdonald D.R., et al. Randomized, Double-Blind, Placebo-Controlled, Multicenter Phase II Study of Onartuzumab Plus Bevacizumab Versus Placebo Plus Bevacizumab in Patients With Recurrent Glioblastoma: Efficacy, Safety, and Hepatocyte Growth Factor and O(6)-Methylguanine-DNA Methyltransferase Biomarker Analyses. J. Clin. Oncol. 2017;35:343–351. doi: 10.1200/JCO.2015.64.7685.
    1. Kalpathy-Cramer J., Chandra V., Da X., Ou Y., Emblem K.E., Muzikansky A., Cai X., Douw L., Evans J.G., Dietrich J., et al. Phase II study of tivozanib, an oral VEGFR inhibitor, in patients with recurrent glioblastoma. J. Neurooncol. 2017;131:603–610. doi: 10.1007/s11060-016-2332-5.
    1. Phuphanich S., Raizer J., Chamberlain M., Canelos P., Narwal R., Hong S., Miday R., Nade M., Laubscher K. Phase II study of MEDI-575, an anti-platelet-derived growth factor-alpha antibody, in patients with recurrent glioblastoma. J. Neurooncol. 2017;131:185–191. doi: 10.1007/s11060-016-2287-6.
    1. McCracken D.J., Celano E.C., Voloschin A.D., Read W.L., Olson J.J. Phase I trial of dose-escalating metronomic temozolomide plus bevacizumab and bortezomib for patients with recurrent glioblastoma. J. Neurooncol. 2016;130:193–201. doi: 10.1007/s11060-016-2234-6.
    1. Aoki T., Arakawa Y., Ueba T., Oda M., Nishida N., Akiyama Y., Tsukahara T., Iwasaki K., Mikuni N., Miyamoto S. Phase I/II Study of Temozolomide Plus Nimustine Chemotherapy for Recurrent Malignant Gliomas: Kyoto Neuro-oncology Group. Neurol. Med. Chir. (Tokyo) 2017;57:17–27. doi: 10.2176/nmc.oa.2016-0162.
    1. Batchelor T.T., Gerstner E.R., Ye X., Desideri S., Duda D.G., Peereboom D., Lesser G.J., Chowdhary S., Wen P.Y., Grossman S., et al. Feasibility, phase I, and phase II studies of tandutinib, an oral platelet-derived growth factor receptor-beta tyrosine kinase inhibitor, in patients with recurrent glioblastoma. Neuro Oncol. 2017;19:567–575. doi: 10.1093/neuonc/now185.
    1. Sautter L., Hofheinz R., Tuettenberg J., Grimm M., Vajkoczy P., Groden C., Schmieder K., Hochhaus A., Wenz F., Giordano F.A. Open-Label Phase II Evaluation of Imatinib in Primary Inoperable or Incompletely Resected and Recurrent Glioblastoma. Oncology. 2019;98:1–7. doi: 10.1159/000502483.
    1. Hainsworth J.D., Becker K.P., Mekhail T., Chowdhary S.A., Eakle J.F., Wright D., Langdon R.M., Yost K.J., Padula G.D.A., West-Osterfield K., et al. Phase I/II study of bevacizumab with BKM120, an oral PI3K inhibitor, in patients with refractory solid tumors (phase I) and relapsed/refractory glioblastoma (phase II) J. Neurooncol. 2019;144:303–311. doi: 10.1007/s11060-019-03227-7.
    1. Kaley T.J., Panageas K.S., Mellinghoff I.K., Nolan C., Gavrilovic I.T., DeAngelis L.M., Abrey L.E., Holland E.C., Lassman A.B. Phase II trial of an AKT inhibitor (perifosine) for recurrent glioblastoma. J. Neurooncol. 2019;144:403–407. doi: 10.1007/s11060-019-03243-7.
    1. Sharma M., Schilero C., Peereboom D.M., Hobbs B.P., Elson P., Stevens G.H.J., McCrae K., Nixon A.B., Ahluwalia M.S. Phase II study of Dovitinib in recurrent glioblastoma. J. Neurooncol. 2019;144:359–368. doi: 10.1007/s11060-019-03236-6.
    1. Du X.J., Li X.M., Cai L.B., Sun J.C., Wang S.Y., Wang X.C., Pang X.L., Deng M.L., Chen F.F., Wang Z.Q., et al. Efficacy and safety of nimotuzumab in addition to radiotherapy and temozolomide for cerebral glioblastoma: A phase II multicenter clinical trial. J. Cancer. 2019;10:3214–3223. doi: 10.7150/jca.30123.
    1. Lee E.Q., Muzikansky A., Duda D.G., Gaffey S., Dietrich J., Nayak L., Chukwueke U.N., Beroukhim R., Doherty L., Laub C.K., et al. Phase II trial of ponatinib in patients with bevacizumab-refractory glioblastoma. Cancer Med. 2019;8:5988–5994. doi: 10.1002/cam4.2505.
    1. Weller J., Tzaridis T., Mack F., Steinbach J.P., Schlegel U., Hau P., Krex D., Grauer O., Goldbrunner R., Bahr O., et al. Health-related quality of life and neurocognitive functioning with lomustine-temozolomide versus temozolomide in patients with newly diagnosed, MGMT-methylated glioblastoma (CeTeG/NOA-09): A randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2019;20:1444–1453. doi: 10.1016/S1470-2045(19)30502-9.
    1. Lapointe S., Mason W., MacNeil M., Harlos C., Tsang R., Sederias J., Luchman H.A., Weiss S., Rossiter J.P., Tu D., et al. A phase I study of vistusertib (dual mTORC1/2 inhibitor) in patients with previously treated glioblastoma multiforme: A CCTG study. Investig. New Drugs. 2019 doi: 10.1007/s10637-019-00875-4.
    1. Allen B.G., Bodeker K.L., Smith M.C., Monga V., Sandhu S., Hohl R., Carlisle T., Brown H., Hollenbeck N., Vollstedt S., et al. First-in-Human Phase I Clinical Trial of Pharmacologic Ascorbate Combined with Radiation and Temozolomide for Newly Diagnosed Glioblastoma. Clin. Cancer Res. 2019;25:6590–6597. doi: 10.1158/1078-0432.CCR-19-0594.
    1. Thomas R.P., Nagpal S., Iv M., Soltys S.G., Bertrand S., Pelpola J.S., Ball R., Yang J., Sundaram V., Lavezo J., et al. Macrophage Exclusion after Radiation Therapy (MERT): A First in Human Phase I/II Trial using a CXCR4 Inhibitor in Glioblastoma. Clin. Cancer Res. 2019;25:6948–6957. doi: 10.1158/1078-0432.CCR-19-1421.
    1. Van den Bent M., Eoli M., Sepulveda J.M., Smits M., Walenkamp A., Frenel J.S., Franceschi E., Clement P.M., Chinot O., de Vos F., et al. INTELLANCE 2/EORTC 1410 randomized phase II study of Depatux-M alone and with temozolomide vs temozolomide or lomustine in recurrent EGFRamplified glioblastoma. Neuro Oncol. 2019 doi: 10.1093/neuonc/noz222.
    1. Cloughesy T.F., Brenner A., de Groot J.F., Butowski N.A., Zach L., Campian J.L., Ellingson B.M., Freedman L.S., Cohen Y.C., Lowenton-Spier N., et al. A randomized controlled phase III study of VB-111 combined with bevacizumab vs. bevacizumab monotherapy in patients with recurrent glioblastoma (GLOBE) Neuro Oncol. 2019 doi: 10.1093/neuonc/noz232.
    1. Kamath A.A., Friedman D.D., Akbari S.H.A., Kim A.H., Tao Y., Luo J., Leuthardt E.C. Glioblastoma Treated With Magnetic Resonance Imaging-Guided Laser Interstitial Thermal Therapy: Safety, Efficacy, and Outcomes. Neurosurgery. 2019;84:836–843. doi: 10.1093/neuros/nyy375.
    1. Mahmoudi K., Bouras A., Bozec D., Ivkov R., Hadjipanayis C. Magnetic hyperthermia therapy for the treatment of glioblastoma: A review of the therapy’s history, efficacy and application in humans. Int. J. Hyperth. 2018;34:1316–1328. doi: 10.1080/02656736.2018.1430867.
    1. Leuthardt E.C., Duan C., Kim M.J., Campian J.L., Kim A.H., Miller-Thomas M.M., Shimony J.S., Tran D.D. Hyperthermic Laser Ablation of Recurrent Glioblastoma Leads to Temporary Disruption of the Peritumoral Blood Brain Barrier. PLoS ONE. 2016;11:e0148613. doi: 10.1371/journal.pone.0148613.
    1. Patel P., Patel N.V., Danish S.F. Intracranial MR-guided laser-induced thermal therapy: Single-center experience with the Visualase thermal therapy system. J. Neurosurg. 2016;125:853–860. doi: 10.3171/2015.7.JNS15244.
    1. Thomas J.G., Rao G., Kew Y., Prabhu S.S. Laser interstitial thermal therapy for newly diagnosed and recurrent glioblastoma. Neurosurg. Focus. 2016;41:E12. doi: 10.3171/2016.7.FOCUS16234.
    1. Mohammadi A.M., Hawasli A.H., Rodriguez A., Schroeder J.L., Laxton A.W., Elson P., Tatter S.B., Barnett G.H., Leuthardt E.C. The role of laser interstitial thermal therapy in enhancing progression-free survival of difficult-to-access high-grade gliomas: A multicenter study. Cancer Med. 2014;3:971–979. doi: 10.1002/cam4.266.
    1. Davies A.M., Weinberg U., Palti Y. Tumor treating fields: A new frontier in cancer therapy. Ann. N. Y. Acad. Sci. 2013;1291:86–95. doi: 10.1111/nyas.12112.
    1. Rick J., Chandra A., Aghi M.K. Tumor treating fields: A new approach to glioblastoma therapy. J. Neurooncol. 2018;137:447–453. doi: 10.1007/s11060-018-2768-x.
    1. Optune® Elevate Expectations INSTRUCTIONS FOR USE. [(accessed on 10 March 2020)]; Available online: .
    1. Stupp R., Taillibert S., Kanner A., Read W., Steinberg D., Lhermitte B., Toms S., Idbaih A., Ahluwalia M.S., Fink K., et al. Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma: A Randomized Clinical Trial. JAMA. 2017;318:2306–2316. doi: 10.1001/jama.2017.18718.
    1. Taphoorn M.J.B., Dirven L., Kanner A.A., Lavy-Shahaf G., Weinberg U., Taillibert S., Toms S.A., Honnorat J., Chen T.C., Sroubek J., et al. Influence of Treatment With Tumor-Treating Fields on Health-Related Quality of Life of Patients With Newly Diagnosed Glioblastoma: A Secondary Analysis of a Randomized Clinical Trial. JAMA Oncol. 2018;4:495–504. doi: 10.1001/jamaoncol.2017.5082.
    1. Desjardins A., Vlahovic G., Friedman H.S. Vaccine Therapy, Oncolytic Viruses, and Gliomas. Oncology (Williston Park) 2016;30:211–218.
    1. Tivnan A., Heilinger T., Lavelle E.C., Prehn J.H. Advances in immunotherapy for the treatment of glioblastoma. J. Neurooncol. 2017;131:1–9. doi: 10.1007/s11060-016-2299-2.
    1. Lim M., Xia Y., Bettegowda C., Weller M. Current state of immunotherapy for glioblastoma. Nat. Rev. Clin. Oncol. 2018;15:422–442. doi: 10.1038/s41571-018-0003-5.
    1. Huang J., Liu F., Liu Z., Tang H., Wu H., Gong Q., Chen J. Immune Checkpoint in Glioblastoma: Promising and Challenging. Front. Pharmacol. 2017;8:242. doi: 10.3389/fphar.2017.00242.
    1. 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 Oncol. 2018;20:1429–1438. doi: 10.1093/neuonc/noy032.
    1. Martikainen M., Essand M. Virus-Based Immunotherapy of Glioblastoma. Cancers (Basel) 2019;11:186. doi: 10.3390/cancers11020186.
    1. Srivastava S., Jackson C., Kim T., Choi J., Lim M. A Characterization of Dendritic Cells and Their Role in Immunotherapy in Glioblastoma: From Preclinical Studies to Clinical Trials. Cancers (Basel) 2019;11:537. doi: 10.3390/cancers11040537.
    1. Sayegh E.T., Oh T., Fakurnejad S., Bloch O., Parsa A.T. Vaccine therapies for patients with glioblastoma. J. Neurooncol. 2014;119:531–546. doi: 10.1007/s11060-014-1502-6.
    1. McGranahan T., Therkelsen K.E., Ahmad S., Nagpal S. Current State of Immunotherapy for Treatment of Glioblastoma. Curr. Treat. Options Oncol. 2019;20:24. doi: 10.1007/s11864-019-0619-4.

Source: PubMed

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