cancerspЮжно-Российский онкологический журнал/ South Russian Journal of CancerSouth Russian Journal of Cancer2686-9039АНО "Перспективы онкологии"10.37748/2686-9039-2023-4-1-6IICMMCcancersp-192Research ArticleОБЗОРЫREVIEWSСовременные подходы к терапии глиобластомыModern approaches to glioblastoma therapyhttps://orcid.org/0000-0002-2337-326XКузнецоваН. С.KuznetsovaN. S.

 

Кузнецова Наталья Сергеевна – врач-онколог, ФГБУ «НМИЦ онкологии» Минздрава России, г. Ростов-на-Дону, Российская Федерация.

ORCID: https://orcid.org/0000-0002-2337-326X, SPIN: 8553-3081, AuthorID: 920734, ResearcherID: AGG-8960-2020

 

Natalia S. Kuznetsova – MD, oncologist, National Medical Research Centre for Oncology, Rostov-on-Don, Russian Federation.

ORCID: https://orcid.org/0000-0002-2337-326X, SPIN: 8553-3081, AuthorID: 920734, ResearcherID: AGG-8960-2020

https://orcid.org/0000-0002-9747-8515ГуроваС. В.GurovaS. V.

 

Гурова Софья Валерьевна – младший научный сотрудник испытательного лабораторного центра, ФГБУ «НМИЦ онкологии» Минздрава России, г. Ростов-на-Дону, Российская Федерация.

ORCID: https://orcid.org/0000-0002-9747-8515, SPIN: 5413-6901, AuthorID: 1147419

 

Sofya V. Gurova – junior research fellow of the testing laboratory center, National Medical Research Centre for Oncology, Rostov-on-Don, Russian Federation.

ORCID: https://orcid.org/0000-0002-9747-8515, SPIN: 5413-6901, AuthorID: 1147419

gurova.sophie@gmail.comhttps://orcid.org/0000-0003-0676-0871ГончароваA. С.GoncharovaA. S.

 

Гончарова Анна Сергеевна – к.б.н., заведующая испытательным лабораторным центром, ФГБУ «НМИЦ онкологии» Минздрава России, г. Ростов-на-Дону, Российская Федерация.

ORCID: https://orcid.org/0000-0003-0676-0871, SPIN: 7512-2039, AuthorID: 553424, Scopus Author ID: 57215862139

 

Anna S. Goncharova – Cand. Sci. (Biol.), head of the testing laboratory center, National Medical Research Centre for Oncology, Rostov-on-Don, Russian Federation.

ORCID: https://orcid.org/0000-0003-0676-0871, SPIN: 7512-2039, AuthorID: 553424, Scopus Author ID: 57215862139

https://orcid.org/0000-0003-0088-2990ЗаикинаЕ. В.ZaikinaE. V.

 

Заикина Екатерина Владиславовна – младший научный сотрудник испытательного лабораторного центра, ФГБУ «НМИЦ онкологии» Минздрава России, г. Ростов-на-Дону, Российская Федерация.

ORCID: https://orcid.org/0000-0003-0088-2990, SPIN: 4000-4369, AuthorID: 1045258, Scopus Author ID: 57221463270

 

Ekaterina V. Zaikina – junior research fellow of the testing laboratory center, National Medical Research Centre for Oncology, Rostov-on-Don, Russian Federation.

ORCID: https://orcid.org/0000-0003-0088-2990, SPIN: 4000-4369, AuthorID: 1045258, Scopus Author ID: 57221463270гуса

https://orcid.org/0000-0002-9426-9662ГусареваМ. А.GusarevaM. A.

 

Гусарева Марина Александровна – к.м.н., заведующая отделением радиотерапии № 1, ФГБУ «НМИЦ онкологии» Минздрава России, г. Ростов-на-Дону, Российская Федерация.

ORCID: https://orcid.org/0000-0002-9426-9662, SPIN: 9040-5476, AuthorID: 705242

 

Marina A. Gusareva – Cand. Sci. (Med.), head of the department of radiotherapy No. 1, National Medical Research Centre for Oncology, Rostov-on-Don, Russian Federation

ORCID: https://orcid.org/0000-0002-9426-9662, SPIN: 9040-5476, AuthorID: 705242

https://orcid.org/0000-0003-2460-0038ЗиньковичМ. С.ZinkovichM. S.

 

Зинькович Михаил Сергеевич – к.м.н., врач-радиотерапевт отделением радиотерапии № 1, ФГБУ «НМИЦ онкологии» Минздрава России, г. Ростов-на-Дону, Российская Федерация.

ORCID: https://orcid.org/0000-0003-2460-0038, SPIN: 1072-9674, AuthorID: 735168

 

Mikhail S. Zinkovich – Cand. Sci. (Med.), radiotherapist, radiotherapy department No. 1, National Medical Research Centre for Oncology, Rostov-on-Don, Russian Federation.

ORCID: https://orcid.org/0000-0003-2460-0038, SPIN: 1072-9674, AuthorID: 735168

ФГБУ «НМИЦ онкологии» Минздрава РоссииРоссияNational Medical Research Centre for OncologyRussian Federation202301022023415264Copyright © Кузнецова Н.С., Гурова С.В., Гончарова A.С., Заикина Е.В., Гусарева М.А., Зинькович М.С., 20232023Кузнецова Н.С., Гурова С.В., Гончарова A.С., Заикина Е.В., Гусарева М.А., Зинькович М.С.Kuznetsova N.S., Gurova S.V., Goncharova A.S., Zaikina E.V., Gusareva M.A., Zinkovich M.S.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.cancersp.com/jour/article/view/192

Глиобластома (ГБМ) является наиболее злокачественной и часто встречающейся первичной опухолью центральной нервной системы. В течение последних лет ГБМ классифицировали и лечили в соответствии с критериями Всемирной организации здравоохранения (ВОЗ), которая подразделяет ее на первичную и вторичную. Считается, что ГБМ происходит из глиальных клеток, имеет диффузный характер роста, однако ее этиология и патофизиология не вполне изучены на сегодняшний день. Быстрое прогрессирование опухоли, её анатомическая локализация в головном мозге часто ограничивают эффективность терапевтических вмешательств. Несмотря на все научно-технические достижения, ГБМ остается неизлечимым заболеванием с медианой выживаемости пациентов примерно 18 мес. Стандартные схемы лечения, включающие в себя максимальное хирургическое удаление опухоли с последующим облучением и химиотерапией, не обеспечивают удовлетворительных результатов.Значительные успехи в понимании молекулярной патологии ГБМ и связанных с ней сигнальных путей открыли возможности для новых методов лечения впервые диагностированных и рецидивирующих опухолей. Многоцелевой терапевтический подход, направленный на использование соединений, способных ингибировать более чем одну конкретную молекулярную мишень, представляет собой многообещающую альтернативу стандартным методам лечения. В настоящее время изучаются такие инновационные варианты лечения как применение низкомолекулярных ингибиторов, нацеленных на нарушение сигнальных путей, иммунотерапия, включающая ингибиторы контрольных точек, онколитические вакцины, САR-T-терапия, использование систем доставки лекарств. С точки зрения применения инновационного подхода особый интерес представляет разработка систем адресной доставки лекарств, так как именно эта стратегия выглядит наиболее перспективной в связи с ее способностью увеличивать биодоступность и эффективность как стандартных, так и впервые тестируемых препаратов. В данном обзоре обсуждаются результаты доклинических и клинических исследований инновационных терапевтических подходов, их преимущества и недостатки. Ожидается, что реализация междисциплинарного подхода способна объединить результаты передовых исследований в этой области, привести к созданию новых обнадеживающих терапевтических стратегий в отношении пациентов с ГБМ.

Glioblastoma (GBM) is the most malignant and the most common primary tumor of the central nervous system. During the last several years GBM has been classified and managed according to the World Health Organization (WHO) criteria which subdivide it into primary and secondary GBM. As it is suggested, GBM originates from glial cells and has a diffuse growth pattern, but its etiology and pathophysiology are poorly investigated up to date. Its rapid progression and anatomical location in the brain often limits the effectiveness of therapeutic interventions. Despite all scientific and technological advances, GBM remains an incurable disease with a median survival of approximately 18 months. Standard treatment options involving maximal safe resection of the tumor followed with radiotherapy and chemotherapy do not provide satisfactory Results.

Better understanding of the molecular pathology of GBM and its associated signaling pathways has opened up possibilities for new treatments for newly diagnosed and relapsing tumors. A multitargeted therapeutic approach using compounds capable of inhibiting more than one specific molecular target is a promising alternative to conventional therapies.

Currently, specialists study such innovative treatment options as small molecule inhibitors aimed at signaling pathway disruptions, immunotherapy, including checkpoint inhibitors, oncolytic vaccines, CAR T-cell therapy, and drug delivery systems. In terms of an innovative approach, the elaboration of targeted drug delivery systems is of particular interest, since this strategy looks the most promising due to its ability to increase the bioavailability and effectiveness of both standard and newly tested agents. This review discusses results of preclinical and clinical studies of innovative therapeutic approaches, their advantages and disadvantages. An interdisciplinary approach is expected to be able to combine the results of cutting-edge research in this area and to provide novel promising therapeutic strategies for patients with GBM.

глиобластомананочастицыиммунотерапиянизкомолекулярные ингибиторыglioblastomananoparticlesimmunotherapysmall-molecule inhibitorsReferencesGoenka A, Tiek D, Song X, Huang T, Hu B, Cheng SY. The Many Facets of Therapy Resistance and Tumor Recurrence in Glioblastoma. Cells. 2021 Feb 24;10(3):484. https://doi.org/10.3390/cells10030484Goenka A, Tiek D, Song X, Huang T, Hu B, Cheng SY. The Many Facets of Therapy Resistance and Tumor Recurrence in Glio- blastoma. Cells. 2021 Feb 24;10(3):484. https://doi.org/10.3390/cells10030484Davis ME. Glioblastoma: Overview of Disease and Treatment. Clin J Oncol Nurs. 2016 Oct 1;20(5 Suppl):S2–8. https://doi.org/10.1188/16.cjon.s1.2-8Davis ME. Glioblastoma: Overview of Disease and Treatment. Clin J Oncol Nurs. 2016 Oct 1;20(5 Suppl):S2–8. https://doi.org/10.1188/16.cjon.s1.2-8Кит О. И., Максимов А. Ю., Новикова И. А., Гончарова А. С., Лукбанова Е. А., и др. Применение биосовместимых композитных структур (скаффолдов) в онкологии. Сибирский онкологический журнал. 2022;21(1):130–136. https://doi.org/10.21294/1814-4861-2022-21-1-130-136, EDN: XVDMLLKit OI, Maksimov AYu, Novikova IA, Goncharova AS, Lukbanova EA, Sitkovskaya AO, et al. The use of biocompatible composite scaffolds in oncology. Siberian Journal of Oncology. 2022;21(1):130–136. (In Russ.). https://doi.org/10.21294/1814-4861- 2022-21-1-130-136, EDN: XVDMLLFernandes GFDS, Fernandes BC, Valente V, Dos Santos JL. Recent advances in the discovery of small molecules targeting glioblastoma. Eur J Med Chem. 2019 Feb 15;164:8–26. https://doi.org/10.1016/j.ejmech.2018.12.033Fernandes GFDS, Fernandes BC, Valente V, Dos Santos JL. Recent advances in the discovery of small molecules targeting glioblastoma. Eur J Med Chem. 2019 Feb 15;164:8–26. https://doi.org/10.1016/j.ejmech.2018.12.033Lim M, Xia Y, Bettegowda C, Weller M. Current state of immunotherapy for glioblastoma. Nat Rev Clin Oncol. 2018 Jul;15(7):422– 442. https://doi.org/10.1038/s41571-018-0003-5Lim M, Xia Y, Bettegowda C, Weller M. Current state of immunotherapy for glioblastoma. Nat Rev Clin Oncol. 2018 Jul;15(7):422– 442. https://doi.org/10.1038/s41571-018-0003-5Росторгуев Э. Е., Кит О. И., Гончарова А. С., Непомнящая Е. М., Волкова А. В., Заикина Е. В. и др. Изучение противоопухолевой эффективности комбинации бортезомиба и темозоломида на подкожных PDX-моделях глиобластомы человека. Современные проблемы науки и образования. 2020;5:121. https://doi.org/10.17513/spno.30191, EDN: WXCLJZRostorguev EE, Kit OI, Goncharova AS, Nepomnyaschaya EM, Volkova AV, Zaikina EV, et al. Study of antitumor efficacy of bortezomib combined with temozolomide in subcutaneous pdx models of human glioblastoma. Modern Problems of Science and Education. 2020;5:121. (In Russ.). https://doi.org/10.17513/spno.30191, EDN: WXCLJZSfifou F, Hakkou EM, Bouaiti EA, Slaoui M, Errihani H, Al Bouzidi A, et al. Correlation of immunohistochemical expression of HIF-1alpha and IDH1 with clinicopathological and therapeutic data of moroccan glioblastoma and survival analysis. Ann Med Surg (Lond). 2021 Aug 17;69:102731. https://doi.org/10.1016/j.amsu.2021.102731Sfifou F, Hakkou EM, Bouaiti EA, Slaoui M, Errihani H, Al Bouzidi A, et al. Correlation of immunohistochemical expression of HIF-1alpha and IDH1 with clinicopathological and therapeutic data of moroccan glioblastoma and survival analysis. Ann Med Surg (Lond). 2021 Aug 17;69:102731. https://doi.org/10.1016/j.amsu.2021.102731Fang Y, Liao G, Yu B. Small-molecule MDM2/X inhibitors and PROTAC degraders for cancer therapy: advances and perspectives. Acta Pharm Sin B. 2020 Jul;10(7):1253–1278. https://doi.org/10.1016/j.apsb.2020.01.003Fang Y, Liao G, Yu B. Small-molecule MDM2/X inhibitors and PROTAC degraders for cancer therapy: advances and perspec- tives. Acta Pharm Sin B. 2020 Jul;10(7):1253–1278. https://doi.org/10.1016/j.apsb.2020.01.003Яковленко Ю. Г. Глиобластомы: современное состояние проблемы. Медицинский вестник Юга России. 2019;10(4):28–35. https://doi.org/10.21886/2219-8075-2019-10-4-28-35, EDN: TBNEMLYakovlenko YuG. Glioblastoma: the current state of the problem. Medical Herald of the South of Russia. 2019;10(4):28–35. (In Russ.). https://doi.org/10.21886/2219-8075-2019-10-4-28-35, EDN: TBNEMLDaniele S, La Pietra V, Barresi E, Di Maro S, Da Pozzo E, Robello M, et al. Lead Optimization of 2-Phenylindolylglyoxylyldipeptide Murine Double Minute (MDM)2/Translocator Protein (TSPO) Dual Inhibitors for the Treatment of Gliomas. J Med Chem. 2016 May 26;59(10):4526–4538. https://doi.org/10.1021/acs.jmedchem.5b01767Daniele S, La Pietra V, Barresi E, Di Maro S, Da Pozzo E, Robello M, et al. Lead Optimization of 2-Phenylindolylglyoxylyldipep- tide Murine Double Minute (MDM)2/Translocator Protein (TSPO) Dual Inhibitors for the Treatment of Gliomas. J Med Chem. 2016 May 26;59(10):4526–4538. https://doi.org/10.1021/acs.jmedchem.5b01767Rew Y, Sun D. Discovery of a small molecule MDM2 inhibitor (AMG 232) for treating cancer. J Med Chem. 2014 Aug 14;57(15):6332–6341. https://doi.org/10.1021/jm500627sRew Y, Sun D. Discovery of a small molecule MDM2 inhibitor (AMG 232) for treating cancer. J Med Chem. 2014 Aug 14;57(15):6332–6341. https://doi.org/10.1021/jm500627sStupp R, Hegi ME, Gorlia T, Erridge SC, Perry J, Hong YK, et al. Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Sep;15(10):1100–1108. https://doi.org/10.1016/s1470-2045(14)70379-1Stupp R, Hegi ME, Gorlia T, Erridge SC, Perry J, Hong YK, et al. Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, ran- domised, open-label, phase 3 trial. Lancet Oncol. 2014 Sep;15(10):1100–1108. https://doi.org/10.1016/s1470-2045(14)70379-1Khoo KH, Verma CS, Lane DP. Drugging the p53 pathway: understanding the route to clinical efficacy. Nat Rev Drug Discov. 2014 Mar;13(3):217–236. https://doi.org/10.1038/nrd4236Khoo KH, Verma CS, Lane DP. Drugging the p53 pathway: understanding the route to clinical efficacy. Nat Rev Drug Discov. 2014 Mar;13(3):217–236. https://doi.org/10.1038/nrd4236Masica DL, Karchin R. Collections of simultaneously altered genes as biomarkers of cancer cell drug response. Cancer Res. 2013 Mar 15;73(6):1699–1708. https://doi.org/10.1158/0008-5472.can-12-3122Masica DL, Karchin R. Collections of simultaneously altered genes as biomarkers of cancer cell drug response. Cancer Res. 2013 Mar 15;73(6):1699–1708. https://doi.org/10.1158/0008-5472.can-12-3122Ding Q, Zhang Z, Liu JJ, Jiang N, Zhang J, Ross TM, et al. Discovery of RG7388, a potent and selective p53-MDM2 inhibitor in clinical development. J Med Chem. 2013 Jul 25;56(14):5979–5983. https://doi.org/10.1021/jm400487cDing Q, Zhang Z, Liu JJ, Jiang N, Zhang J, Ross TM, et al. Discovery of RG7388, a potent and selective p53-MDM2 inhibitor in clinical development. J Med Chem. 2013 Jul 25;56(14):5979–5983. https://doi.org/10.1021/jm400487cAdzemovic MV, Zeitelhofer M, Eriksson U, Olsson T, Nilsson I. Imatinib ameliorates neuroinflammation in a rat model of multiple sclerosis by enhancing blood-brain barrier integrity and by modulating the peripheral immune response. PLoS One. 2013;8(2):e56586. https://doi.org/10.1371/journal.pone.0056586Adzemovic MV, Zeitelhofer M, Eriksson U, Olsson T, Nilsson I. Imatinib ameliorates neuroinflammation in a rat model of multiple sclerosis by enhancing blood-brain barrier integrity and by modulating the peripheral immune response. PLoS One. 2013;8(2):e56586. doi: https://doi.org/10.1371/journal.pone.0056586Papadopoulos N, Lennartsson J. The PDGF/PDGFR pathway as a drug target. Mol Aspects Med. 2018 Aug;62:75–88. https://doi.org/10.1016/j.mam.2017.11.007Papadopoulos N, Lennartsson J. The PDGF/PDGFR pathway as a drug target. Mol Aspects Med. 2018 Aug;62:75–88. https://doi.org/10.1016/j.mam.2017.11.007Appiah-Kubi K, Wang Y, Qian H, Wu M, Yao X, Wu Y, et al. Platelet-derived growth factor receptor/platelet-derived growth factor (PDGFR/PDGF) system is a prognostic and treatment response biomarker with multifarious therapeutic targets in cancers. Tumour Biol. 2016 Aug;37(8):10053–10066. https://doi.org/10.1007/s13277-016-5069-zAppiah-Kubi K, Wang Y, Qian H, Wu M, Yao X, Wu Y, et al. Platelet-derived growth factor receptor/platelet-derived growth fac- tor (PDGFR/PDGF) system is a prognostic and treatment response biomarker with multifarious therapeutic targets in cancers. Tumour Biol. 2016 Aug;37(8):10053–10066. https://doi.org/10.1007/s13277-016-5069-zLewandowski SA, Fredriksson L, Lawrence DA, Eriksson U. Pharmacological targeting of the PDGF-CC signaling pathway for blood–brain barrier restoration in neurological disorders. Pharmacology & Therapeutics. 2016;167:108–119. https://doi.org/10.1016/j.pharmthera.2016.07.016Lewandowski SA, Fredriksson L, Lawrence DA, Eriksson U. Pharmacological targeting of the PDGF-CC signaling pathway for blood–brain barrier restoration in neurological disorders. Pharmacology & Therapeutics. 2016;167:108–119. https://doi.org/10.1016/j.pharmthera.2016.07.016Westermark B. Platelet-derived growth factor in glioblastoma-driver or biomarker? Ups J Med Sci. 2014 Nov;119(4):298– 305. https://doi.org/10.3109/03009734.2014.970304Westermark B. Platelet-derived growth factor in glioblastoma-driver or biomarker? Ups J Med Sci. 2014 Nov;119(4):298– 305. https://doi.org/10.3109/03009734.2014.970304Lau D, Magill ST, Aghi MK. Molecularly targeted therapies for recurrent glioblastoma: current and future targets. Neurosurg Focus. 2014 Dec;37(6):E15. https://doi.org/10.3171/2014.9.focus14519Lau D, Magill ST, Aghi MK. Molecularly targeted therapies for recurrent glioblastoma: current and future targets. Neurosurg Focus. 2014 Dec;37(6):E15. https://doi.org/10.3171/2014.9.focus14519Lindberg N, Holland EC. PDGF in gliomas: more than just a growth factor? Ups J Med Sci. 2012 May;117(2):92–98. https://doi.org/10.3109/03009734.2012.654860Lindberg N, Holland EC. PDGF in gliomas: more than just a growth factor? Ups J Med Sci. 2012 May;117(2):92–98. https://doi.org/10.3109/03009734.2012.654860Nagarajan PP, Tora MS, Neill SG, Federici T, Texakalidis P, Donsante A, et al. Lentiviral-Induced Spinal Cord Gliomas in Rat Model. Int J Mol Sci. 2021 Nov 30;22(23):12943. https://doi.org/10.3390/ijms222312943Nagarajan PP, Tora MS, Neill SG, Federici T, Texakalidis P, Donsante A, et al. Lentiviral-Induced Spinal Cord Gliomas in Rat Model. Int J Mol Sci. 2021 Nov 30;22(23):12943. https://doi.org/10.3390/ijms222312943Le X, Nilsson M, Goldman J, Reck M, Nakagawa K, Kato T, et al. Dual EGFR-VEGF Pathway Inhibition: A Promising Strategy for Patients With EGFR-Mutant NSCLC. J Thorac Oncol. 2021 Feb;16(2):205–215. https://doi.org/10.1016/j.jtho.2020.10.006Le X, Nilsson M, Goldman J, Reck M, Nakagawa K, Kato T, et al. Dual EGFR-VEGF Pathway Inhibition: A Promising Strategy for Patients With EGFR-Mutant NSCLC. J Thorac Oncol. 2021 Feb;16(2):205–215. https://doi.org/10.1016/j.jtho.2020.10.006Wick W, Gorlia T, Bendszus M, Taphoorn M, Sahm F, Harting I, et al. Lomustine and Bevacizumab in Progressive Glioblastoma. N Engl J Med. 2017 Nov 16;377(20):1954–1963. https://doi.org/10.1056/nejmoa1707358Wick W, Gorlia T, Bendszus M, Taphoorn M, Sahm F, Harting I, et al. Lomustine and Bevacizumab in Progressive Glioblasto- ma. N Engl J Med. 2017 Nov 16;377(20):1954–1963. https://doi.org/10.1056/nejmoa1707358Goel HL, Mercurio AM. VEGF targets the tumour cell. Nat Rev Cancer. 2013 Dec;13(12):871–882. https://doi.org/10.1038/nrc3627Goel HL, Mercurio AM. VEGF targets the tumour cell. Nat Rev Cancer. 2013 Dec;13(12):871–882. https://doi.org/10.1038/nrc3627Cruz 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 Apr 9;13(8):1795. https://doi.org/10.3390/cancers13081795Cruz 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 Apr 9;13(8):1795. https://doi.org/10.3390/cancers13081795Li X, Wu C, Chen N, Gu H, Yen A, Cao L, Wang E, Wang L. PI3K/Akt/mTOR signaling pathway and targeted therapy for glioblastoma. Oncotarget. 2016 May 31;7(22):33440–33450. https://doi.org/10.18632/oncotarget.7961Li X, Wu C, Chen N, Gu H, Yen A, Cao L, Wang E, Wang L. PI3K/Akt/mTOR signaling pathway and targeted therapy for glio- blastoma. Oncotarget. 2016 May 31;7(22):33440–33450. https://doi.org/10.18632/oncotarget.7961Yu Z, Xie G, Zhou G, Cheng Y, Zhang G, Yao G, et al. NVP-BEZ235, a novel dual PI3K-mTOR inhibitor displays anti-glioma activity and reduces chemoresistance to temozolomide in human glioma cells. Cancer Lett. 2015 Oct 10;367(1):58–68. https://doi.org/10.1016/j.canlet.2015.07.007Yu Z, Xie G, Zhou G, Cheng Y, Zhang G, Yao G, et al. NVP-BEZ235, a novel dual PI3K-mTOR inhibitor displays anti-glioma ac- tivity and reduces chemoresistance to temozolomide in human glioma cells. Cancer Lett. 2015 Oct 10;367(1):58–68. https://doi.org/10.1016/j.canlet.2015.07.007Yang Z, Guo Q, Wang Y, Chen K, Zhang L, Cheng Z, et al. AZD3759, a BBB-penetrating EGFR inhibitor for the treatment of EGFR mutant NSCLC with CNS metastases. Sci Transl Med. 2016 Dec 7;8(368):368ra172. https://doi.org/10.1126/scitranslmed.aag0976Yang Z, Guo Q, Wang Y, Chen K, Zhang L, Cheng Z, et al. AZD3759, a BBB-penetrating EGFR inhibitor for the treatment of EGFR mutant NSCLC with CNS metastases. Sci Transl Med. 2016 Dec 7;8(368):368ra172. https://doi.org/10.1126/scitranslmed.aag0976Westphal M, Maire CL, Lamszus K. EGFR as a Target for Glioblastoma Treatment: An Unfulfilled Promise. CNS Drugs. 2017 Sep;31(9):723–735. https://doi.org/10.1007/s40263-017-0456-6Westphal M, Maire CL, Lamszus K. EGFR as a Target for Glioblastoma Treatment: An Unfulfilled Promise. CNS Drugs. 2017 Sep;31(9):723–735. https://doi.org/10.1007/s40263-017-0456-6Wolin E, Mita A, Mahipal A, Meyer T, Bendell J, Nemunaitis J, et al. A phase 2 study of an oral mTORC1/mTORC2 kinase inhibitor (CC-223) for non-pancreatic neuroendocrine tumors with or without carcinoid symptoms. PLoS One. 2019 Sep 17;14(9):e0221994. https://doi.org/10.1371/journal.pone.0221994Wolin E, Mita A, Mahipal A, Meyer T, Bendell J, Nemunaitis J, et al. A phase 2 study of an oral mTORC1/mTORC2 kinase inhibitor (CC-223) for non-pancreatic neuroendocrine tumors with or without carcinoid symptoms. PLoS One. 2019 Sep 17;14(9):e0221994. https://doi.org/10.1371/journal.pone.0221994Massacesi C, Di Tomaso E, Urban P, Germa C, Quadt C, Trandafir L, et al. PI3K inhibitors as new cancer therapeutics: implications for clinical trial design. Onco Targets Ther. 2016 Jan 7;9:203–210. https://doi.org/10.2147/ott.s89967Massacesi C, Di Tomaso E, Urban P, Germa C, Quadt C, Trandafir L, et al. PI3K inhibitors as new cancer therapeutics: impli- cations for clinical trial design. Onco Targets Ther. 2016 Jan 7;9:203–210. https://doi.org/10.2147/ott.s89967Wahl M, Chang SM, Phillips JJ, Molinaro AM, Costello JF, Mazor T, et al. Probing the phosphatidylinositol 3-kinase/mammalian target of rapamycin pathway in gliomas: A phase 2 study of everolimus for recurrent adult low-grade gliomas. Cancer. 2017 Dec 1;123(23):4631–4639. https://doi.org/10.1002/cncr.30909Wahl M, Chang SM, Phillips JJ, Molinaro AM, Costello JF, Mazor T, et al. Probing the phosphatidylinositol 3-kinase/mam- malian target of rapamycin pathway in gliomas: A phase 2 study of everolimus for recurrent adult low-grade gliomas. Cancer. 2017 Dec 1;123(23):4631–4639. https://doi.org/10.1002/cncr.30909Beaufils F, Cmiljanovic N, Cmiljanovic V, Bohnacker T, Melone A, Marone R, et al. 5-(4, 6-Dimorpholino-1, 3, 5-triazin-2-yl)-4-(trifluoromethyl) pyridin-2-amine (PQR309), a potent, brain-penetrant, orally bioavailable, pan-class I PI3K/mTOR inhibitor as clinical candidate in oncology. J Med Chem. 2017 Sep 14;60(17):7524–7538. https://doi.org/10.1021/acs.jmedchem.7b00930Beaufils F, Cmiljanovic N, Cmiljanovic V, Bohnacker T, Melone A, Marone R, et al. 5-(4, 6-Dimorpholino-1, 3, 5-triazin-2-yl)-4-(tri- fluoromethyl) pyridin-2-amine (PQR309), a potent, brain-penetrant, orally bioavailable, pan-class I PI3K/mTOR inhibitor as clinical candidate in oncology. J Med Chem. 2017 Sep 14;60(17):7524–7538. https://doi.org/10.1021/acs.jmedchem.7b00930Behrooz AB, Syahir A. Could We Address the Interplay Between CD133, Wnt/β-Catenin, and TERT Signaling Pathways as a Potential Target for Glioblastoma Therapy? Front Oncol. 2021 Apr 1;11:642719. https://doi.org/10.3389/fonc.2021.642719Behrooz AB, Syahir A. Could We Address the Interplay Between CD133, Wnt/β-Catenin, and TERT Signaling Pathways as a Potential Target for Glioblastoma Therapy? Front Oncol. 2021 Apr 1;11:642719. https://doi.org/10.3389/fonc.2021.642719Delgado-López PD, Riñones-Mena E, Corrales-García EM. Treatment-related changes in glioblastoma: a review on the controversies in response assessment criteria and the concepts of true progression, pseudoprogression, pseudoresponse and radionecrosis. Clin Transl Oncol. 2018 Aug;20(8):939–953. https://doi.org/10.1007/s12094-017-1816-xDelgado-López PD, Riñones-Mena E, Corrales-García EM. Treatment-related changes in glioblastoma: a review on the con- troversies in response assessment criteria and the concepts of true progression, pseudoprogression, pseudoresponse and radionecrosis. Clin Transl Oncol. 2018 Aug;20(8):939–953. https://doi.org/10.1007/s12094-017-1816-xLapointe S, Mason W, MacNeil M, Harlos C, Tsang R, Sederias J, et al. A phase I study of vistusertib (dual mTORC1/2 inhibitor) in patients with previously treated glioblastoma multiforme: a CCTG study. Invest New Drugs. 2020 Aug;38(4):1137–1144. https://doi.org/10.1007/s10637-019-00875-4Lapointe S, Mason W, MacNeil M, Harlos C, Tsang R, Sederias J, et al. A phase I study of vistusertib (dual mTORC1/2 inhib- itor) in patients with previously treated glioblastoma multiforme: a CCTG study. Invest New Drugs. 2020 Aug;38(4):1137–1144. https://doi.org/10.1007/s10637-019-00875-4Alzahrani AS. PI3K/Akt/mTOR inhibitors in cancer: At the bench and bedside. Semin Cancer Biol. 2019 Dec;59:125–132. https://doi.org/10.18632/oncotarget.7961Alzahrani AS. PI3K/Akt/mTOR inhibitors in cancer: At the bench and bedside. Semin Cancer Biol. 2019 Dec;59:125–132. https://doi.org/10.18632/oncotarget.7961Carlsson SK, Brothers SP, Wahlestedt C. Emerging treatment strategies for glioblastoma multiforme. EMBO Mol Med. 2014 Nov;6(11):1359–1370. https://doi.org/10.15252/emmm.201302627Carlsson SK, Brothers SP, Wahlestedt C. Emerging treatment strategies for glioblastoma multiforme. EMBO Mol Med. 2014 Nov;6(11):1359–1370. https://doi.org/10.15252/emmm.201302627Jiapaer S, Furuta T, Tanaka S, Kitabayashi T, Nakada M. Potential Strategies Overcoming the Temozolomide Resistance for Glioblastoma. Neurol Med Chir (Tokyo). 2018 Oct 15;58(10):405–421. https://doi.org/10.2176/nmc.ra.2018-0141Jiapaer S, Furuta T, Tanaka S, Kitabayashi T, Nakada M. Potential Strategies Overcoming the Temozolomide Resistance for Glioblastoma. Neurol Med Chir (Tokyo). 2018 Oct 15;58(10):405–421. https://doi.org/10.2176/nmc.ra.2018-0141Hodges TR, Ferguson SD, Heimberger AB. Immunotherapy in glioblastoma: emerging options in precision medicine. CNS Oncol. 2016 Jul;5(3):175–186. https://doi.org/10.2217/cns-2016-0009Hodges TR, Ferguson SD, Heimberger AB. Immunotherapy in glioblastoma: emerging options in precision medicine. CNS Oncol. 2016 Jul;5(3):175–186. https://doi.org/10.2217/cns-2016-0009Tivnan A, Heilinger T, Lavelle EC, Prehn JH. Advances in immunotherapy for the treatment of glioblastoma. J Neurooncol. 2017 Jan;131(1):1–9. https://doi.org/10.1007/s11060-016-2299-2Tivnan A, Heilinger T, Lavelle EC, Prehn JH. Advances in immunotherapy for the treatment of glioblastoma. J Neurooncol. 2017 Jan;131(1):1–9. https://doi.org/10.1007/s11060-016-2299-2Sanders S, Debinski W. Challenges to Successful Implementation of the Immune Checkpoint Inhibitors for Treatment of Glioblastoma. Int J Mol Sci. 2020 Apr 16;21(8):2759. https://doi.org/10.3390/ijms21082759Sanders S, Debinski W. Challenges to Successful Implementation of the Immune Checkpoint Inhibitors for Treatment of Glioblastoma. Int J Mol Sci. 2020 Apr 16;21(8):2759. https://doi.org/10.3390/ijms21082759Lim M, Xia Y, Bettegowda C, Weller M. Current state of immunotherapy for glioblastoma. Nat Rev Clin Oncol. 2018 Jul;15(7):422–442. https://doi.org/10.1038/s41571-018-0003-5Lim M, Xia Y, Bettegowda C, Weller M. Current state of immunotherapy for glioblastoma. Nat Rev Clin Oncol. 2018 Jul;15(7):422–442. https://doi.org/10.1038/s41571-018-0003-5Reardon DA, Brandes AA, Omuro A, Mulholland P, Lim M, Wick A, et al. Effect of nivolumab vs bevacizumab in patients with recurrent glioblastoma: the CheckMate 143 phase 3 randomized clinical trial. JAMA Oncol. 2020 Jul 1;6(7):1003–1010. https://doi.org/10.1001/jamaoncol.2020.1024Reardon DA, Brandes AA, Omuro A, Mulholland P, Lim M, Wick A, et al. Effect of nivolumab vs bevacizumab in patients with recurrent glioblastoma: the CheckMate 143 phase 3 randomized clinical trial. JAMA Oncol. 2020 Jul 1;6(7):1003–1010. https://doi.org/10.1001/jamaoncol.2020.1024Majc B, Novak M, Kopitar-Jerala N, Jewett A, Breznik B. Immunotherapy of Glioblastoma: Current Strategies and Challenges in Tumor Model Development. Cells. 2021 Jan 29;10(2):265. https://doi.org/10.3390/cells10020265Majc B, Novak M, Kopitar-Jerala N, Jewett A, Breznik B. Immunotherapy of Glioblastoma: Current Strategies and Challenges in Tumor Model Development. Cells. 2021 Jan 29;10(2):265. https://doi.org/10.3390/cells10020265Farber SH, Elsamadicy AA, Atik AF, Suryadevara CM, Chongsathidkiet P, Fecci PE, et al. The Safety of available immunotherapy for the treatment of glioblastoma. Expert Opin Drug Saf. 2017 Mar;16(3):277–287. https://doi.org/10.1080/14740338.2017.1273898Farber SH, Elsamadicy AA, Atik AF, Suryadevara CM, Chongsathidkiet P, Fecci PE, et al. The Safety of available immunother- apy for the treatment of glioblastoma. Expert Opin Drug Saf. 2017 Mar;16(3):277–287. https://doi.org/10.1080/14740338.2017.1273898Wang X, Lu J, Guo G, Yu J. Immunotherapy for recurrent glioblastoma: practical insights and challenging prospects. Cell Death Dis. 2021 Mar 19;12(4):299. https://doi.org/10.1038/s41419-021-03568-0Wang X, Lu J, Guo G, Yu J. Immunotherapy for recurrent glioblastoma: practical insights and challenging prospects. Cell Death Dis. 2021 Mar 19;12(4):299. https://doi.org/10.1038/s41419-021-03568-0Suryadevara CM, Verla T, Sanchez-Perez L, Reap EA, Choi BD, Fecci PE, Sampson JH. Immunotherapy for malignant glioma. Surg Neurol Int. 2015 Feb 13;6(Suppl 1):S68–77. https://doi.org/10.4103/2152-7806.151341Suryadevara CM, Verla T, Sanchez-Perez L, Reap EA, Choi BD, Fecci PE, Sampson JH. Immunotherapy for malignant glioma. Surg Neurol Int. 2015 Feb 13;6(Suppl 1):S68–77. https://doi.org/10.4103/2152-7806.151341Farber SH, Elsamadicy AA, Atik AF, Suryadevara CM, Chongsathidkiet P, Fecci PE, et al. The Safety of available immunotherapy for the treatment of glioblastoma. Expert Opin Drug Saf. 2017 Mar;16(3):277–287. https://doi.org/10.1080/14740338.2017.1273898Farber SH, Elsamadicy AA, Atik AF, Suryadevara CM, Chongsathidkiet P, Fecci PE, et al. The Safety of available immunother- apy for the treatment of glioblastoma. Expert Opin Drug Saf. 2017 Mar;16(3):277–287. https://doi.org/10.1080/14740338.2017.1273898Nguyen HM, Guz-Montgomery K, Lowe DB, Saha D. Pathogenetic Features and Current Management of Glioblastoma. Cancers (Basel). 2021 Feb 18;13(4):856. https://doi.org/10.3390/cancers13040856Nguyen HM, Guz-Montgomery K, Lowe DB, Saha D. Pathogenetic Features and Current Management of Glioblastoma. Can- cers (Basel). 2021 Feb 18;13(4):856. https://doi.org/10.3390/cancers13040856Seleci DA, Seleci M, Walter J-G, Stahl F, Scheper T, et al. Niosomes as nanoparticular drug carriers: fundamentals and recent applications. Journal of Nanomaterials. 2016. https://doi.org/10.1155/2016/7372306Seleci DA, Seleci M, Walter J-G, Stahl F, Scheper T, et al. Niosomes as nanoparticular drug carriers: fundamentals and recent applications. Journal of Nanomaterials. 2016. https://doi.org/10.1155/2016/7372306Chaurasia S, Dogra SS. Transfersomes: Novel approach for intranasal delivery. European Journal of Pharmaceutical and Medical Research. 2017;4(3):192–203.Chaurasia S, Dogra SS. Transfersomes: Novel approach for intranasal delivery. European Journal of Pharmaceutical and Medical Research. 2017;4(3):192–203.Duan Y, Dhar A, Patel C, Khimani M, Neogi S, Sharma P, et al. A brief review on solid lipid nanoparticles: part and parcel of contemporary drug delivery systems. RSC Adv. 2020 Jul 17;10(45):26777–26791. https://doi.org/10.1039/d0ra03491fDuan Y, Dhar A, Patel C, Khimani M, Neogi S, Sharma P, et al. A brief review on solid lipid nanoparticles: part and parcel of contemporary drug delivery systems. RSC Adv. 2020 Jul 17;10(45):26777–26791. https://doi.org/10.1039/d0ra03491fKapadia CH, Melamed JR, Day ES. Spherical Nucleic Acid Nanoparticles: Therapeutic Potential. BioDrugs. 2018 Aug;32(4):297–309. https://doi.org/10.1007/s40259-018-0290-5Kapadia CH, Melamed JR, Day ES. Spherical Nucleic Acid Nanoparticles: Therapeutic Potential. BioDrugs. 2018 Aug;32(4):297–309. https://doi.org/10.1007/s40259-018-0290-5Liu Q, Duo Y, Fu J, Qiu M, Sun Zh, Adahet D, et al. Nano-immunotherapy: Unique mechanisms of nanomaterials in synergizing cancer immunotherapy. Nano Today. 2021;36:101023. https://doi.org/10.1016/j.nantod.2020.101023Liu Q, Duo Y, Fu J, Qiu M, Sun Zh, Adahet D, et al. Nano-immunotherapy: Unique mechanisms of nanomaterials in synergizing cancer immunotherapy. Nano Today. 2021;36:101023. https://doi.org/10.1016/j.nantod.2020.101023Alphandéry E. Nano-Therapies for Glioblastoma Treatment. Cancers (Basel). 2020 Jan 19;12(1):242. https://doi.org/10.3390/cancers12010242Alphandéry E. Nano-Therapies for Glioblastoma Treatment. Cancers (Basel). 2020 Jan 19;12(1):242. https://doi.org/10.3390/cancers12010242Michael JS, Lee BS, Zhang M, Yu JS. Nanotechnology for Treatment of Glioblastoma Multiforme. J Transl Int Med. 2018 Oct 9;6(3):128–133. https://doi.org/10.2478/jtim-2018-0025Michael JS, Lee BS, Zhang M, Yu JS. Nanotechnology for Treatment of Glioblastoma Multiforme. J Transl Int Med. 2018 Oct 9;6(3):128–133. https://doi.org/10.2478/jtim-2018-0025

The authors declare that there are no conflicts of interest present.