Signaling pathways and therapeutic approaches in glioblastoma multiforme (Review)

Darlix A, Zouaoui S, Rigau V, Bessaoud F, Figarella-Branger D, Mathieu-Daudé H, Trétarre B, Bauchet F, Duffau H, Taillandier L and Bauchet L: Epidemiology for primary brain tumors: A nationwide population-based study. J Neurooncol. 131:525–546. 2017. View Article : Google Scholar

Tykocki T and Eltayeb M: Ten-year survival in glioblastoma. A systematic review. J Clin Neurosci. 54:7–13. 2018. View Article : Google Scholar

Faleh TA and Juweid M: Epidemiology and outcome of glioblastoma. Exon Publications. 143–153. 2017.

Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, Hawkins C, Ng HK, Pfister SM, Reifenberger G, et al: The 2021 WHO classification of tumors of the central nervous system: A summary. Neuro Oncol. 23:1231–1251. 2021. View Article : Google Scholar

World Health Organization: Histological classification of tumors of the central nervous system. Lyon, France: IARC; 2016

Zong H, Parada LF and Baker SJ: Cell of origin for malignant gliomas and its implication in therapeutic development. Cold Spring Harb Perspect Biol. 7:a0206102015. View Article : Google Scholar

Pombo Antunes AR, Scheyltjens I, Duerinck J, Neyns B, Movahedi K and Van Ginderachter JA: Understanding the glioblastoma immune microenvironment as basis for the development of new immunotherapeutic strategies. Elife. 9:e521762020. View Article : Google Scholar

Khaddour K, Johanns TM and Ansstas G: The landscape of novel therapeutics and challenges in glioblastoma multiforme: Contemporary state and future directions. Pharmaceuticals (Basel). 13:3892020. View Article : Google Scholar

Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, et al: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 352:987–996. 2005. View Article : Google Scholar

Stupp R, Taillibert S, Kanner A, Read W, Steinberg D, Lhermitte B, Toms S, Idbaih A, Ahluwalia MS, 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. 318:2306–2316. 2017. View Article : Google Scholar

Cloughesy TF, Brenner A, de Groot JF, Butowski NA, Zach L, Campian JL, Ellingson BM, Freedman LS, Cohen YC, 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. 22:705–717. 2020. View Article : Google Scholar

Nabors LB, Portnow J, Ahluwalia M, Baehring J, Brem H, Brem S, Butowski N, Campian JL, Clark SW, Fabiano AJ, et al: Central nervous system cancers, Version 3.2020, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 18:1537–1570. 2020. View Article : Google Scholar

Lombardi G, De Salvo GL, Brandes AA, Eoli M, Rudà 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. 20:110–119. 2019. View Article : Google Scholar

Grothey A, Blay JY, Pavlakis N, Yoshino T and Bruix J: Evolving role of regorafenib for the treatment of advanced cancers. Cancer Treat Rev. 86:1019932020. View Article : Google Scholar

Ostrom QT, Cioffi G, Gittleman H, Patil N, Waite K, Kruchko C and Barnholtz-Sloan JS: CBTRUS statistical report: Primary brain and other central nervous system tumors diagnosed in the United States in 2012-2016. Neuro Oncol. 21(Suppl 5): v1–v100. 2019. View Article : Google Scholar

Levin VA, Leibel SA and Gutin PH: Neoplasms of the central nervous system In: Cancer: Principles and Practice of Oncology. 6th edition. Lippincott Williams and Wilkins; Philadelphia, PA: pp. 2100–2160. 2001

Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, et al: Effects of radiotherapy with concomitant and adjuvant temozolo-mide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 10:459–466. 2009. View Article : Google Scholar

Hanif F, Muzaffar K, Perveen K, Malhi SM and Simjee ShU: Glioblastoma multiforme: A review of its epidemiology and pathogenesis through clinical presentation and treatment. Asian Pac J Cancer Prev. 18:3–9. 2017.

Amirian ES, Ostrom QT, Armstrong GN, Lai RK, Gu X, Jacobs DI, Jalali A, Claus EB, Barnholtz-Sloan JS, Il'yasova D, et al: Aspirin, NSAIDs, and Glioma Risk: Original data from the glioma international Case-Control study and a meta-analysis. Cancer Epidemiol Biomarkers Prev. 28:555–562. 2019.

Scheurer ME, El-Zein R, Thompson PA, Aldape KD, Levin VA, Gilbert MR, Weinberg JS and Bondy ML: Long-term anti-inflam-matory and antihistamine medication use and adult glioma risk. Cancer Epidemiol Biomarkers Prev. 17:1277–1281. 2008. View Article : Google Scholar

Dziurzynski K, Chang SM, Heimberger AB, Kalejta RF, McGregor Dallas SR, Smit M, Soroceanu L and Cobbs CS; HCMV and Gliomas Symposium: Consensus on the role of human cytomegalovirus in glioblastoma. Neuro Oncol. 14:246–255. 2012. View Article : Google Scholar

Söderberg-Nauclér C, Rahbar A and Stragliotto G: Survival in patients with glioblastoma receiving valganciclovir. N Engl J Med. 369:985–986. 2013. View Article : Google Scholar

Bei R, Marzocchella L and Turriziani M: The use of temozolo-mide for the treatment of malignant tumors: Clinical evidence and molecular mechanisms of action. Recent Pat Anticancer Drug Discov. 5:172–187. 2010. View Article : Google Scholar

Lacal PM, D'Atri S, Orlando L, Bonmassar E and Graziani G: In vitro inactivation of human O6-alkylguanine DNA alkyl-transferase by antitumor triazene compounds. J Pharmacol Exp Ther. 279:416–422. 1996.

D'Atri S, Tentori L, Lacal PM, Graziani G, Pagani E, Benincasa E, Zambruno G, Bonmassar E and Jiricny J: Involvement of the mismatch repair system in temozolomide-induced apoptosis. Mol Pharmacol. 54:334–341. 1998. View Article : Google Scholar

Baer JC, Freeman AA, Newlands ES, Watson AJ, Rafferty JA and Margison GP: Depletion of O 6-alkylguanine-DNA alkyltrans-ferase correlates with potentiation of temozolomide and CCNU toxicity in human tumour cells. Br J Cancer. 67:1299–1302. 1993. View Article : Google Scholar

Wu W, Klockow JL, Zhang M, Lafortune F, Chang E, Jin L, Wu Y and Daldrup-Link HE: Glioblastoma Multiforme (GBM): An overview of current therapies and mechanisms of resistance. Pharmacol Res. 17:1057802021. View Article : Google Scholar

Grossmann P, Narayan V, Chang K, Rahman R, Abrey L, Reardon DA, Schwartz LH, Wen PY, Alexander BM, Huang R and Aerts HJWL: Quantitative imaging biomarkers for risk stratification of patients with recurrent glioblastoma treated with bevacizumab. Neuro Oncol. 19:1688–1697. 2017. View Article : Google Scholar

Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, Yung WK, Paleologos N, Nicholas MK, Jensen R, et al: Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 27:4733–4740. 2009. View Article : Google Scholar

Chinot OL, de La Motte Rouge T, Moore N, Zeaiter A, Das A, Phillips H, Modrusan Z and Cloughesy T: AVAglio: Phase 3 trial of bevacizumab plus temozolomide and radiotherapy in newly diagnosed glioblastoma multiforme. Adv Ther. 28:334–340. 2011. View Article : Google Scholar

Gilbert MR, Dignam J, Won M, Blumenthal DT, Vogelbaum MA, AldapeHoward Colman KD, Chakravarti A, Jeraj R, Armstrong TS, Scott Wefel J, et al: RTOG 0825: Phase III double-blind placebo-controlled trial evaluating bevacizumab (Bev) in patients (Pts) with newly diagnosed glioblastoma (GBM). J Clin Oncol. 31:12013. View Article : Google Scholar

Diaz RJ, Ali S, Qadir MG, De La Fuente MI, Ivan ME and Komotar RJ: The role of bevacizumab in the treatment of glio-blastoma. J Neurooncol. 133:455–467. 2017. View Article : Google Scholar

Taal W, Oosterkamp HM, Walenkamp AM, Dubbink HJ, Beerepoot LV, Hanse MC, Buter J, Honkoop AH, Boerman D, de Vos FY, et al: Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): A randomised controlled phase 2 Trial. Lancet Oncol. 15:943–953. 2014. View Article : Google Scholar

Brandsma D and van den Bent MJ: Pseudoprogression and pseu-doresponse in the treatment of gliomas. Curr Opin Neurol. 22:633–638. 2009. View Article : Google Scholar

Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, Degroot J, Wick W, Gilbert MR, Lassman AB, et al: Updated response assessment criteria for high-grade gliomas: Response assessment in Neuro-Oncology working group. J Clin Oncol. 28:1963–1972. 2010. View Article : Google Scholar

Batchelor TT, Mulholland P, Neyns B, Nabors LB, Campone M, Wick A, Mason W, Mikkelsen T, Phuphanich S, Ashby LS, et al: Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma. J Clin Oncol. 31:32122013. View Article : Google Scholar

de Groot JF, Lamborn KR, Chang SM, Gilbert MR, Cloughesy TF, Aldape K, Yao J, Jackson EF, Lieberman F, Robins HI, et al: Phase II study of aflibercept in recurrent malignant glioma: A North American Brain Tumor Consortium study. J Clin Oncol. 29:2689–2995. 2011. View Article : Google Scholar

Stupp R, Taillibert S, Kanner AA, Kesari S, Steinberg DM, Toms SA, Taylor LP, Lieberman F, Silvani A, Fink KL, et al: Maintenance therapy with tumor-treating fields plus temozolomide vs temozolomide alone for glioblastoma: A randomized clinical trial. JAMA. 314:2535–2543. 2015. View Article : Google Scholar

Fabian D, Guillermo Prieto Eibl MDP, Alnahhas I, Sebastian N, Giglio P, Puduvalli V, Gonzalez J and Palmer JD: Treatment of glioblastoma (GBM) with the addition of tumor-treating fields (TTF): A review. Cancers (Basel). 11:1742019. View Article : Google Scholar

Brown TJ, Brennan MC, Li M, Church EW, Brandmeir NJ, Rakszawski KL, Patel AS, Rizk EB, Suki D, Sawaya R and Glantz M: Association of the extent of resection with survival in glioblastoma: A systematic review and meta-analysis. JAMA Oncol. 2:1460–1469. 2016. View Article : Google Scholar

Noorbakhsh A, Tang JA, Marcus LP, McCutcheon B, Gonda DD, Schallhorn CS, Talamini MA, Chang DC, Carter BS and Chen CC: Gross-total resection outcomes in an elderly population with glioblastoma: A SEER-based analysis. J Neurosurg. 120:31–39. 2014. View Article : Google Scholar

Eigenbrod S, Trabold R, Brucker D, Erös C, Egensperger R, La Fougere C, Göbel W, Rühm A, Kretzschmar HA, Tonn JC, et al: Molecular stereotactic biopsy technique improves diagnostic accuracy and enables personalized treatment strategies in glioma patients. Acta Neurochir (Wien). 156:1427–1440. 2014. View Article : Google Scholar

Stummer W, Tonn JC, Mehdorn HM, Nestler U, Franz K, Goetz C, Bink A and Pichlmeier U; ALA-Glioma Study Group: Counterbalancing risks and gains from extended resections in malignant glioma surgery: A supplemental analysis from the randomized 5-aminolevulinic acid glioma resection study. J Neurosurg. 114:613–623. 2011. View Article : Google Scholar

Berntsen EM, Gulati S, Solheim O, Kvistad KA, Torp SH, Selbekk T, Unsgård G and Håberg AK: Functional magnetic resonance imaging and diffusion tensor tractography incorporated into an intraoperative 3-dimensional ultrasound-based neuronavigation system: Impact on therapeutic strategies, extent of resection, and clinical outcome. Neurosurgery. 67:251–264. 2010. View Article : Google Scholar

Ringel F, Pape H, Sabel M, Krex D, Bock HC, Misch M, Weyerbrock A, Westermaier T, Senft C, Schucht P, et al: Clinical benefit from resection of recurrent glioblastomas: Results of a multicenter study including 503 patients with recurrent glioblastomas undergoing surgical resection. Neuro Oncol. 18:96–104. 2016. View Article : Google Scholar

Zuccarini M, Giuliani P, Ziberi S, Carluccio M, Iorio PD, Caciagli F and Ciccarelli R: The role of Wnt signal in glioblastoma development and progression: A possible new pharmacological target for the therapy of this tumor. Genes (Basel). 9:1052018. View Article : Google Scholar

Sigismund S, Avanzato D and Lanzetti L: Emerging functions of the EGFR in cancer. Mol Oncol. 12:3–20. 2018. View Article : Google Scholar

Xiao A, Brenneman B, Floyd D, Comeau L, Spurio K, Olmez I, Lee J, Nakano I, Godlewski J, Bronisz A, et al: Statins affect human glioblastoma and other cancers through TGF-β inhibition. Oncotarget. 10:1716–1728. 2019. View Article : Google Scholar

Keunen O, Johansson M, Oudin A, Sanzey M, Rahim SA, Fack F, Thorsen F, Taxt T, Bartos M, Jirik R, et al: Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma. Proc Natl Acad Sci USA. 108:3749–3754. 2011. View Article : Google Scholar

Cyclin-dependent kinase inhibitor 2A. GeneCards. Weizmann institute of science. Retrieved December 15, 2021.

Albensi BC: What is nuclear factor kappa B (NF-κB) doing in and to the mitochondrion? Front Cell Dev Biol. 7:1542019. View Article : Google Scholar

Xia L, Tan S, Zhou Y, Lin J, Wang H, Oyang L, Tian Y, Liu L, Su M, Wang H, et al: Role of the NFκB-signaling pathway in cancer. Onco Targets Ther. 11:2063–2073. 2018. View Article : Google Scholar

Xia Y, Shen S and Verma IM: NF-κB, an active player in human cancers. Cancer Immunol Res. 2:823–830. 2014. View Article : Google Scholar

Li X, Wu C, Chen N, Gu H, Yen A, Cao L, Wang E and Wang L: PI3K/Akt/mTOR signaling pathway and targeted therapy for glioblastoma. Oncotarget. 7:33440–33450. 2016. View Article : Google Scholar

Markman B, Dienstmann R and Tabernero J: Targeting the PI3K/Akt/mTOR pathway-beyond rapalogs. Oncotarget. 1:5302010. View Article : Google Scholar

Crespo I, Vital AL, Gonzalez-Tablas M, Patino Mdel C, Otero A, Lopes MC, de Oliveira C, Domingues P, Orfao A and Tabernero MD: Molecular and genomic alterations in glioblastoma multiforme. Am J Pathol. 185:1820–1833. 2015. View Article : Google Scholar

Balça-Silva J, Matias D, Carmo AD, Sarmento-Ribeiro AB, Lopes MC and Moura-Neto V: Cellular and molecular mechanisms of glioblastoma malignancy: Implications in resistance and therapeutic strategies. Semin Cancer Biol. 58:130–141. 2019. View Article : Google Scholar

Rajesh Y, Pal I, Banik P, Chakraborty S, Borkar SA, Dey G, Mukherjee A and Mandal M: Insights into molecular therapy of glioma: Current challenges and next generation blueprint. Acta Pharmacol Sin. 38:591–613. 2017. View Article : Google Scholar

Cancer Genome Atlas and Research Network: Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 455:1061–1068. 2008. View Article : Google Scholar

Hegi ME, Genbrugge E, Gorlia T, Stupp R, Gilbert MR, Chinot OL, Nabors LB, Jones G, Van Criekinge W, Straub J and Weller M: MGMT promoter methylation cutoff with safety margin for selecting glioblastoma patients into trials omitting temozolomide: A pooled analysis of four clinical trials. Clin Cancer Res. 25:1809–1816. 2019. View Article : Google Scholar

Chai RC, Zhang KN, Chang YZ, Wu F, Liu YQ, Zhao Z, Wang KY, Chang YH, Jiang T and Wang YZ: Systematically characterize the clinical and biological significances of 1p19q genes in 1p/19q non-codeletion glioma. Carcinogenesis. 40:1229–1239. 2019. View Article : Google Scholar

Wang Y, Li S, Chen L, You G, Bao Z, Yan W, Shi Z, Chen Y, Yao K, Zhang W, et al: Glioblastoma with an oligodendroglioma component: Distinct clinical behavior, genetic alterations, and outcome. Neuro Oncol. 14:518–525. 2012. View Article : Google Scholar

Clark KH, Villano JL, Nikiforova MN, Hamilton RL and Horbinski C: 1p/19q testing has no significance in the workup of glioblastomas. Neuropathol Appl Neurobiol. 39:706–717. 2013. View Article : Google Scholar

Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, Xie M, Zhang Q, McMichael JF, Wyczalkowski MA, et al: Mutational landscape and significance across 12 major cancer types. Nature. 502:333–339. 2013. View Article : Google Scholar

Brosh R and Rotter V: When mutants gain new powers: News from the mutant p53 field. Nat Rev Cancer. 9:701–713. 2009. View Article : Google Scholar

Brennan CW, Verhaak RG, McKenna A, Campos B, Noushmehr H, Salama SR, Zheng S, Chakravarty D, Sanborn JZ, Berman SH, et al: Erratum: The somatic genomic landscape of glioblastoma. Cell. 155:462–477. 2013. View Article : Google Scholar

Liu F, Huang J, Liu X, Cheng Q, Luo C and Liu Z: CTLA-4 correlates with immune and clinical characteristics of glioma. Cancer Cell Int. 20:72020. View Article : Google Scholar

Garofano L, Migliozzi S, Oh YT, D'Angelo F, Najac RD, Ko A, Frangaj B, Caruso FP, Yu K, Yuan J, et al: Pathway-based clas-sification of glioblastoma uncovers a mitochondrial subtype with therapeutic vulnerabilities. Nat Cancer. 2:141–156. 2021. View Article : Google Scholar

Lu VM, O'Connor KP, Shah AH, Eichberg DG, Luther EM, Komotar RJ and Ivan ME: The prognostic significance of CDKN2A homozygous deletion in IDH-mutant lower-grade glioma and glioblastoma: A systematic review of the contemporary literature. J Neurooncol. 148:221–229. 2020. View Article : Google Scholar

William D, Mokri P, Lamp N, Linnebacher M, Classen CF, Erbersdobler A and Schneider B: Amplification of the EGFR gene can be maintained and modulated by variation of EGF concentrations in in vitro models of glioblastoma multiforme. PLoS One. 12:e01852082017. View Article : Google Scholar

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. 23:6846–6855. 2017. View Article : Google Scholar

An Z, Aksoy O, Zheng T, Fan QW and Weiss WA: Epidermal growth factor receptor and EGFRvIII in glioblastoma: Signaling pathways and targeted therapies. Oncogene. 37:1561–1575. 2018. View Article : Google Scholar

Xu H, Zong H, Ma C, Ming X, Shang M, Li K, He X, Du H and Cao L: Epidermal growth factor receptor in glioblastoma. Oncol Lett. 14:512–516. 2017. View Article : Google Scholar

De S, Dermawan JK and Stark GR: EGF receptor uses SOS1 to drive constitutive activation of NFκB in cancer cells. Proc Natl Acad Sci USA. 111:11721–11726. 2014. View Article : Google Scholar

Talasila KM, Soentgerath A, Euskirchen P, Rosland GV, Wang J, Huszthy PC, Prestegarden L, Skaftnesmo KO, Sakariassen PØ, Eskilsson E, et al: EGFR wild-type amplification and activation promote invasion and development of glioblastoma independent of angiogenesis. Acta Neuropathol. 125:683–698. 2013. View Article : Google Scholar

Katanasaka Y, Kodera Y, Kitamura Y, Morimoto T, Tamura T and Koizumi F: Epidermal growth factor receptor variant type III markedly accelerates angiogenesis and tumor growth via inducing c-myc mediated angiopoietin-like 4 expression in malignant glioma. Mol Cancer. 12:312013. View Article : Google Scholar

Sarkaria JN, Yang L, Grogan PT, Kitange GJ, Carlson BL, Schroeder MA, Galanis E, Giannini C, Wu W, Dinca EB and James CD: Identification of molecular characteristics correlated with glioblastoma sensitivity to EGFR kinase inhibition through use of an intracranial xenograft test panel. Mol Cancer Ther. 6:1167–1174. 2007. View Article : Google Scholar

Cetintas VB and Batada NN: Is there a causal link between PTEN deficient tumors and immunosuppressive tumor microenvironment? J Transl Med. 18:452020. View Article : Google Scholar

Raizer JJ, Abrey LE, Lassman AB, Chang SM, Lamborn KR, Kuhn JG, Yung WK, Gilbert MR, Aldape KA, Wen PY, et al: A phase II trial of erlotinib in patients with recurrent malignant gliomas and nonprogressive glioblastoma multiforme postradiation therapy. Neuro Oncol. 12:95–103. 2010. View Article : Google Scholar

Mellinghoff IK, Wang MY, Vivanco I, Haas-Kogan DA, Zhu S, Dia EQ, Lu KV, Yoshimoto K, Huang JH, Chute DJ, et al: Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med. 353:2012–2024. 2005. View Article : Google Scholar

Chakravarti A, Wang M, Robins HI, Lautenschlaeger T, Curran WJ, Brachman DG, Schultz CJ, Choucair A, Dolled-Filhart M, Christiansen J, et al: RTOG 0211: A phase 1/2 study of radiation therapy with concurrent gefitinib for newly diagnosed glioblastoma patients. Int J Radiat Oncol Biol Phy. 85:1206–1211. 2013. View Article : Google Scholar

Uhm JH, Ballman KV, Wu W, Giannini C, Krauss JC, Buckner JC, James CD, Scheithauer BW, Behrens RJ, Flynn PJ, et al: Phase II evaluation of gefitinib in patients with newly diagnosed Grade 4 astrocytoma: Mayo/North central cancer treatment group study N0074. Int J Radiat Oncol Biol Phys. 80:347–353. 2011. View Article : Google Scholar

Inda MM, Bonavia R, Mukasa A, Narita Y, Sah DW, Vandenberg S, Brennan C, Johns TG, Bachoo R, Hadwiger P, et al: Tumor heterogeneity is an active process maintained by a mutant EGFR-induced cytokine circuit in glioblastoma. Genes Dev. 24:1731–1745. 2010. View Article : Google Scholar

Mazzoleni S, Politi LS, Pala M, Cominelli M, Franzin A, Sergi Sergi L, Falini A, De Palma M, Bulfone A, Poliani PL and Galli R: Epidermal growth factor receptor expression identifies functionally and molecularly distinct tumor-initiating cells in human glioblastoma multiforme and is required for gliomagenesis. Cancer Res. 70:7500–7513. 2010. View Article : Google Scholar

Van Den Bent M, Eoli M, Sepulveda JM, Smits M, Walenkamp A, Frenel JS, Franceschi E, Clement PM, 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 EGFR amplified glioblastoma. Neuro Oncol. 22:684–693. 2020. View Article : Google Scholar

Oeckinghaus A and Ghosh S: The NF-kappaB family of transcription factors and its regulation. Cold Spring Harb Perspect Biol. 1:a0000342009. View Article : Google Scholar

Dresselhaus EC and Meffert MK: Cellular specificity of NF-κB function in the nervous system. Front Immunol. 10:10432019. View Article : Google Scholar

Friedmann-Morvinski D, Narasimamurthy R, Xia Y, Myskiw C, Soda Y and Verma IM: Targeting NF-κB in glioblastoma: A therapeutic approach. Sci Adv. 2:e15012922016. View Article : Google Scholar

Wang H, Wang H, Zhang W, Huang HJ, Liao WS and Fuller GN: Analysis of the activation status of Akt, NFkappaB, and Stat3 in human diffuse gliomas. Lab Invest. 84:941–951. 2004. View Article : Google Scholar

Yang W, Xia Y, Cao Y, Zheng Y, Bu W, Zhang L, You MJ, Koh MY, Cote G, Aldape K, et al: EGFR-induced and PKCε monoubiquitylation-dependent NF-κB activation upregulates PKM2 expression and promotes tumorigenesis. Mol Cell. 48:771–784. 2012. View Article : Google Scholar

Yap YS, McPherson JR, Ong CK, Rozen SG, The BT, Lee AS and Callen DF: The NF1 gene revisited-from bench to bedside. Oncotarget. 5:5873–5892. 2014. View Article : Google Scholar

Schäfer C, Göder A, Beyer M, Kiweler N, Mahendrarajah N, Rauch A, Nikolova T, Stojanovic N, Wieczorek M, Reich TR, et al: Class I histone deacetylases regulate p53/NF-κB crosstalk in cancer cells. Cell Signal. 29:218–225. 2018. View Article : Google Scholar

Zanotto-Filho A, Braganhol E, Schröder R, de Souza LH, Dalmolin RJ, Pasquali MA, Gelain DP, Battastini AM and Moreira JC: NFκB inhibitors induce cell death in glioblastomas. Biochem Pharmacol. 81:412–424. 2011. View Article : Google Scholar

Shinoda K, Kuboki S, Shimizu H, Ohtsuka M, Kato A, Yoshitomi H, Furukawa K and Miyazaki M: Pin1 facilitates NF-κ B activation and promotes tumour progression in human hepatocellular carcinoma. Br J Cancer. 113:1323–1331. 2015. View Article : Google Scholar

Medeiros M, Candido MF, Valera ET and Brassesco MS: The multifaceted NF-kB: Are there still prospects of its inhibition for clinical intervention in pediatric central nervous system tumors? Cell Mol Life Sci. 78:6161–6200. 2021. View Article : Google Scholar

Phesse T, Flanagan D and Vincan E: Frizzled7: A promising Achilles' Heel for targeting the Wnt receptor complex to treat cancer. Cancers (Basel). 8:502016. View Article : Google Scholar

Gao J, Liao Y, Qiu M and Shen W: Wnt/β-catenin signaling in neural stem cell homeostasis and neurological diseases. Neuroscientist. 27:58–72. 2021. View Article : Google Scholar

Tang C, Guo J, Chen H, Yao CJ, Zhuang DX, Wang Y, Tang WJ, Ren G, Yao Y, Wu JS, et al: Gene mutation profiling of primary glioblastoma through multiple tumor biopsy guided by 1H-magnetic resonance spectroscopy. Int J Clin Exp Pathol. 8:5327–5335. 2015.

Yun EJ, Kim S, Hsieh JT and Baek ST: Wnt/β-catenin signaling pathway induces autophagy-mediated temozolomide-resistance in human glioblastoma. Cell Death Dis. 11:7712020. View Article : Google Scholar

Tompa M, Kalovits F, Nagy A and Kalman B: Contribution of the Wnt pathway to defining biology of glioblastoma. Neuromolecular Med. 20:437–451. 2018. View Article : Google Scholar

Mori H, Yao Y, Learman BS, Kurozumi K, Ishida J, Ramakrishnan SK, Overmyer KA, Xue X, Cawthorn WP, Reid MA, et al: Induction of WNT11 by hypoxia and hypoxia-inducible factor-1α regulates cell proliferation, migration and invasion. Sci Rep. 6:215202016. View Article : Google Scholar

Rampazzo E, Persano L, Pistollato F, Moro E, Frasson C, Porazzi P, Della Puppa A, Bresolin S, Battilana G, Indraccolo S, et al: Wnt activation promotes neuronal differentiation of glioblastoma. Cell Death Dis. 4:e5002013. View Article : Google Scholar

Liu C, Takada K and Di Z: Targeting Wnt/β-catenin pathway for drug therapy. Med Drug Discovery. 8:1000662020. View Article : Google Scholar

Diamond JR, Becerra C, Richards D, Mita A, Osborne C, O'Shaughnessy J, Zhang C, Henner R, Kapoun AM, Xu L, et al: Phase Ib clinical trial of the anti-frizzled antibody vantictumab (OMP-18R5) plus paclitaxel in patients with locally advanced or metastatic HER2-negative breast cancer. Breast Cancer Res Treat. 184:53–62. 2020. View Article : Google Scholar

Selivanova LS, Volganova KS and Abrosimov AY: Telomerase reverse transcriptase (TERT) promoter mutations in the tumors of human endocrine organs: Biological and prognostic value. Arkh Patol. 78:62–69. 2016.In Russian. View Article : Google Scholar

Pekmezci M, Rice T, Molinaro AM, Walsh KM, Decker PA, Hansen H, Sicotte H, Kollmeyer TM, McCoy LS, Sarkar G, et al: Adult infiltrating gliomas with WHO 2016 integrated diagnosis: Additional prognostic roles of ATRX and TERT. Acta Neuropathol. 133:1001–1016. 2017. View Article : Google Scholar

Bell RJ, Rube HT, Xavier-Magalhães A, Costa BM, Mancini A, Song JS and Costello JF: Understanding TERT promoter mutations: A common path to immortality. Mol Cancer Res. 14:315–323. 2016. View Article : Google Scholar

Huang JJ, Lin MC, Bai YX, Jing DD, Wong BC, Han SW, Lin J, Xu B, Huang CF and Kung HF: Ectopic expression of a COOH-terminal fragment of the human telomerase reverse transcriptase leads to telomere dysfunction and reduction of growth and tumorigenicity in HeLa cells. Cancer Res. 62:3226–3232. 2002.

Ng SS, Gao Y, Chau DH, Li GH, Lai LH, Huang PT, Huang CF, Huang JJ, Chen YC, Kung HF and Lin MC: A novel glioblastoma cancer gene therapy using AAV-mediated long-term expression of human TERT C-terminal polypeptide. Cancer Gene Ther. 14:561–572. 2007. View Article : Google Scholar

Lavanya C, Sibin MK, Srinivas Bharath MM, Manoj MJ, Venkataswamy MM, Bhat DI, Narasinga Rao KV and Chetan GK: RNA interference mediated downregulation of human telomerase reverse transcriptase (hTERT) in LN18 cells. Cytotechnology. 68:2311–2321. 2016. View Article : Google Scholar

Li X, Qian X, Wang B, Xia Y, Zheng Y, Du L, Xu D, Xing D, DePinho RA and Lu Z: Programmable base editing of mutated TERT promoter inhibits brain tumour growth. Nat Cell Biol. 22:282–288. 2020. View Article : Google Scholar

McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Montalto G, Cervello M, Nicoletti F, Fagone P, Malaponte G, Mazzarino MC, et al: Mutations and deregulation of Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades which alter therapy response. Oncotarget. 3:954–987. 2012. View Article : Google Scholar

Zhao HF, Wang J, Shao W, Wu CP, Chen ZP, To ST and Li WP: Recent advances in the use of PI3K inhibitors for glioblastoma multiforme: Current preclinical and clinical development. Mol Cancer. 16:1002017. View Article : Google Scholar

Gymnopoulos M, Elsliger MA and Vogt PK: Rare cancer-specific mutations in PIK3CA show gain of function. Proc Natl Acad Sci USA. 104:5569–5574. 2007. View Article : Google Scholar

Höland K, Boller D, Hagel C, Dolski S, Treszl A, Pardo OE, Cwiek P, Salm F, Leni Z, Shepherd PR, et al: Targeting class IA PI3K isoforms selectively impairs cell growth, survival, and migration in glioblastoma. PLoS One. 9:e941322014. View Article : Google Scholar

Chen H, Mei L, Zhou L, Shen X, Guo C, Zheng Y, Zhu H, Zhu Y and Huang L: PTEN restoration and PIK3CB knockdown synergistically suppress glioblastoma growth in vitro and in xenografts. J Neurooncol. 104:155–167. 2011. View Article : Google Scholar

Huang H, Regan KM, Wang F, Wang D, Smith DI, van Deursen JM and Tindall DJ: Skp2 inhibits FOXO1 in tumor suppression through ubiquitin-mediated degradation. Proc Natl Acad Sci USA. 102:1649–1654. 2005. View Article : Google Scholar

Baretić D and Williams RL: PIKKs-the solenoid nest where partners and kinases meet. Curr Opin Struct Biol. 29:134–142. 2014. View Article : Google Scholar

Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, Tempst P and Sabatini DM: Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol. 14:1296–1302. 2004. View Article : Google Scholar

Cornu M, Albert V and Hall MN: mTOR in aging, metabolism, and cancer. Curr Opin Genet Dev. 23:53–62. 2013. View Article : Google Scholar

Lawlor MA and Alessi DR: PKB/Akt: A key mediator of cell proliferation, survival and insulin responses? J Cell Sci. 114:2903–2910. 2001. View Article : Google Scholar

Gini B, Zanca C, Guo D, Matsutani T, Masui K, Ikegami S, Yang H, Nathanson D, Villa GR, Shackelford D, et al: The mTOR kinase inhibitors, CC214-1 and CC214-2, preferentially block the growth of EGFRvIII-activated glioblastomas. Clin Cancer Res. 19:5722–5732. 2013. View Article : Google Scholar

Masri J, Bernath A, Martin J, Jo OD, Vartanian R, Funk A and Gera J: mTORC2 activity is elevated in gliomas and promotes growth and cell motility via overexpression of rictor. Cancer Res. 67:11712–11720. 2007. View Article : Google Scholar

Agliano A, Balarajah G, Ciobota DM, Sidhu J, Clarke PA, Jones C, Workman P, Leach MO and Al-Saffar NMS: Pediatric and adult glioblastoma radiosensitization induced by PI3K/mTOR inhibition causes early metabolic alterations detected by nuclear magnetic resonance spectroscopy. Oncotarget. 8:47969–47983. 2017. View Article : Google Scholar

Chinnaiyan P, Won M, Wen PY, Rojiani AM, Werner-Wasik M, Shih HA, Ashby LS, Michael Yu HH, Stieber VW, Malone SC, et al: A randomized phase II study of everolimus in combination with chemoradiation in newly diagnosed glioblas-toma: Results of NRG Oncology RTOG 0913. Neuro Oncol. 20:666–673. 2018. View Article : Google Scholar

Reardon DA, Wen PY, Alfred Yung WK, Berk L, Narasimhan N, Turner CD, Clackson T, Rivera VM and Vogelbaum MA: Ridaforolimus for patients with progressive or recurrent malignant glioma: A perisurgical, sequential, ascending-dose trial. Cancer Chemother Pharmacol. 69:849–860. 2012. View Article : Google Scholar

Wick W, Gorlia T, Bady P, Platten M, van den Bent MJ, Taphoorn MJ, Steuve J, Brandes AA, Hamou MF, Wick A, et al: Phase II study of radiotherapy and temsirolimus versus radiochemotherapy with temozolomide in patients with newly diagnosed glioblastoma without MGMT promoter hypermethylation (EORTC 26082). Clin Cancer Res. 22:4797–4806. 2016. View Article : Google Scholar

U.S National Library of Medincine (NIH): NCT Neuro Master Match-N²M² (NOA-20). ClinicalTrials.gov Identifier: NCT03158389. https://clinicaltrials.gov/ct2/show/NCT03158389. Accessed May 18, 2017.

Rodrik-Outmezguine VS, Okaniwa M, Yao Z, Novotny CJ, McWhirter C, Banaji A, Won H, Wong W, Berger M, de Stanchina E, et al: Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor. Nature. 534:272–276. 2016. View Article : Google Scholar

Babak S and Mason WP: mTOR inhibition in glioblastoma: Requiem for a dream? Neuro Oncol. 20:584–585. 2018. View Article : Google Scholar

Zhang Y, Xia M, Jin K, Wang S, Wei H, Fan C, Wu Y, Li X, Li X, Li G, et al: Function of the c-Met receptor tyrosine kinase in carcinogenesis and associated therapeutic opportunities. Mol Cancer. 17:752018. View Article : Google Scholar

Carvalho B, Lopes JM, Silva R, Peixoto J, Leitão D, Soares P, Fernandes AC, Linhares P, Vaz R and Lima J: The role of c-Met and VEGFR2 in glioblastoma resistance to bevacizumab. Sci Rep. 11:60672021. View Article : Google Scholar

McCarty JH: Glioblastoma resistance to anti-VEGF therapy: Has the challenge been MET? Clin Cancer Res. 19:1631–1633. 2013. View Article : Google Scholar

Manneh Kopp RA, Sepúlveda-Sánchez JM, Ruano Y, Toldos O, Pérez Núñez A, Cantero D, Hilario A, Ramos A, de Velasco G, Sánchez-Gómez P and Hernández-Laín A: Correlation of radiological and immunochemical parameters with clinical outcome in patients with recurrent glioblastoma treated with Bevacizumab. Clin Transl Oncol. 21:1413–1423. 2019. View Article : Google Scholar

Merchant M, Ma X, Maun HR, Zheng Z, Peng J, Romero M, Huang A, Yang NY, Nishimura M, Greve J, et al: Monovalent antibody design and mechanism of action of onartuzumab, a MET antagonist with anti-tumor activity as a therapeutic agent. Proc Natl Acad Sci USA. 110:E2987–E2996. 2013. View Article : Google Scholar

Cloughesy T, Finocchiaro G, Belda-Iniesta C, Recht L, Brandes AA, Pineda E, Mikkelsen T, Chinot OL, Balana C, Macdonald DR, 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 O⁶-methylguanine-DNA methyltransferase biomarker analyses. J Clin Oncol. 35:343–351. 2017. View Article : Google Scholar

Garcia MM, Gil MJ, Losada E, Martin Soberón MC, Mesia Barroso C, Foro P, Capellades J, Sarmiento B, Bruna J, Verger E, et al: GEINO 1402: A phase Ib dose-escalation study followed by an extension phase to evaluate safety and efficacy of crizotinib in combination with temozolomide (TMZ) and radiotherapy (RT) in patients with newly diagnosed glioblastoma (GB. Ann Oncol. 30:v1472019. View Article : Google Scholar

Guillemot F and Zimmer C: From cradle to grave: The multiple roles of fibroblast growth factors in neural development. Neuron. 71:574–588. 2011. View Article : Google Scholar

Frinchi M, Bonomo A, Trovato-Salinaro A, Condorelli DF, Fuxe K, Spampinato MG and Mudò G: Fibroblast growth factor-2 and its receptor expression in proliferating precursor cells of the subventricular zone in the adult rat brain. Neurosci Lett. 447:20–25. 2008. View Article : Google Scholar

Dienstmann R, Rodon J, Prat A, Perez-Garcia J, Adamo B, Felip E, Cortes J, Iafrate AJ, Nuciforo P and Tabernero J: Genomic aberrations in the FGFR pathway: Opportunities for targeted therapies in solid tumors. Ann Oncol. 25:552–563. 2014. View Article : Google Scholar

Forbes SA, Beare D, Boutselakis H, Bamford S, Bindal N, Tate J, Cole CG, Ward S, Dawson E, Ponting L, et al: COSMIC: Somatic cancer genetics at high-resolution. Nucleic Acids Res. 45:D777–D783. 2017. View Article : Google Scholar

Hatlen MA, Schmidt-Kittler O, Sherwin CA, Rozsahegyi E, Rubin N, Sheets MP, Kim JL, Miduturu C, Bifulco N, Brooijmans N, et al: Acquired on-target clinical resistance validates FGFR4 as a driver of hepatocellular carcinoma. Cancer Discov. 9:1686–1695. 2019.

Kim RD, Sarker D, Meyer T, Yau T, Macarulla T, Park JW, Choo SP, Hollebecque A, Sung MW, Lim HY, et al: First-in-human phase I study of fisogatinib (BLU-554) validates aberrant FGF19 signaling as a driver event in hepatocellular carcinoma. Cancer Discov. 9:1696–1707. 2019. View Article : Google Scholar

Li W, Sparidans R, El-Lari M, Wang Y, Lebre MC, Beijnen JH and Schinkel AH: P-glycoprotein (ABCB1/MDR1) limits brain accumulation and Cytochrome P450-3A (CYP3A) restricts oral availability of the novel FGFR4 inhibitor fisogatinib (BLU-554). Int J Pharm. 573:1188422020. View Article : Google Scholar

Sootome H, Fujita H, Ito K, Ochiiwa H, Fujioka Y, Ito K, Miura A, Sagara T, Ito S, Ohsawa H, et al: Futibatinib is a novel irreversible FGFR 1-4 inhibitor that shows selective antitumor activity against FGFR-deregulated tumors. Cancer Res. 80:4986–4997. 2020. View Article : Google Scholar

Singh D, Chan JM, Zoppoli P, Niola F, Sullivan R, Castano A, Liu EM, Reichel J, Porrati P, Pellegatta S, et al: Transforming fusions of FGFR and TACC genes in human glioblastoma. Science. 337:1231–1235. 2012. View Article : Google Scholar

Andre F, Ranson M, Dean E, Varga A, van der Noll R, Stockman PK, Ghiorghiu D, Kilgour E, Smith PD, Macpherson M, et al: Abstract LB-145: Results of a phase I study of AZD4547, an inhibitor of fibroblast growth factor receptor (FGFR), in patients with advanced solid tumors. Cancer Res. 73:LB–145. 2013.

Takahashi Y, Akahane T, Sawada T, Ikeda H, Tempaku A, Yamauchi S, Nishihara H, Tanaka S, Nitta K, Ide W, et al: Adult classical glioblastoma with a BRAF V600E mutation. World J Surg Oncol. 13:1002015. View Article : Google Scholar

Tosuner Z, Geçer MÖ, Hatiboğlu MA, Abdallah A and Turna S: BRAF V600E mutation and BRAF VE1 immunoexpression profiles in different types of glioblastoma. Oncol Lett. 16:2402–2408. 2018.

Raabe EH, Lim KS, Kim JM, Meeker A, Mao XG, Nikkhah G, Maciaczyk J, Kahlert U, Jain D, Bar E, et al: BRAF activation induces transformation and then senescence in human neural stem cells: A pilocytic astrocytoma model. Clin Cancer Res. 17:3590–3599. 2011. View Article : Google Scholar

Behling F and Schittenhelm J: Oncogenic BRAF alterations and their role in brain tumors. Cancers (Basel). 11:7942019. View Article : Google Scholar

Cantwell-Dorris ER, O'Leary JJ and Sheils OM: BRAFV600E: Implications for carcinogenesis and molecular therapy. Mol Cancer Ther. 10:385–394. 2011. View Article : Google Scholar

Nakajima N, Nobusawa S, Nakata S, Nakada M, Yamazaki T, Matsumura N, Harada K, Matsuda H, Funata N, Nagai S, et al: BRAF V600E, TERT promoter mutations and CDKN2A/B homozygous deletions are frequent in epithelioid glioblastomas: A histological and molecular analysis focusing on intratumoral heterogeneity. Brain Pathol. 28:663–673. 2018. View Article : Google Scholar

Chapman PB, Robert C, Larkin J, Haanen JB, Ribas A, Hogg D, Hamid O, Ascierto PA, Testori A, Lorigan PC, et al: Vemurafenib in patients with BRAFV600 mutation-positive metastatic melanoma: Final overall survival results of the randomized BRIM-3 study. Ann Oncol. 28:2581–2587. 2017. View Article : Google Scholar

Burger MC, Ronellenfitsch MW, Lorenz NI, Wagner M, Voss M, Capper D, Tzaridis T, Herrlinger U, Steinbach JP, Stoffels G, et al: Dabrafenib in patients with recurrent, BRAF V600E mutated malignant glioma and leptomeningeal disease. Oncol Rep. 38:3291–3296. 2017.

Woo PYM, Lam TC, Pu JKS, Li LF, Leung RCY, Ho JMK, Zhung JTF, Wong B, Chan TSK, Loong HHF and Ng HK: Regression of BRAFV600E mutant adult glioblastoma after primary combined BRAF-MEK inhibitor targeted therapy: A report of two cases. Oncotarget. 10:3818–3826. 2019. View Article : Google Scholar

Schiff D and Sarkaria J: Dasatinib in recurrent glioblastoma: Failure as a teacher. Neuro Oncol. 17:910–911. 2015. View Article : Google Scholar

Dumont RA, Hildebrandt I, Su H, Haubner R, Reischl G, Czernin JG, Mischel PS and Weber WA: Noninvasive imaging of alphaVbeta3 function as a predictor of the antimigratory and anti-proliferative effects of dasatinib. Cancer Res. 69:3173–3179. 2009. View Article : Google Scholar

Galanis E, Anderson SK, Twohy EL, Carrero XW, Dixon JG, Tran DD, Jeyapalan SA, Anderson DM, Kaufmann TJ, Feathers RW, et al: A phase 1 and randomized, placebo-controlled phase 2 trial of bevacizumab plus dasatinib in patients with recurrent glioblastoma: Alliance/North Central Cancer Treatment Group N0872. Cancer. 125:3790–3800. 2019. View Article : Google Scholar

Srivastava S, Jackson C, Kim T, Choi J and Lim M: A characterization of dendritic cells and their role in immunotherapy in glioblastoma: From preclinical studies to clinical trials. Cancers. 11:5372019. View Article : Google Scholar

Wen PY, Reardon DA, Armstrong TS, Phuphanich S, Aiken RD, Landolfi JC, Curry WT, Zhu JJ, Glantz M, Peereboom DM, et al: A randomized double-blind placebo-controlled phase II trial of dendritic cell vaccine ICT-107 in newly diagnosed patients with glioblastoma. Clin Cancer Res. 25:5799–5807. 2019. View Article : Google Scholar

Polson ES, Kuchler VB, Abbosh C, Ross EM, Mathew RK, Beard HA, da Silva B, Holding AN, Ballereau S, Chuntharpursat-Bon E, et al: KHS101 disrupts energy metabolism in human glioblastoma cells and reduces tumor growth in mice. Sci Transl Med. 10:eaar27182018. View Article : Google Scholar

Gruslova A, Cavazos DA, Miller JR, Breitbart E, Cohen YC, Bangio L, Yakov N, Soundararajan A, Floyd JR and Brenner AJ: VB-111: A novel anti-vascular therapeutic for glioblastoma multiforme. J Neurooncol. 124:365–372. 2015. View Article : Google Scholar

Brenner AJ, Peters KB, Vredenburgh J, Bokstein F, Blumenthal DT, Yust-Katz S, Peretz I, Oberman B, Freedman LS, Ellingson BM, et al: Safety and efficacy of VB-111, an anticancer gene therapy, in patients with recurrent glioblastoma: Results of a phase I/II study. Neuro Oncol. 22:694–704. 2020. View Article : Google Scholar

Weller M, Butowski N, Tran DD, Recht LD, Lim M, Hirte H, Ashby L, Mechtler L, Goldlust SA, Iwamoto F, et al: Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): A randomized, double-blind, international phase 3 trial. Lancet Oncol. 18:1373–1385. 2017. View Article : Google Scholar

Reardon DA, Desjardins A, Vredenburgh JJ, O'Rourke DM, Tran DD, Fink KL, Nabors LB, Li G, Bota DA, Lukas RV, 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. 26:1586–1594. 2020. View Article : Google Scholar

Heimberger AB, Archer GE, Crotty LE, McLendon RE, Friedman AH, Friedman HS, Bigner DD and Sampson JH: Dendritic cells pulsed with a tumor-specific peptide induce long-lasting immunity and are effective against murine intrace-rebral melanoma. Neurosurgery. 50:158–166. 2002.

Filley AC, Henriquez M and Dey M: Recurrent glioma clinical trial, CheckMate-143: The game is not over yet. Oncotarget. 8:91779–91794. 2017. View Article : Google Scholar

Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, Harrington K, Kasper S, Vokes EE, Even C, et al: Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 375:1856–1867. 2016. View Article : Google Scholar

Reardon DA, Brandes AA, Omuro A, Mulholland P, Lim M, Wick A, Baehring J, Ahluwalia MS, Roth P, Bähr O, et al: Effect of nivolumab vs bevaci-zumab in patients with recurrent glioblastoma: The CheckMate 143 phase 3 randomized clinical trial. JAMA Oncol. 6:1003–1010. 2020. View Article : Google Scholar

Sampson JH, Padula Omuro AM, Preusser M, Lim M, Butowski NA, Cloughesy TF, Strauss LC, Latek RR, Paliwal P, Weller M and Reardon DA: A randomized, phase 3, open-label study of nivolumab versus temozolomide (TMZ) in combination with radiotherapy (RT) in adult patients (pts) with newly diagnosed, O-6-methylguanine DNA methyltransferase (MGMT)-unmethylated glioblastoma (GBM): CheckMate-498. J Clin Oncol. 34:TPS20792016. View Article : Google Scholar

Reardon DA, Nayak L, Peters KB, Clarke JL, Jordan JT, De Groot JF, Nghiemphu PL, Kaley TJ, Colman H, Gaffey SC, et al: Phase II study of pembrolizumab or pembrolizumab plus bevacizumab for recurrent glioblastoma (rGBM) patients. J Clin Oncol. 36:20062018. View Article : Google Scholar

Schalper KA, Rodriguez-Ruiz ME, Diez-Valle R, López-Janeiro A, Porciuncula A, Idoate MA, Inogés S, de Andrea C, López-Diaz de Cerio A, Tejada S, et al: Neoadjuvant nivolumab modifies the tumor immune microenvironment in resectable glioblastoma. Nat Med. 25:470–476. 2019. View Article : Google Scholar

Cloughesy TF, Mochizuki AY, Orpilla JR, Hugo W, Lee AH, Davidson TB, Wang AC, Ellingson BM, Rytlewski JA, Sanders CM, et al: Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma. Nat Med. 25:477–486. 2019. View Article : Google Scholar

Li R, Pourpak A and Morris SW: Inhibition of the insulin-like growth factor-1 receptor (IGF1R) tyrosine kinase as a novel cancer therapy approach. J Med Chem. 52:4981–5004. 2009. View Article : Google Scholar

Chakravarti A, Loeffler JS and Dyson NJ: Insulin-like growth factor receptor I mediates resistance to anti-epidermal growth factor receptor therapy in primary human glioblastoma cells through continued activation of phosphoinositide 3-kinase signaling. Cancer Res. 62:200–207. 2002.

Zhou X, Shen F, Ma P, Hui H, Pei S, Chen M, Wang Z, Zhou W and Jin B: GSK1838705A, an IGF-1R inhibitor, inhibits glioma cell proliferation and suppresses tumor growth in vivo. Mol Med Rep. 12:5641–5646. 2015. View Article : Google Scholar

Osher E and Macaulay VM: Therapeutic targeting of the IGF axis. Cells. 8:8952019. View Article : Google Scholar

Janes PW, Vail ME, Gan HK and Scott AM: Antibody targeting of eph receptors in cancer. Pharmaceuticals. 13:882020. View Article : Google Scholar

Anderton M, van der Meulen E, Blumenthal MJ and Schäfer G: The role of the Eph receptor family in tumorigenesis. Cancers (Basel). 13:2062021. View Article : Google Scholar

Binda E, Visioli A, Giani F, Lamorte G, Copetti M, Pitter KL, Huse JT, Cajola L, Zanetti N, DiMeco F, et al: The EphA2 receptor drives self-renewal and tumorigenicity in stem-like tumor-propagating cells from human glioblastomas. Cancer Cell. 22:765–780. 2012. View Article : Google Scholar

Wykosky J, Gibo DM, Stanton C and Debinski W: EphA2 as a novel molecular marker and target in glioblastoma multiforme. Mol Cancer Res. 3:541–551. 2005. View Article : Google Scholar

Swords RT, Greenberg PL, Wei AH, Durrant S, Advani AS, Hertzberg MS, Jonas BA, Lewis ID, Rivera G, Gratzinger D, et al: KB004, a first in class monoclonal antibody targeting the receptor tyrosine kinase EphA3, in patients with advanced hematologic malignancies: Results from a phase 1 study. Leuk Res. 50:123–131. 2016. View Article : Google Scholar

Wade M, Li YC and Wahl GM: MDM2, MDMX and p53 in oncogenesis and cancer therapy. Nat Rev Cancer. 13:83–96. 2013. View Article : Google Scholar

Avci NG, Ebrahimzadeh-Pustchi S, Akay YM, Esquenazi Y, Tandon N, Zhu JJ and Akay M: NF-κB inhibitor with Temozolomide results in significant apoptosis in glioblastoma via the NF-κB(p65) and actin cytoskeleton regulatory pathways. Sci Rep. 10:133522020. View Article : Google Scholar

Beck S, Jin X, Sohn YW, Kim JK, Kim SH, Yin J, Pian X, Kim SC, Nam DH, Choi YJ and Kim H: Telomerase activity-independent function of TERT allows glioma cells to attain cancer stem cell characteristics by inducing EGFR expression. Mol Cells. 31:9–15. 2011. View Article : Google Scholar

Olympios N, Gilard V, Marguet F, Clatot F, Di Fiore F and Fontanilles M: TERT promoter alterations in glioblastoma: A systematic review. Cancers (Basel). 13:11472021. View Article : Google Scholar

Metro G, Pierini T and La Starza R: TERT Mutations in Glioma: ESMO Biomarker Factsheet. European Society for Medical Oncology; Lugano: 2019, https://oncologypro.esmo.org/education-library/factsheets-on-biomarkers/tert-mutations-in-glioma. Accessed January 25, 2019.