CC BY 4.0 · Glob Med Genet 2023; 10(02): 042-047
DOI: 10.1055/s-0043-57028
Review Article

Role of Molecular Targeted Therapeutic Drugs in Treatment of Glioblastoma: A Review Article

Himanshu Singh
1   Department of Oral and Maxillofacial Pathology and Oral Microbiology, Index Institute of Dental Sciences, Indore, Madhya Pradesh, India
› Author Affiliations

Abstract

Glioblastoma is remarkably periodic primary brain tumor, characterizing an eminently heterogeneous pattern of neoplasms that are utmost destructive and threatening cancers.

An enhanced and upgraded knowledge of the various molecular pathways that cause malignant changes in glioblastoma has resulted in advancement of numerous biomarkers and the interpretation of various agents that pointedly target tumor cells and microenvironment. In this review, literature or information on various targeted therapy for glioblastoma is discussed. English language articles were scrutinized in plentiful directory or databases like PubMed, ScienceDirect, Web of Sciences, Google Scholar, and Scopus. The important keywords used for searching databases are “Glioblastoma,” “Targeted therapy in glioblastoma,” “Therapeutic drugs in glioblastoma,” and “Molecular targets in glioblastoma.”



Publication History

Article published online:
17 April 2023

© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 Ostrom QT, Gittleman H, Liao P. et al. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007-2011. Neuro-oncol 2014; 16 Suppl 4 (Suppl. 04) iv1-iv63
  • 2 Stupp R, Mason WP, van den Bent MJ. et al; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups, National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005; 352 (10) 987-996
  • 3 Rønning PA, Helseth E, Meling TR, Johannesen TB. A population-based study on the effect of temozolomide in the treatment of glioblastoma multiforme. Neuro-oncol 2012; 14 (09) 1178-1184
  • 4 Stupp R, Taillibert S, Kanner AA. et al. Maintenance therapy with tumor-treating fields plus temozolomide vs temozolomide alone for glioblastoma: a randomized clinical trial. JAMA 2015; 314 (23) 2535-2543
  • 5 Louis DN, Perry A, Reifenberger G. et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol 2016; 131 (06) 803-820
  • 6 Snuderl M, Fazlollahi L, Le LP. et al. Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma. Cancer Cell 2011; 20 (06) 810-817
  • 7 Sottoriva A, Spiteri I, Piccirillo SG. et al. Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics. Proc Natl Acad Sci U S A 2013; 110 (10) 4009-4014
  • 8 Johnson BE, Mazor T, Hong C. et al. Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma. Science 2014; 343 (6167): 189-193
  • 9 Kim H, Zheng S, Amini SS. et al. Whole-genome and multisector exome sequencing of primary and post-treatment glioblastoma reveals patterns of tumor evolution. Genome Res 2015; 25 (03) 316-327
  • 10 Kim J, Lee IH, Cho HJ. et al. Spatiotemporal evolution of the primary glioblastoma genome. Cancer Cell 2015; 28 (03) 318-328
  • 11 Verhaak RGW, Hoadley KA, Purdom E. et al; Cancer Genome Atlas Research Network. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 2010; 17 (01) 98-110
  • 12 Hubbard SR. Structural analysis of receptor tyrosine kinases. Prog Biophys Mol Biol 1999; 71 (3-4): 343-358
  • 13 Montor WR, Salas AROSE, Melo FHM. Receptor tyrosine kinases and downstream pathways as druggable targets for cancer treatment: the current arsenal of inhibitors. Mol Cancer 2018; 17 (01) 55
  • 14 Blume-Jensen P, Hunter T. Oncogenic kinase signalling. Nature 2001; 411 (6835): 355-365
  • 15 Brennan CW, Verhaak RGW, McKenna A. et al; TCGA Research Network. The somatic genomic landscape of glioblastoma. Cell 2013; 155 (02) 462-477
  • 16 Chakravarti A, Chakladar A, Delaney MA, Latham DE, Loeffler JS. The epidermal growth factor receptor pathway mediates resistance to sequential administration of radiation and chemotherapy in primary human glioblastoma cells in a RAS-dependent manner. Cancer Res 2002; 62 (15) 4307-4315
  • 17 Mazzoleni S, Politi LS, Pala M. et al. Epidermal growth factor receptor expression identifies functionally and molecularly distinct tumor-initiating cells in human glioblastoma multiforme and is required for gliomagenesis. Cancer Res 2010; 70 (19) 7500-7513
  • 18 Li L, Dutra A, Pak E. et al. EGFRvIII expression and PTEN loss synergistically induce chromosomal instability and glial tumors. Neuro-oncol 2009; 11 (01) 9-21
  • 19 Wen PY, Kesari S. Malignant gliomas in adults. N Engl J Med 2008; 359 (05) 492-507
  • 20 Cruz Da Silva E, Mercier MC, Etienne-Selloum N, Dontenwill M, Choulier L. A systematic review of glioblastoma- targeted therapies in phases II, III, IV clinical trials. Cancers (Basel) 2021; 13 (08) 1795
  • 21 Van Den Bent M, Eoli M, Sepulveda JM. 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 2020; 22 (05) 684-693
  • 22 Solomon MT, Miranda N, Jorrín E. et al. Nimotuzumab in combination with radiotherapy in high grade glioma patients: a single institution experience. Cancer Biol Ther 2014; 15 (05) 504-509
  • 23 Reardon DA, Nabors LB, Mason WP. et al; BI 1200 36 Trial Group and the Canadian Brain Tumour Consortium. Phase I/randomized phase II study of afatinib, an irreversible ErbB family blocker, with or without protracted temozolomide in adults with recurrent glioblastoma. Neuro-oncol 2015; 17 (03) 430-439
  • 24 Plate KH, Breier G, Farrell CL, Risau W. Platelet-derived growth factor receptor-beta is induced during tumor development and upregulated during tumor progression in endothelial cells in human gliomas. Lab Invest 1992; 67 (04) 529-534
  • 25 Camorani S, Esposito CL, Rienzo A. et al. Inhibition of receptor signaling and of glioblastoma-derived tumor growth by a novel PDGFRβ aptamer. Mol Ther 2014; 22 (04) 828-841
  • 26 Cheng F, Guo D. MET in glioma: signaling pathways and targeted therapies. J Exp Clin Cancer Res 2019; 38 (01) 270
  • 27 Xie Q, Bradley R, Kang L. et al. Hepatocyte growth factor (HGF) autocrine activation predicts sensitivity to MET inhibition in glioblastoma. Proc Natl Acad Sci U S A 2012; 109 (02) 570-575
  • 28 Wen PY, Schiff D, Cloughesy TF. et al. A phase II study evaluating the efficacy and safety of AMG 102 (rilotumumab) in patients with recurrent glioblastoma. Neuro-oncol 2011; 13 (04) 437-446
  • 29 Cloughesy T, Finocchiaro G, Belda-Iniesta C. 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 2017; 35 (03) 343-351
  • 30 Wen PY, Drappatz J, de Groot 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 (02) 249-258
  • 31 Cloughesy TF, Drappatz J, de Groot 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 (02) 259-267
  • 32 Hoxhaj G, Manning BD. The PI3K-AKT network at the interface of oncogenic signalling and cancer metabolism. Nat Rev Cancer 2020; 20 (02) 74-88
  • 33 Zhao H-F, Wang J, Shao W. et al. Recent advances in the use of PI3K inhibitors for glioblastoma multiforme: current preclinical and clinical development. Mol Cancer 2017; 16 (01) 100
  • 34 Wen PY, Touat M, Alexander BM. 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 (09) 741-750
  • 35 Rosenthal M, Clement PM, Campone M. et al. Buparlisib plus carboplatin or lomustine in patients with recurrent glioblastoma: a phase Ib/II, open-label, multicentre, randomised study. ESMO Open 2020; 5 (04) e000672
  • 36 Singh D, Chan JM, Zoppoli P. et al. Transforming fusions of FGFR and TACC genes in human glioblastoma. Science 2012; 337 (6099): 1231-1235
  • 37 Di Stefano AL, Fucci A, Frattini V. et al. Detection, characterization, and inhibition of FGFR-TACC Fusions in IDH wild-type glioma. Clin Cancer Res 2015; 21 (14) 3307-3317
  • 38 Sharma M, Schilero C, Peereboom DM. et al. Phase II study of dovitinib in recurrent glioblastoma. J Neurooncol 2019; 144 (02) 359-368
  • 39 Planchard D, Besse B, Groen HJM. et al. Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Lancet Oncol 2016; 17 (07) 984-993
  • 40 Brose MS, Cabanillas ME, Cohen EEW. et al. Vemurafenib in patients with BRAF(V600E)-positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: a non-randomised, multicentre, open-label, phase 2 trial. Lancet Oncol 2016; 17 (09) 1272-1282
  • 41 Subbiah V, Kreitman RJ, Wainberg ZA. et al. Dabrafenib and trametinib treatment in patients with locally advanced or metastatic BRAF V600-mutant anaplastic thyroid cancer. J Clin Oncol 2018; 36 (01) 7-13
  • 42 Robert C, Grob JJ, Stroyakovskiy D. et al. Five-year outcomes with dabrafenib plus trametinib in metastatic melanoma. N Engl J Med 2019; 381 (07) 626-636
  • 43 Woo HY, Na K, Yoo J. et al. Glioblastomas harboring gene fusions detected by next-generation sequencing. Brain Tumor Pathol 2020; 37 (04) 136-144
  • 44 Ferguson SD, Zhou S, Huse JT. et al. Targetable gene fusions associate with the IDH wild-type astrocytic lineage in adult gliomas. J Neuropathol Exp Neurol 2018; 77 (06) 437-442
  • 45 Alharbi M, Mobark NA, Balbaid AAO. et al. Regression of ETV6-NTRK3 infantile glioblastoma after first-line treatment with larotrectinib. JCO Precis Oncol 2020; 4: PO.20.00017
  • 46 Ku DT-L, Shing MM-K, Chan GC-F. et al. HGG-48. ROS1 inhibitor entrectinib use in relapse/ refractory infantile glioblastoma with positive ROS1 fusion - a case report with promising response. Neuro-oncol 2020; 22 (Supplement_3): iii352-iii352
  • 47 Taylor JW, Parikh M, Phillips JJ. et al. Phase-2 trial of palbociclib in adult patients with recurrent RB1-positive glioblastoma. J Neurooncol 2018; 140 (02) 477-483
  • 48 Miller TW, Traphagen NA, Li J. et al. Tumor pharmacokinetics and pharmacodynamics of the CDK4/6 inhibitor ribociclib in patients with recurrent glioblastoma. J Neurooncol 2019; 144 (03) 563-572
  • 49 Tien AC, Li J, Bao X. et al. A phase 0 trial of ribociclib in recurrent glioblastoma patients incorporating a tumor pharmacodynamic- and pharmacokinetic-guided expansion cohort. Clin Cancer Res 2019; 25 (19) 5777-5786
  • 50 Goldberg AL. Protein degradation and protection against misfolded or damaged proteins. Nature 2003; 426 (6968): 895-899
  • 51 Narayanan S, Cai C-Y, Assaraf YG. et al. Targeting the ubiquitin-proteasome pathway to overcome anti-cancer drug resistance. Drug Resist Updat 2020; 48: 100663
  • 52 Friday BB, Anderson SK, Buckner J. et al. Phase II trial of vorinostat in combination with bortezomib in recurrent glioblastoma: a north central cancer treatment group study. Neuro-oncol 2012; 14 (02) 215-221
  • 53 Kong XT, Nguyen NT, Choi YJ. 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 (05) 1195-1203
  • 54 Huang J, Campian JL, Gujar AD. et al. 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 (01) 105-111
  • 55 Szabo E, Schneider H, Seystahl K. et al. Autocrine VEGFR1 and VEGFR2 signaling promotes survival in human glioblastoma models in vitro and in vivo. Neuro-oncol 2016; 18 (09) 1242-1252
  • 56 Ferrara N, Hillan KJ, Novotny W. Bevacizumab (Avastin), a humanized anti-VEGF monoclonal antibody for cancer therapy. Biochem Biophys Res Commun 2005; 333 (02) 328-335
  • 57 Friedman HS, Prados MD, Wen PY. et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 2009; 27 (28) 4733-4740
  • 58 Kreisl TN, Kim L, Moore K. et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 2009; 27 (05) 740-745
  • 59 Raizer JJ, Grimm S, Chamberlain MC. et al. A phase 2 trial of single-agent bevacizumab given in an every-3-week schedule for patients with recurrent high-grade gliomas. Cancer 2010; 116 (22) 5297-5305
  • 60 Gilbert MR, Dignam JJ, Armstrong TS. et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med 2014; 370 (08) 699-708
  • 61 Gilbert MR, Pugh SL, Aldape K. et al. NRG oncology RTOG 0625: a randomized phase II trial of bevacizumab with either irinotecan or dose-dense temozolomide in recurrent glioblastoma. J Neurooncol 2017; 131 (01) 193-199
  • 62 Sathornsumetee S, Desjardins A, Vredenburgh JJ. et al. Phase II trial of bevacizumab and erlotinib in patients with recurrent malignant glioma. Neuro-oncol 2010; 12 (12) 1300-1310
  • 63 Reardon DA, Desjardins A, Vredenburgh JJ. et al. Metronomic chemotherapy with daily, oral etoposide plus bevacizumab for recurrent malignant glioma: a phase II study. Br J Cancer 2009; 101 (12) 1986-1994
  • 64 Batchelor TT, Duda DG, di Tomaso E. et al. Phase II study of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. J Clin Oncol 2010; 28 (17) 2817-2823
  • 65 Batchelor TT, Gerstner ER, Emblem KE. et al. Improved tumor oxygenation and survival in glioblastoma patients who show increased blood perfusion after cediranib and chemoradiation. Proc Natl Acad Sci U S A 2013; 110 (47) 19059-19064
  • 66 Du Four S, Maenhout SK, Benteyn D. et al. Disease progression in recurrent glioblastoma patients treated with the VEGFR inhibitor axitinib is associated with increased regulatory T cell numbers and T cell exhaustion. Cancer Immunol Immunother 2016; 65 (06) 727-740
  • 67 de Groot JF, Piao Y, Tran H. et al. Myeloid biomarkers associated with glioblastoma response to anti-VEGF therapy with aflibercept. Clin Cancer Res 2011; 17 (14) 4872-4881
  • 68 Schnell O, Krebs B, Carlsen J. et al. Imaging of integrin alpha(v)beta(3) expression in patients with malignant glioma by [18F] Galacto-RGD positron emission tomography. Neuro-oncol 2009; 11 (06) 861-870
  • 69 Mikkelsen T, Brodie C, Finniss S. et al. Radiation sensitization of glioblastoma by cilengitide has unanticipated schedule-dependency. Int J Cancer 2009; 124 (11) 2719-2727
  • 70 Blumenthal DT, Yalon M, Vainer GW. et al. Pembrolizumab: first experience with recurrent primary central nervous system (CNS) tumors. J Neurooncol 2016; 129 (03) 453-460
  • 71 Bouffet E, Larouche V, Campbell BB. et al. Immune checkpoint inhibition for hypermutant glioblastoma multiforme resulting from germline biallelic mismatch repair deficiency. J Clin Oncol 2016; 34 (19) 2206-2211
  • 72 Johanns TM, Miller CA, Dorward IG. et al. Immunogenomics of hypermutated glioblastoma: a patient with germline POLE deficiency treated with checkpoint blockade immunotherapy. Cancer Discov 2016; 6 (11) 1230-1236
  • 73 Lukas RV, Rodon J, Becker K. et al. Clinical activity and safety of atezolizumab in patients with recurrent glioblastoma. J Neurooncol 2018; 140 (02) 317-328
  • 74 Reardon DA, Brandes AA, Omuro A. et al. Effect of nivolumab vs bevacizumab in patients with recurrent glioblastoma: the CheckMate 143 phase 3 randomized clinical trial. JAMA Oncol 2020; 6 (07) 1003-1010
  • 75 Workman CJ, Rice DS, Dugger KJ, Kurschner C, Vignali DAA. Phenotypic analysis of the murine CD4-related glycoprotein, CD223 (LAG-3). Eur J Immunol 2002; 32 (08) 2255-2263
  • 76 Triebel F, Jitsukawa S, Baixeras E. et al. LAG-3, a novel lymphocyte activation gene closely related to CD4. J Exp Med 1990; 171 (05) 1393-1405
  • 77 Maruhashi T, Sugiura D, Okazaki I-M, Okazaki T. LAG-3: from molecular functions to clinical applications. J Immunother Cancer 2020; 8 (02) e001014
  • 78 Harris-Bookman S, Mathios D, Martin AM. et al. Expression of LAG-3 and efficacy of combination treatment with anti-LAG-3 and anti-PD-1 monoclonal antibodies in glioblastoma. Int J Cancer 2018; 143 (12) 3201-3208
  • 79 Mair MJ, Kiesel B, Feldmann K. et al. LAG-3 expression in the inflammatory microenvironment of glioma. J Neurooncol 2021; 152 (03) 533-539
  • 80 Azambuja JH, Schuh RS, Michels LR. et al. Nasal administration of cationic nanoemulsions as CD73-siRNA delivery system for glioblastoma treatment: a new therapeutical approach. Mol Neurobiol 2020; 57 (02) 635-649
  • 81 Wang L, Rubinstein R, Lines JL. et al. VISTA, a novel mouse Ig superfamily ligand that negatively regulates T cell responses. J Exp Med 2011; 208 (03) 577-592
  • 82 Huang X, Zhang X, Li E. et al. VISTA: an immune regulatory protein checking tumor and immune cells in cancer immunotherapy. J Hematol Oncol 2020; 13 (01) 83
  • 83 Flies DB, Han X, Higuchi T. et al. Coinhibitory receptor PD-1H preferentially suppresses CD4+ T cell-mediated immunity. J Clin Invest 2014; 124 (05) 1966-1975
  • 84 Ghouzlani A, Rafii S, Karkouri M, Lakhdar A, Badou A. The Promising IgSF11 immune checkpoint is highly expressed in advanced human gliomas and associates to poor prognosis. Front Oncol 2021; 10: 608609
  • 85 Wischhusen J, Jung G, Radovanovic I. et al. Identification of CD70-mediated apoptosis of immune effector cells as a novel immune escape pathway of human glioblastoma. Cancer Res 2002; 62 (09) 2592-2599
  • 86 Jin L, Ge H, Long Y. et al. CD70, a novel target of CAR T-cell therapy for gliomas. Neuro-oncol 2018; 20 (01) 55-65
  • 87 Hu F, Ku M-C, Markovic D. et al. Glioma-associated microglial MMP9 expression is upregulated by TLR2 signaling and sensitive to minocycline. Int J Cancer 2014; 135 (11) 2569-2578
  • 88 Cohen AL, Anker CJ, Salzman K, Jensen RL, Shrleve DC, Colman H. A phase 1 study of repeat radiation, minocycline, and bevacizumab in patients with recurrent glioma (RAMBO). J Clin Oncol 2014; 32 (15) 2066-2066
  • 89 Gabrusiewicz K, Ellert-Miklaszewska A, Lipko M, Sielska M, Frankowska M, Kaminska B. Characteristics of the alternative phenotype of microglia/macrophages and its modulation in experimental gliomas. PLoS One 2011; 6 (08) e23902
  • 90 Jacobs VL, Landry RP, Liu Y, Romero-Sandoval EA, De Leo JA. Propentofylline decreases tumor growth in a rodent model of glioblastoma multiforme by a direct mechanism on microglia. Neuro-oncol 2012; 14 (02) 119-131