{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T21:33:24Z","timestamp":1792100004385,"version":"4.4.0"},"reference-count":126,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T00:00:00Z","timestamp":1766966400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100017638","name":"Ministry of Health of the Russian Federation","doi-asserted-by":"crossref","award":["124021400005\u20133"],"award-info":[{"award-number":["124021400005\u20133"]}],"id":[{"id":"10.13039\/501100017638","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Current Oncology"],"abstract":"<jats:p>Glioblastoma is currently an incurable disease despite the development of a wide variety of therapeutic approaches, from surgical methods to immunotherapy. In current clinical practice, treatment typically involves a combination of existing methods, often comprising three stages: tumor resection, radiotherapy, and chemotherapy. Modern research offers improved chemotherapy strategies, as well as combinations of chemotherapy with immunotherapy. However, the efficacy of these therapies is profoundly influenced by factors such as tumor and peritumoral heterogeneity, alongside complex molecular signaling pathways. Optimizing glioma treatment requires a rigorous mechanistic understanding of individual approaches and their synergistic effects. This review comprehensively details current glioblastoma therapeutic strategies and critically evaluates key reference models for assessing combination therapy efficacy and their inherent limitations. A deeper understanding of these mechanisms and models will refine the investigation of observed therapeutic effects and accelerate the translation of promising in vitro approaches to effective clinical management of malignant gliomas.<\/jats:p>","DOI":"10.3390\/curroncol33010019","type":"journal-article","created":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T14:33:25Z","timestamp":1767191605000},"page":"19","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Combination Cancer Therapy and Reference Models for Assessing Drug Synergy in Glioblastoma"],"prefix":"10.3390","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-2994-4857","authenticated-orcid":false,"given":"Semyon A.","family":"Sinyavskiy","sequence":"first","affiliation":[{"name":"Department of Synthetic Neurotechnologies, Pirogov Russian National Research Medical University, Ministry of Health of the Russian Federation, Moscow 117513, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2434-2465","authenticated-orcid":false,"given":"Nelly S.","family":"Chmelyuk","sequence":"additional","affiliation":[{"name":"Department of Synthetic Neurotechnologies, Pirogov Russian National Research Medical University, Ministry of Health of the Russian Federation, Moscow 117513, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daria Yu.","family":"Travnikova","sequence":"additional","affiliation":[{"name":"Department of Synthetic Neurotechnologies, Pirogov Russian National Research Medical University, Ministry of Health of the Russian Federation, Moscow 117513, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vsevolod V.","family":"Belousov","sequence":"additional","affiliation":[{"name":"Department of Synthetic Neurotechnologies, Pirogov Russian National Research Medical University, Ministry of Health of the Russian Federation, Moscow 117513, Russia"},{"name":"Federal Center of Brain Research and Neurotechnologies, Federal Medical Biological Agency, Moscow 117513, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatiana O.","family":"Abakumova","sequence":"additional","affiliation":[{"name":"Department of Synthetic Neurotechnologies, Pirogov Russian National Research Medical University, Ministry of Health of the Russian Federation, Moscow 117513, Russia"},{"name":"Federal Center of Brain Research and Neurotechnologies, Federal Medical Biological Agency, Moscow 117513, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"n1560","DOI":"10.1136\/bmj.n1560","article-title":"Glioblastoma: Clinical presentation, diagnosis, and management","volume":"374","author":"McKinnon","year":"2021","journal-title":"BMJ"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1007\/s11684-020-0760-2","article-title":"Intratumor heterogeneity, microenvironment, and mechanisms of drug resistance in glioma recurrence and evolution","volume":"15","author":"Bao","year":"2021","journal-title":"Front. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1007\/s11060-016-2171-4","article-title":"Technical principles in glioma surgery and preoperative considerations","volume":"130","author":"Krivosheya","year":"2016","journal-title":"J. Neurooncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1186\/s13014-023-02342-0","article-title":"Advancements of radiotherapy for recurrent head and neck cancer in modern era","volume":"18","author":"Zhang","year":"2023","journal-title":"Radiat. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"179","DOI":"10.2217\/cns.15.2","article-title":"Chemotherapy in glioma","volume":"4","author":"Taal","year":"2015","journal-title":"CNS Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1007\/s10238-025-01631-0","article-title":"Emerging therapeutic strategies in glioblastsoma: Drug repurposing, mechanisms of resistance, precision medicine, and technological innovations","volume":"25","author":"Anwer","year":"2025","journal-title":"Clin. Exp. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1023\/A:1008267312782","article-title":"Malignant glioma: Should chemotherapy be overthrown by experimental treatments?","volume":"9","author":"Sappino","year":"1998","journal-title":"Ann. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1126\/science.1142946","article-title":"Coactivation of Receptor Tyrosine Kinases Affects the Response of Tumor Cells to Targeted Therapies","volume":"318","author":"Stommel","year":"2007","journal-title":"Science"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1038\/nn.4584","article-title":"A TNF\u2013JNK\u2013Axl\u2013ERK signaling axis mediates primary resistance to EGFR inhibition in glioblastoma","volume":"20","author":"Guo","year":"2017","journal-title":"Nat. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Yasinjan, F., Xing, Y., Geng, H., Guo, R., Yang, L., Liu, Z., and Wang, H. (2023). Immunotherapy: A promising approach for glioma treatment. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1255611"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1056\/NEJMoa1308573","article-title":"A Randomized Trial of Bevacizumab for Newly Diagnosed Glioblastoma","volume":"370","author":"Gilbert","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Becker, A.P., Sells, B.E., Haque, S.J., and Chakravarti, A. (2021). Tumor Heterogeneity in Glioblastomas: From Light Microscopy to Molecular Pathology. Cancers, 13.","DOI":"10.3390\/cancers13040761"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1016\/j.jconrel.2020.04.028","article-title":"Synergistic drug combinations for a precision medicine approach to interstitial glioblastoma therapy","volume":"323","author":"Murthy","year":"2020","journal-title":"J. Control. Release"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"188616","DOI":"10.1016\/j.bbcan.2021.188616","article-title":"Elucidating the mechanisms of Temozolomide resistance in gliomas and the strategies to overcome the resistance","volume":"1876","author":"Tomar","year":"2021","journal-title":"Biochim. Biophys. Acta BBA Rev. Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1056\/NEJMoa043330","article-title":"Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma","volume":"352","author":"Stupp","year":"2005","journal-title":"N. Engl. J. Med. NEJM\/MMS"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3994","DOI":"10.3390\/curroncol31070296","article-title":"Temozolomide (TMZ) in the Treatment of Glioblastoma Multiforme\u2014A Literature Review and Clinical Outcomes","volume":"31","author":"Nafalska","year":"2024","journal-title":"Curr. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1093\/neuonc\/noab003","article-title":"PARP-mediated PARylation of MGMT is critical to promote repair of temozolomide-induced O6-methylguanine DNA damage in glioblastoma","volume":"23","author":"Wu","year":"2021","journal-title":"Neuro Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1724","DOI":"10.1007\/s13311-022-01238-3","article-title":"Targeting IDH-Mutant Glioma","volume":"19","author":"Miller","year":"2022","journal-title":"Neurotherapeutics"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1016\/S1470-2045(21)00090-5","article-title":"Adjuvant and concurrent temozolomide for 1p\/19q non-co-deleted anaplastic glioma (CATNON.; EORTC study 26053-22054): Second interim analysis of a randomised, open-label, phase 3 study","volume":"22","author":"Bent","year":"2021","journal-title":"Lancet Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Smerdi, D., Moutafi, M., Kotsantis, I., Stavrinou, L.C., and Psyrri, A. (2024). Overcoming Resistance to Temozolomide in Glioblastoma: A Scoping Review of Preclinical and Clinical Data. Life, 14.","DOI":"10.3390\/life14060673"},{"key":"ref_21","first-page":"113","article-title":"Practical recommendations for drug treatment of primary tumors of the central nervous system. Malignant tumors: Practical recommendations","volume":"12","author":"Kobyakov","year":"2022","journal-title":"Malig. Tumours"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1200\/JCO.21.02036","article-title":"Therapy for Diffuse Astrocytic and Oligodendroglial Tumors in Adults: ASCO-SNO Guideline","volume":"40","author":"Mohile","year":"2022","journal-title":"J. Clin. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2402","DOI":"10.1200\/JCO.2017.73.0119","article-title":"Adult Glioblastoma","volume":"35","author":"Alexander","year":"2017","journal-title":"J. Clin. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1007\/s11060-020-03601-w","article-title":"Congress of neurological surgeons systematic review and evidence-based guidelines update on the role of chemotherapeutic management and antiangiogenic treatment of newly diagnosed glioblastoma in adults","volume":"150","author":"Redjal","year":"2020","journal-title":"J. Neurooncol."},{"key":"ref_25","unstructured":"(2025, December 16). Central Nervous System Cancers\u2014Guidelines Detail. Available online: https:\/\/www.nccn.org\/guidelines\/guidelines-detail?category=1&id=1425."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1398","DOI":"10.1002\/1097-0142(197505)35:5<1398::AID-CNCR2820350524>3.0.CO;2-C","article-title":"Phase II study of procarbazine, CCNU, and vincristine combination chemotherapy in the treatment of malignant brain tumors","volume":"35","author":"Gutin","year":"1975","journal-title":"Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.bbcan.2017.01.004","article-title":"Chloroethylating nitrosoureas in cancer therapy: DNA damage, repair and cell death signaling","volume":"1868","author":"Nikolova","year":"2017","journal-title":"Biochim. Biophys. Acta BBA Rev. Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.dnarep.2019.04.007","article-title":"DNA repair in personalized brain cancer therapy with temozolomide and nitrosoureas","volume":"78","author":"Kaina","year":"2019","journal-title":"DNA Repair"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"121395","DOI":"10.1016\/j.ijpharm.2021.121395","article-title":"Comparison of three synthetic transferrin mimetic small peptides to promote the blood\u2013brain barrier penetration of vincristine liposomes for improved glioma targeted therapy","volume":"613","author":"Farshbaf","year":"2022","journal-title":"Int. J. Pharm."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1007\/BF02897227","article-title":"Brain uptake and anticancer activities of vincristine and vinblastine are restricted by their low cerebrovascular permeability and binding to plasma constituents in rat","volume":"26","author":"Greig","year":"1990","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1016\/j.mam.2012.02.003","article-title":"The disturbed blood\u2013brain barrier in human glioblastoma","volume":"33","author":"Wolburg","year":"2012","journal-title":"Mol. Asp. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1054\/bjoc.2000.1316","article-title":"A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse","volume":"83","author":"Yung","year":"2000","journal-title":"Br. J. Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4412","DOI":"10.1200\/JCO.2006.06.9104","article-title":"Phase II Trial of Lomustine Plus Temozolomide Chemotherapy in Addition to Radiotherapy in Newly Diagnosed Glioblastoma: UKT-03","volume":"24","author":"Herrlinger","year":"2006","journal-title":"J. Clin. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4601","DOI":"10.1200\/JCO.2009.27.1932","article-title":"Temozolomide Versus Procarbazine, Lomustine, and Vincristine in Recurrent High-Grade Glioma","volume":"28","author":"Brada","year":"2010","journal-title":"J. Clin. Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1568","DOI":"10.1093\/neuonc\/noaa149","article-title":"Phase 0 and window of opportunity clinical trial design in neuro-oncology: A RANO review","volume":"22","author":"Krivosheya","year":"2020","journal-title":"Neuro Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5819","DOI":"10.1038\/onc.2016.85","article-title":"A comprehensive profile of recurrent glioblastoma","volume":"35","author":"Campos","year":"2016","journal-title":"Oncogene"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1007\/s11060-022-04053-0","article-title":"Comparison of tumor immune environment between newly diagnosed and recurrent glioblastoma including matched patients","volume":"159","author":"Wang","year":"2022","journal-title":"J. Neurooncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1007\/s10157-024-02490-x","article-title":"An integrated view of cisplatin-induced nephrotoxicity, hepatotoxicity, and cardiotoxicity: Characteristics, common molecular mechanisms, and current clinical management","volume":"28","author":"Oliveira","year":"2024","journal-title":"Clin. Exp. Nephrol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"303","DOI":"10.2147\/JEP.S267383","article-title":"Advances in Our Understanding of the Molecular Mechanisms of Action of Cisplatin in Cancer Therapy","volume":"13","author":"Tchounwou","year":"2021","journal-title":"J. Exp. Pharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"van den Boogaard, W.M.C., Komninos, D.S.J., and Vermeij, W.P. (2022). Chemotherapy Side-Effects: Not All DNA Damage Is Equal. Cancers, 14.","DOI":"10.3390\/cancers14030627"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/j.ejphar.2014.07.025","article-title":"Cisplatin in cancer therapy: Molecular mechanisms of action","volume":"740","author":"Dasari","year":"2014","journal-title":"Eur. J. Pharmacol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1016\/S0022-3565(24)39120-7","article-title":"Attenuation of O(6)-methylguanine-DNA methyltransferase activity and mRNA levels by cisplatin and temozolomide in jurkat cells","volume":"294","author":"Graziani","year":"2000","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_43","first-page":"1629","article-title":"A Phase I and pharmacokinetic study of temozolomide and cisplatin in patients with advanced solid malignancies","volume":"5","author":"Britten","year":"1999","journal-title":"Clin. Cancer Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1023\/A:1008382516636","article-title":"Multicenter phase II trial of temozolomide in patients with glioblastoma multiforme at first relapse","volume":"12","author":"Brada","year":"2001","journal-title":"Ann. Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1159\/000012158","article-title":"Temozolomide in Patients with High Grade Gliomas","volume":"59","author":"Brandes","year":"2000","journal-title":"Oncology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.1200\/JCO.2004.11.019","article-title":"First-Line Chemotherapy with Cisplatin Plus Fractionated Temozolomide in Recurrent Glioblastoma Multiforme: A Phase II Study of the Gruppo Italiano Cooperativo di Neuro-Oncologia","volume":"22","author":"Brandes","year":"2004","journal-title":"J. Clin. Oncol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"9543","DOI":"10.1200\/jco.2007.25.18_suppl.9543","article-title":"Phase II study of the combination of cisplatin + temozolomide in malignant glial tumours in children and adolescents at diagnosis or in relapse (cistem2\/nct00147160)","volume":"25","author":"Grill","year":"2007","journal-title":"J. Clin. Oncol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1038\/nrd1381","article-title":"Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer","volume":"3","author":"Ferrara","year":"2004","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/s12943-019-0950-1","article-title":"Bevacizumab treatment for radiation brain necrosis: Mechanism, efficacy and issues","volume":"18","author":"Zhuang","year":"2019","journal-title":"Mol. Cancer"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1038\/s41571-021-00529-6","article-title":"The blood\u2013tumour barrier in cancer biology and therapy","volume":"18","author":"Steeg","year":"2021","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"371","DOI":"10.4161\/cc.6.3.3835","article-title":"Induction of ATM Activation, Histone H2AX Phosphorylation and Apoptosis by Etoposide: Relation to Cell Cycle Phase","volume":"6","author":"Tanaka","year":"2007","journal-title":"Cell Cycle"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1007\/s10495-009-0440-9","article-title":"Cellular responses to etoposide: Cell death despite cell cycle arrest and repair of DNA damage","volume":"15","author":"Schonn","year":"2010","journal-title":"Apoptosis"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.canlet.2006.11.005","article-title":"Cellular response to etoposide treatment","volume":"252","author":"Montecucco","year":"2007","journal-title":"Cancer Lett."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"12234","DOI":"10.3748\/wjg.v21.i43.12234","article-title":"Irinotecan, a key chemotherapeutic drug for metastatic colorectal cancer","volume":"21","author":"Fujita","year":"2015","journal-title":"World J. Gastroenterol."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Donnini, S., Filippelli, A., Ciccone, V., Spini, A., Ristori, E., Ziche, M., and Morbidelli, L. (2022). Antiangiogenic drugs: Chemosensitizers for combination cancer therapy. Antiangiogenic Drugs as Chemosensitizers in Cancer Therapy, Elsevier.","DOI":"10.1016\/B978-0-323-90190-1.00008-1"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"14325","DOI":"10.1073\/pnas.1518808112","article-title":"Role of vascular density and normalization in response to neoadjuvant bevacizumab and chemotherapy in breast cancer patients","volume":"112","author":"Tolaney","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1589841","DOI":"10.3389\/fbioe.2025.1589841","article-title":"Bevacizumab in ovarian cancer therapy: Current advances, clinical challenges, and emerging strategies","volume":"13","author":"Zhang","year":"2025","journal-title":"Front. Bioeng. Biotechnol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1038\/s41698-023-00359-y","article-title":"Integrated molecular and clinical analysis of BRAF-mutant glioma in adults","volume":"7","author":"Schreck","year":"2023","journal-title":"NPJ Precis. Oncol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1007\/s40265-018-0884-8","article-title":"BRAF and MEK Inhibitors: Use and Resistance in BRAF-Mutated Cancers","volume":"78","author":"Sanchez","year":"2018","journal-title":"Drugs"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1038\/s43018-025-00962-x","article-title":"A population-based analysis of the molecular landscape of glioma in adolescents and young adults reveals insights into gliomagenesis","volume":"6","author":"Bennett","year":"2025","journal-title":"Nat. Cancer"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1038\/nature10662","article-title":"RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E)","volume":"480","author":"Poulikakos","year":"2011","journal-title":"Nature"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"4023","DOI":"10.1200\/JCO.2015.63.2471","article-title":"Combined BRAF and MEK Inhibition with Dabrafenib and Trametinib in BRAF V600\u2013Mutant Colorectal Cancer","volume":"33","author":"Corcoran","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1158\/1078-0432.CCR-14-2339","article-title":"The BRAF and MEK Inhibitors Dabrafenib and Trametinib: Effects on Immune Function and in Combination with Immunomodulatory Antibodies Targeting PD-1, PD-L1, and CTLA-4","volume":"21","author":"Liu","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"3697","DOI":"10.1200\/JCO.2014.57.3535","article-title":"Combined BRAF (Dabrafenib) and MEK Inhibition (Trametinib) in Patients with BRAF V600 -Mutant Melanoma Experiencing Progression With Single-Agent BRAF Inhibitor","volume":"32","author":"Johnson","year":"2014","journal-title":"J. Clin. Oncol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1158\/2159-8290.CD-17-1226","article-title":"Combined BRAF, EGFR, and MEK Inhibition in Patients with BRAF V600E-Mutant Colorectal Cancer","volume":"8","author":"Corcoran","year":"2018","journal-title":"Cancer Discov."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1186\/1479-5876-10-85","article-title":"The role of BRAF V600 mutation in melanoma","volume":"10","author":"Ascierto","year":"2012","journal-title":"J. Transl. Med."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1038\/s41586-020-2760-4","article-title":"Structural basis for the action of the drug trametinib at KSR-bound MEK","volume":"588","author":"Khan","year":"2020","journal-title":"Nature"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.phrs.2016.12.009","article-title":"Allosteric MEK1\/2 inhibitors including cobimetanib and trametinib in the treatment of cutaneous melanomas","volume":"117","author":"Roskoski","year":"2017","journal-title":"Pharmacol. Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"38022","DOI":"10.18632\/oncotarget.16723","article-title":"Combination therapy in combating cancer","volume":"8","author":"Mokhtari","year":"2017","journal-title":"Oncotarget"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1038\/nrc3309","article-title":"The ERBB network: At last, cancer therapy meets systems biology","volume":"12","author":"Yarden","year":"2012","journal-title":"Nat. Rev. Cancer"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s12943-022-01513-z","article-title":"Glioma targeted therapy: Insight into future of molecular approaches","volume":"21","author":"Yang","year":"2022","journal-title":"Mol. Cancer"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1158\/0008-5472.CAN-14-2004","article-title":"A Urokinase Receptor\u2013Bim Signaling Axis Emerges during EGFR Inhibitor Resistance in Mutant EGFR Glioblastoma","volume":"75","author":"Wykosky","year":"2015","journal-title":"Cancer Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1158\/2159-8290.CD-12-0502","article-title":"De-Repression of PDGFR\u03b2 Transcription Promotes Acquired Resistance to EGFR Tyrosine Kinase Inhibitors in Glioblastoma Patients","volume":"3","author":"Akhavan","year":"2013","journal-title":"Cancer Discov."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1126\/science.1241328","article-title":"Targeted Therapy Resistance Mediated by Dynamic Regulation of Extrachromosomal Mutant EGFR DNA","volume":"343","author":"Nathanson","year":"2014","journal-title":"Science"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s12943-018-0796-y","article-title":"Function of the c-Met receptor tyrosine kinase in carcinogenesis and associated therapeutic opportunities","volume":"17","author":"Zhang","year":"2018","journal-title":"Mol. Cancer"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1186\/s13046-019-1264-2","article-title":"Afatinib and Temozolomide combination inhibits tumorigenesis by targeting EGFRvIII-cMet signaling in glioblastoma cells","volume":"38","author":"Vengoji","year":"2019","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1016\/j.tibs.2014.08.010","article-title":"Feedback and redundancy in receptor tyrosine kinase signaling: Relevance to cancer therapies","volume":"39","author":"Sun","year":"2014","journal-title":"Trends Biochem. Sci."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.1093\/neuonc\/noz127","article-title":"Efficacy of EGFR plus TNF inhibition in a preclinical model of temozolomide-resistant glioblastoma","volume":"21","author":"Guo","year":"2019","journal-title":"Neuro Oncol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1158\/0008-5472.CAN-09-1751","article-title":"AZD8055 Is a Potent, Selective, and Orally Bioavailable ATP-Competitive Mammalian Target of Rapamycin Kinase Inhibitor with In vitro and In vivo Antitumor Activity","volume":"70","author":"Chresta","year":"2010","journal-title":"Cancer Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"5756","DOI":"10.1158\/1078-0432.CCR-13-3389","article-title":"Dual mTORC1\/2 Blockade Inhibits Glioblastoma Brain Tumor Initiating Cells In vitro and In vivo and Synergizes with Temozolomide to Increase Orthotopic Xenograft Survival","volume":"20","author":"Luchman","year":"2014","journal-title":"Clin. Cancer Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"2715","DOI":"10.3892\/or.2015.4232","article-title":"Interferon-\u03b1\/\u03b2 enhances temozolomide activity against MGMT-positive glioma stem-like cells","volume":"34","author":"Shen","year":"2015","journal-title":"Oncol Rep."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"e2253285","DOI":"10.1001\/jamanetworkopen.2022.53285","article-title":"Adjuvant Temozolomide Chemotherapy With or Without Interferon Alfa Among Patients with Newly Diagnosed High-grade Gliomas: A Randomized Clinical Trial","volume":"6","author":"Guo","year":"2023","journal-title":"JAMA Netw. Open"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Iskusnykh, I.Y., Zakharova, A.A., and Pathak, D. (2022). Glutathione in Brain Disorders and Aging. Molecules, 27.","DOI":"10.3390\/molecules27010324"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"6102","DOI":"10.1046\/j.1432-1327.2000.01701.x","article-title":"Physiological functions of thioredoxin and thioredoxin reductase","volume":"267","author":"Holmgren","year":"2000","journal-title":"Eur. J. Biochem."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Szeliga, M., and Rola, R. (2022). Menadione Potentiates Auranofin-Induced Glioblastoma Cell Death. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232415712"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1248\/cpb.c18-00767","article-title":"Potential Anticancer Activity of Auranofin","volume":"67","author":"Onodera","year":"2019","journal-title":"Chem. Pharm. Bull."},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Chmelyuk, N., Kordyukova, M., Sorokina, M., Sinyavskiy, S., Meshcheryakova, V., Belousov, V., and Abakumova, T. (2025). Inhibition of Thioredoxin-Reductase by Auranofin as a Pro-Oxidant Anticancer Strategy for Glioblastoma: In vitro and In vivo Studies. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26052084"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1186\/s13148-025-01900-5","article-title":"A novel approach to enhance glioblastoma multiforme treatment efficacy: Non-coding RNA targeted therapy and adjuvant approaches","volume":"17","author":"Liu","year":"2025","journal-title":"Clin. Epigenetics"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1226","DOI":"10.1093\/neuonc\/noaa074","article-title":"5-Azacitidine in patients with IDH1\/2-mutant recurrent glioma","volume":"22","author":"Federici","year":"2020","journal-title":"Neuro Oncol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"2086","DOI":"10.1016\/j.immuni.2023.07.015","article-title":"CTLA-4 blockade induces a microglia-Th1 cell partnership that stimulates microglia phagocytosis and anti-tumor function in glioblastoma","volume":"56","author":"Chen","year":"2023","journal-title":"Immunity"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1007\/s11899-023-00687-7","article-title":"CAR-T Cell Therapy: The Efficacy and Toxicity Balance","volume":"18","author":"Chohan","year":"2023","journal-title":"Curr. Hematol. Malig. Rep."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"2001","DOI":"10.1093\/neuonc\/noad108","article-title":"Chimeric antigen receptor T cell-based targeting of CD317 as a novel immunotherapeutic strategy against glioblastoma","volume":"25","author":"Peipp","year":"2023","journal-title":"Neuro Oncol."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Ma, K., and Hu, P. (2023). Chimeric Antigen Receptor T-Cell Therapy for Glioblastoma. Cancers, 15.","DOI":"10.3390\/cancers15235652"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1007\/s12672-023-00769-1","article-title":"Clinical advances in oncolytic virus therapy for malignant glioma: A systematic review","volume":"14","author":"Jiang","year":"2023","journal-title":"Discov. Oncol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/s41467-023-44576-2","article-title":"Overcoming therapeutic resistance in oncolytic herpes virotherapy by targeting IGF2BP3-induced NETosis in malignant glioma","volume":"15","author":"Dai","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"108518","DOI":"10.1016\/j.pharmthera.2023.108518","article-title":"Anticancer drug delivery by focused ultrasound-mediated blood-brain\/tumor barrier disruption for glioma therapy: From benchside to bedside","volume":"250","author":"Truillet","year":"2023","journal-title":"Pharmacol. Ther."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"E10281","DOI":"10.1073\/pnas.1713328114","article-title":"Closed-loop control of targeted ultrasound drug delivery across the blood\u2013brain\/tumor barriers in a rat glioma model","volume":"114","author":"Sun","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"\u0106wikli\u0144ska, A., Przewodowska, D., Koziorowski, D., and Szlufik, S. (2024). Innovative Approaches to Brain Cancer: The Use of Magnetic Resonance-guided Focused Ultrasound in Glioma Therapy. Cancers, 16.","DOI":"10.3390\/cancers16244235"},{"key":"ref_99","first-page":"133","article-title":"Drug delivery and nanoparticles: Applications and hazards","volume":"3","author":"Borm","year":"2008","journal-title":"Int. J. Nanomed."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"2563","DOI":"10.2147\/IJN.S243223","article-title":"Nanoparticle Drug Delivery System for Glioma and Its Efficacy Improvement Strategies: A Comprehensive Review","volume":"15","author":"Li","year":"2020","journal-title":"Int. J. Nanomed."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"2938","DOI":"10.1158\/1078-0432.CCR-21-4053","article-title":"Ultrasmall Nanoparticle Delivery of Doxorubicin Improves Therapeutic Index for High-Grade Glioma","volume":"28","author":"Aditya","year":"2022","journal-title":"Clin. Cancer Res."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1007\/s40259-022-00549-3","article-title":"Therapeutic siRNA: State-of-the-Art and Future Perspectives","volume":"36","author":"Friedrich","year":"2022","journal-title":"BioDrugs"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1021\/acsami.2c17802","article-title":"Iron Oxide Nanoparticles Decorated with Functional Peptides for a Targeted siRNA Delivery to Glioma Cells","volume":"15","author":"Chung","year":"2023","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"2637","DOI":"10.2147\/IJN.S189871","article-title":"Targeting EZH2 for glioma therapy with a novel nanoparticle\u2013siRNA complex","volume":"14","author":"Wang","year":"2019","journal-title":"Int. J. Nanomed."},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Tang, J., Wennerberg, K., and Aittokallio, T. (2015). What is synergy? The Saariselk\u00e4 agreement revisited. Front. Pharmacol., 6.","DOI":"10.3389\/fphar.2015.00181"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"104381","DOI":"10.1016\/j.drudis.2025.104381","article-title":"Synergism or mirage: Current progress and an empirical approach for elucidating combination drug effects","volume":"30","author":"Tuszynski","year":"2025","journal-title":"Drug Discov. Today"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"100110","DOI":"10.1016\/j.crphar.2022.100110","article-title":"Evaluation of synergism in drug combinations and reference models for future orientations in oncology","volume":"3","author":"Duarte","year":"2022","journal-title":"Curr. Res. Pharmacol. Drug Discov."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1038\/nn.2886","article-title":"Erroneous analyses of interactions in neuroscience: A problem of significance","volume":"14","author":"Nieuwenhuis","year":"2011","journal-title":"Nat. Neurosci."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1038\/s41467-023-36630-w","article-title":"Dietary restriction of cysteine and methionine sensitizes gliomas to ferroptosis and induces alterations in energetic metabolism","volume":"14","author":"Upadhyayula","year":"2023","journal-title":"Nat. Commun. Nat. Res."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1038\/msb4100116","article-title":"Chemical combination effects predict connectivity in biological systems","volume":"3","author":"Zimmermann","year":"2007","journal-title":"Mol. Syst. Biol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1158\/1535-7163.MCT-20-0319","article-title":"Dianhydrogalactitol Overcomes Multiple Temozolomide Resistance Mechanisms in Glioblastoma","volume":"20","author":"Nogales","year":"2021","journal-title":"Mol. Cancer Ther."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1006\/jmcc.1998.0655","article-title":"The Statistics of Synergism","volume":"30","author":"Slinker","year":"1998","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"101365","DOI":"10.1016\/j.isci.2020.101365","article-title":"Rapid Processing and Drug Evaluation in Glioblastoma Patient-Derived Organoid Models with 4D Bioprinted Arrays","volume":"23","author":"Chadwick","year":"2020","journal-title":"iScience"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1124\/jpet.104.067264","article-title":"Isobolographic Analysis for Combinations of a Full and Partial Agonist: Curved Isoboles","volume":"310","author":"Grabovsky","year":"2004","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/0022-5193(76)90169-7","article-title":"Derivation and properties of Michaelis-Menten type and Hill type equations for reference ligands","volume":"59","author":"Chou","year":"1976","journal-title":"J. Theor. Biol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1158\/0008-5472.CAN-09-1947","article-title":"Drug combination studies and their synergy quantification using the chou-talalay method","volume":"70","author":"Chou","year":"2010","journal-title":"Cancer Res."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"312","DOI":"10.3892\/ijo.2021.5177","article-title":"APR-246 combined with 3-deazaneplanocin A, panobinostat or temozolomide reduces clonogenicity and induces apoptosis in glioblastoma cells","volume":"58","author":"Urdiciain","year":"2021","journal-title":"Int. J. Oncol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1016\/j.csbj.2015.09.001","article-title":"Searching for Drug Synergy in Complex Dose-Response Landscapes Using an Interaction Potency Model","volume":"13","author":"Yadav","year":"2015","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"2286","DOI":"10.1016\/j.drudis.2019.09.002","article-title":"Applying synergy metrics to combination screening data: Agreements, disagreements and pitfalls","volume":"24","author":"Vlot","year":"2019","journal-title":"Drug Discov. Today"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"3974","DOI":"10.1210\/en.2013-1420","article-title":"Synergy: A Concept in Search of a Definition","volume":"154","author":"Berthoud","year":"2013","journal-title":"Endocrinology"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"2161","DOI":"10.1093\/annonc\/mdr608","article-title":"How valid are claims for synergy in published clinical studies?","volume":"23","author":"Ocana","year":"2012","journal-title":"Ann. Oncol."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"e00149","DOI":"10.1002\/prp2.149","article-title":"Analysis of drug combinations: Current methodological landscape","volume":"3","author":"Foucquier","year":"2015","journal-title":"Pharmacol. Res. Perspect."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1097\/ALN.0b013e318242a4a7","article-title":"All Models Are Wrong","volume":"116","author":"Shafer","year":"2012","journal-title":"Anesthesiology"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1038\/s41420-024-02085-1","article-title":"The combination of temozolomide and perifosine synergistically inhibit glioblastoma by impeding DNA repair and inducing apoptosis","volume":"10","author":"Zhao","year":"2024","journal-title":"Cell Death Discov."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"e1505","DOI":"10.1038\/cddis.2014.465","article-title":"Glutathione depletion sensitizes cisplatin- and temozolomide-resistant glioma cells in vitro and in vivo","volume":"5","author":"Rocha","year":"2014","journal-title":"Cell Death Dis."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"3759","DOI":"10.1038\/s41598-024-53684-y","article-title":"The Temozolomide\u2013Doxorubicin paradox in Glioblastoma in vitro\u2013in silico preclinical drug-screening","volume":"14","author":"Oraiopoulou","year":"2024","journal-title":"Sci. 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