Current Protein & Peptide ScienceCurrent Protein & Peptide ScienceCurrent Protein & Peptide Science1389-20371875-5550Bentham Science64546910.2174/1389203724666230830125102Life SciencesResearch ArticlePI3K Signaling Pathways as a Molecular Target for Glioblastoma Multiformeda SilvaAndressa Letíciainfo@benthamscience.netde AraújoThiagoinfo@benthamscience.netde Albuquerque FerreiraShakirainfo@benthamscience.netLeiteAndersoninfo@benthamscience.netda SilvaJoão Kayckeinfo@benthamscience.netAlbuquerqueLilyanainfo@benthamscience.netde LimaAna Rachelinfo@benthamscience.netSilva BarrosHerbert Charlesinfo@benthamscience.netSilvaLeandroinfo@benthamscience.netda Silva-JúniorEdeildoinfo@benthamscience.netde Araújo-JúniorJoãoinfo@benthamscience.netNetoVivaldoinfo@benthamscience.netde QueirozAlineinfo@benthamscience.netAlexandre-MoreiraMagnainfo@benthamscience.netLaboratory of Pharmacology and Immunity, Institute of Biological and Health Sciences, Federal University of AlagoasFederal University of Alagoas, Federal University of AlagoasMunicipal Secretary of Health of Maceio, Governo do estado de AlagoasBiological and Molecular Chemistry Research Group, Institute of Chemistry and Biotechnology, Federal University of AlagoaBiological and Molecular Chemistry Research Group, Institute of Chemistry and Biotechnology, Federal University of AlagoasLaboratory of Medicinal Chemistry, Institute of Pharmaceutical Sciences, Federal University of AlagoasPaulo Niemeyer State Brain Institute, Study and Research Center, Brain Biomedicine Laboratory, Federal University of Rio de Janeiro01012024251122611012025Copyright ©; 2024, Bentham Science Publishers2024Bentham Science Publishershttps://journals.eco-vector.com/1389-2037/article/view/645469

Glioblastoma multiforme (GBM) is the most common type of cancer that affects the central nervous system (CNS). It currently accounts for about 2% of diagnosed malignant tumors worldwide, with 296,000 new cases reported per year. The first-choice treatment consists of surgical resection, radiotherapy, and adjuvant chemotherapy, which increases patients' survival by 15 months. New clinical and pre-clinical research aims to improve this prognosis by proposing the search for new drugs that effectively eliminate cancer cells, circumventing problems such as resistance to treatment. One of the promising therapeutic strategies in the treatment of GBM is the inhibition of the phosphatidylinositol 3-kinase (PI3K) pathway, which is closely related to the process of tumor carcinogenesis. This review sought to address the main scientific studies of synthetic or natural drug prototypes that target specific therapy co-directed via the PI3K pathway, against human glioblastoma.

Glioblastomatherapyphosphatidylinositol 3-kinase (PI3K)cancerpharmacologyoncology.Kontomanolis, E.N.; Koutras, A.; Syllaios, A.; Schizas, D.; Mastoraki, A.; Garmpis, N.; Diakosavvas, M.; Angelou, K.; Tsatsaris, G.; Pagkalos, A.; Ntounis, T.; Fasoulakis, Z. Role of oncogenes and tumor-suppressor genes in carcinogenesis: A review. Anticancer Res., 2020, 40(11), 6009-6015. doi: 10.21873/anticanres.14622 PMID: 33109539Anderson, N.M.; Simon, M.C. The tumor microenvironment. Curr. Biol., 2020, 30(16), R921-R925. doi: 10.1016/j.cub.2020.06.081 PMID: 32810447Merabishvili, V. Cancer Incidence in Five Continents Volume XI; Bray, F.; Colombet, M.; Mery, L.; Piñeros, M.; Znaor, A.; Zanetti, R.; Ferlay, J., Eds.; IARC Scientific Publication, 2021. (166.)Salimi, A.; Zali, A.; Seddighi, A.S.; Seddighi, A.; Meshkat, S.; Hosseini, M.; Nikouei, A.; Akbari, M.E. Descriptive epidemiology of brain and central nervous system tumours: Results from Iran national cancer registry, 2010-2014. J. Cancer Epidemiol., 2020, 2020, 1-10. doi: 10.1155/2020/3534641 PMID: 33014059Stewart, B.W. World Health Organization, For A, De M, Cancer L. World cancer report; Iarc Press: Lyon, 2014.Brain, central nervous system. Available from: https://gco.iarc.fr/today/data/factsheets/cancers/31-Brain-central-nervous-system-fact- sheet.pdfLouis, D.N.; Ohgaki, H.; Wiestler, O.D.; Cavenee, W.K.; Burger, P.C.; Jouvet, A.; Scheithauer, B.W.; Kleihues, P. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol., 2007, 114(2), 97-109. doi: 10.1007/s00401-007-0243-4 PMID: 17618441Thakkar, J.P.; Dolecek, T.A.; Horbinski, C.; Ostrom, Q.T.; Lightner, D.D.; Barnholtz-Sloan, J.S.; Villano, J.L. Epidemiologic and molecular prognostic review of glioblastoma. Cancer Epidemiol. Biomarkers Prev., 2014, 23(10), 1985-1996. doi: 10.1158/1055-9965.EPI-14-0275 PMID: 25053711Tan, A.C.; Ashley, D.M.; López, G.Y.; Malinzak, M.; Friedman, H.S.; Khasraw, M. Management of glioblastoma: State of the art and future directions. CA Cancer J. Clin., 2020, 70(4), 299-312. doi: 10.3322/caac.21613 PMID: 32478924Alexander, B.M.; Cloughesy, T.F. Adult Glioblastoma. J. Clin. Oncol., 2017, 35(21), 2402-2409. doi: 10.1200/JCO.2017.73.0119 PMID: 28640706DeCordova, S.; Shastri, A.; Tsolaki, A.G.; Yasmin, H.; Klein, L.; Singh, S.K.; Kishore, U. Molecular heterogeneity and immunosuppressive microenvironment in glioblastoma. Front. Immunol., 2020, 11, 1402. doi: 10.3389/fimmu.2020.01402 PMID: 32765498Ostrom, Q.T.; Gittleman, H.; Liao, P.; Vecchione-Koval, T.; Wolinsky, Y.; Kruchko, C.; Barnholtz-Sloan, J.S. CBTRUS statistical report: Primary brain and other central nervous system tumors diagnosed in the United States in 2010–2014. Neuro-oncol., 2017, 19(S5), v1-v88. doi: 10.1093/neuonc/nox158 PMID: 29117289Żukiel, R.; Piestrzeniewicz, R.; Nowak, S.; Jankowski, R.; Wieloch, M. Historia leczenia operacyjnego guzów mózgu. Neuroskop., 2004, 6, 9-19.Louis, D.N.; Perry, A.; Reifenberger, G.; von Deimling, A.; Figarella-Branger, D.; Cavenee, W.K.; Ohgaki, H.; Wiestler, O.D.; Kleihues, P.; Ellison, D.W. The 2016 World Health Organization classification of tumors of the central nervous system: A summary. Acta Neuropathol., 2016, 131(6), 803-820. doi: 10.1007/s00401-016-1545-1 PMID: 27157931Wen, P.Y.; Packer, R.J. The 2021 WHO classification of tumors of the central nervous system: Clinical implications. Neuro-oncol., 2021, 23(8), 1215-1217. doi: 10.1093/neuonc/noab120 PMID: 34185090Zhou, Y.S.; Wang, W.; Chen, N.; Wang, L.C.; Huang, J.B. Research progress of anti-glioma chemotherapeutic drugs (Review). Oncol. Rep., 2022, 47(5), 101. doi: 10.3892/or.2022.8312 PMID: 35362540Louis, D.N.; Perry, A.; Wesseling, P.; Brat, D.J.; Cree, I.A.; Figarella-Branger, D.; Hawkins, C.; Ng, H.K.; Pfister, S.M.; Reifenberger, G.; Soffietti, R.; von Deimling, A.; Ellison, D.W. The 2021 WHO classification of tumors of the central nervous system: A summary. Neuro-oncol., 2021, 23(8), 1231-1251. doi: 10.1093/neuonc/noab106 PMID: 34185076Cruz, J.V.R.; Batista, C.; Afonso, B.H.; Alexandre-Moreira, M.S.; Dubois, L.G.; Pontes, B.; Moura Neto, V.; Mendes, F.A. Obstacles to glioblastoma treatment two decades after temozolomide. Cancers., 2022, 14(13), 3203. doi: 10.3390/cancers14133203 PMID: 35804976Olar, A.; Wani, K.M.; Alfaro-Munoz, K.D.; Heathcock, L.E.; van Thuijl, H.F.; Gilbert, M.R.; Armstrong, T.S.; Sulman, E.P.; Cahill, D.P.; Vera-Bolanos, E.; Yuan, Y.; Reijneveld, J.C.; Ylstra, B.; Wesseling, P.; Aldape, K.D. IDH mutation status and role of WHO grade and mitotic index in overall survival in grade II–III diffuse gliomas. Acta Neuropathol., 2015, 129(4), 585-596. doi: 10.1007/s00401-015-1398-z PMID: 25701198Ohgaki, H.; Kleihues, P. The definition of primary and secondary glioblastoma. Clin. Cancer Res., 2013, 19(4), 764-772. doi: 10.1158/1078-0432.CCR-12-3002 PMID: 23209033Cancer biology: Molecular and genetic basis - Oncology for Medical Students. wiki.cancer.org.auNayak, A.; Ralte, A.M.; Sharma, M.C.; Singh, V.P.; Mahapatra, A.K.; Mehta, V.S.; Sarkar, C. p53 protein alterations in adult astrocytic tumors and oligodendrogliomas. Neurol. India, 2004, 52(2), 228-232. PMID: 15269478Hanif, F.; Muzaffar, K.; Perveen, K.; Malhi, S.M.; Simjee, ShU. Glioblastoma multiforme: A review of its epidemiology and pathogenesis through clinical presentation and treatment. Asian Pac. J. Cancer Prev., 2017, 18(1), 3-9. PMID: 28239999Birbilis, T.A.; Matis, G.K.; Eleftheriadis, S.G.; Theodoropoulou, E.N.; Sivridis, E. Spinal metastasis of glioblastoma multiforme: An uncommon suspect? Spine., 2010, 35(7), E264-E269. doi: 10.1097/BRS.0b013e3181c11748 PMID: 20195200Lun, M.; Lok, E.; Gautam, S.; Wu, E.; Wong, E.T. The natural history of extracranial metastasis from glioblastoma multiforme. J. Neurooncol., 2011, 105(2), 261-273. doi: 10.1007/s11060-011-0575-8 PMID: 21512826Urbańska, K.; Sokołowska, J.; Szmidt, M.; Sysa, P. Review Glioblastoma multiforme – an overview. Contemp. Oncol., 2014, 5(5), 307-312. doi: 10.5114/wo.2014.40559 PMID: 25477751Lohmann, P.; Werner, J.M.; Shah, N.; Fink, G.; Langen, K.J.; Galldiks, N. Combined amino acid positron emission tomography and advanced magnetic resonance imaging in glioma patients. Cancers., 2019, 11(2), 153. doi: 10.3390/cancers11020153 PMID: 30699942Liu, S.; Shi, W.; Zhao, Q.; Zheng, Z.; Liu, Z.; Meng, L.; Dong, L.; Jiang, X. Progress and prospect in tumor treating fields treatment of glioblastoma. Biomed. Pharmacother., 2021, 141, 111810. doi: 10.1016/j.biopha.2021.111810 PMID: 34214730Katsetos, C.D.; Dráberová, E.; Legido, A.; Dumontet, C.; Dráber, P. Tubulin targets in the pathobiology and therapy of glioblastoma multiforme. I. class III β-tubulin. J. Cell. Physiol., 2009, 221(3), 505-513. doi: 10.1002/jcp.21870 PMID: 19650075Mehta, S.; Lo Cascio, C. Developmentally regulated signaling pathways in glioma invasion. Cell. Mol. Life Sci., 2018, 75(3), 385-402. doi: 10.1007/s00018-017-2608-8 PMID: 28821904Haumann, R.; Videira, J.C.; Kaspers, G.J.L.; van Vuurden, D.G.; Hulleman, E. Overview of current drug delivery methods across the blood–brain barrier for the treatment of primary brain tumors. CNS Drugs., 2020, 34(11), 1121-1131. doi: 10.1007/s40263-020-00766-w PMID: 32965590Spangle, J.M.; Roberts, T.M.; Zhao, J.J. The emerging role of PI3K/AKT-mediated epigenetic regulation in cancer. Biochim. Biophys. Acta Rev. Cancer, 2017, 1868(1), 123-131. doi: 10.1016/j.bbcan.2017.03.002 PMID: 28315368Kaplan, D.R.; Whitman, M.; Schaffhausen, B.; Pallas, D.C.; White, M.; Cantley, L.; Roberts, T.M. Common elements in growth factor stimulation and oncogenic transformation: 85 kd phosphoprotein and phosphatidylinositol kinase activity. Cell, 1987, 50(7), 1021-1029. doi: 10.1016/0092-8674(87)90168-1 PMID: 2441878Martini, M.; De Santis, M.C.; Braccini, L.; Gulluni, F.; Hirsch, E. PI3K/AKT signaling pathway and cancer: An updated review. Ann. Med., 2014, 46(6), 372-383. doi: 10.3109/07853890.2014.912836 PMID: 24897931El Sheikh, S.S.; Domin, J.; Tomtitchong, P.; Abel, P.; Stamp, G.; Lalani, E.N. Topographical expression of class IA and class II phosphoinositide 3-kinase enzymes in normal human tissues is consistent with a role in differentiation. BMC Clin. Pathol., 2003, 3(1), 4. doi: 10.1186/1472-6890-3-4 PMID: 14563213Vivanco, I.; Sawyers, C.L. The phosphatidylinositol 3-Kinase–AKT pathway in human cancer. Nat. Rev. Cancer, 2002, 2(7), 489-501. doi: 10.1038/nrc839 PMID: 12094235Alzahrani, A.S. PI3K/Akt/mTOR inhibitors in cancer: At the bench and bedside. Semin. Cancer Biol., 2019, 59, 125-132. doi: 10.1016/j.semcancer.2019.07.009 PMID: 31323288Hay, N.; Sonenberg, N. Upstream and downstream of mTOR. Genes Dev., 2004, 18(16), 1926-1945. doi: 10.1101/gad.1212704 PMID: 15314020Murugan, A.K. mTOR: Role in cancer, metastasis and drug resistance. Semin. Cancer Biol., 2019, 59, 92-111. doi: 10.1016/j.semcancer.2019.07.003 PMID: 31408724Liu, P.; Cheng, H.; Roberts, T.M.; Zhao, J.J. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat. Rev. Drug Discov., 2009, 8(8), 627-644. doi: 10.1038/nrd2926 PMID: 19644473Noorolyai, S.; Shajari, N.; Baghbani, E.; Sadreddini, S.; Baradaran, B. The relation between PI3K/AKT signalling pathway and cancer. Gene, 2019, 698, 120-128. doi: 10.1016/j.gene.2019.02.076 PMID: 30849534Squarize, C.H.; Castilho, R.M.; Abrahao, A.C.; Molinolo, A.; Lingen, M.W.; Gutkind, J.S. PTEN deficiency contributes to the development and progression of head and neck cancer. Neoplasia., 2013, 15(5), 461-471. doi: 10.1593/neo.121024 PMID: 23633918Kurig, B.; Shymanets, A.; Bohnacker, T. Ras is an indispensable coregulator of the class I B phosphoinositide 3-kinase p87/p110γ. Proceedings of the National Academy of Sciences, 2009, pp. 20312-7.Mishra, R.; Patel, H.; Alanazi, S.; Kilroy, M.K.; Garrett, J.T. PI3K inhibitors in cancer: Clinical implications and adverse effects. Int. J. Mol. Sci., 2021, 22(7), 3464. doi: 10.3390/ijms22073464 PMID: 33801659Yoshioka, K. Class II phosphatidylinositol 3-kinase isoforms in vesicular trafficking. Biochem. Soc. Trans., 2021, 49(2), 893-901. doi: 10.1042/BST20200835 PMID: 33666217Merrill, N.M.; Schipper, J.L.; Karnes, J.B.; Kauffman, A.L.; Martin, K.R.; MacKeigan, J.P. PI3K- C2α knockdown decreases autophagy and maturation of endocytic vesicles. Donaldson JG, editor. PLOS ONE., 2017, 12(9), e0184909.Gulluni, F.; De Santis, M.C.; Margaria, J.P.; Martini, M.; Hirsch, E. Class II PI3K functions in cell biology and disease. Trends Cell Biol., 2019, 29(4), 339-359. doi: 10.1016/j.tcb.2019.01.001 PMID: 30691999Cisse, O.; Quraishi, M.; Gulluni, F.; Guffanti, F.; Mavrommati, I.; Suthanthirakumaran, M.; Oh, L.C.R.; Schlatter, J.N.; Sarvananthan, A.; Broggini, M.; Hirsch, E.; Falasca, M.; Maffucci, T. Downregulation of class II phosphoinositide 3-kinase PI3K-C2β delays cell division and potentiates the effect of docetaxel on cancer cell growth. J. Exp. Clin. Cancer Res., 2019, 38(1), 472. doi: 10.1186/s13046-019-1472-9 PMID: 31752944Brown, W.J.; DeWald, D.B.; Emr, S.D.; Plutner, H.; Balch, W.E. Role for phosphatidylinositol 3-kinase in the sorting and transport of newly synthesized lysosomal enzymes in mammalian cells. J. Cell Biol., 1995, 130(4), 781-796. doi: 10.1083/jcb.130.4.781 PMID: 7642697Ellis, H.; Ma, C.X. PI3K inhibitors in breast cancer therapy. Curr. Oncol. Rep., 2019, 21(12), 110. doi: 10.1007/s11912-019-0846-7 PMID: 31828441Fattahi, S.; Amjadi-Moheb, F.; Tabaripour, R.; Ashrafi, G.H.; Akhavan-Niaki, H. PI3K/AKT/mTOR signaling in gastric cancer: Epigenetics and beyond. Life Sci., 2020, 262, 118513. doi: 10.1016/j.lfs.2020.118513 PMID: 33011222Murugan, A.K. Special issue: PI3K/Akt signaling in human cancer. Semin. Cancer Biol., 2019, 59, 1-2. doi: 10.1016/j.semcancer.2019.10.022 PMID: 31689493Colardo, M.; Segatto, M.; Di Bartolomeo, S. Targeting RTK-PI3K-mTOR Axis in gliomas: An update. Int. J. Mol. Sci., 2021, 22(9), 4899. doi: 10.3390/ijms22094899 PMID: 34063168Bleeker, F.E.; Lamba, S.; Zanon, C.; Molenaar, R.J.; Hulsebos, T.J.M.; Troost, D.; van Tilborg, A.A.; Vandertop, W.P.; Leenstra, S.; van Noorden, C.J.F.; Bardelli, A. Mutational profiling of kinases in glioblastoma. BMC Cancer, 2014, 14(1), 718. doi: 10.1186/1471-2407-14-718 PMID: 25256166Langhans, J.; Schneele, L.; Trenkler, N.; von Bandemer, H.; Nonnenmacher, L.; Karpel-Massler, G.; Siegelin, M.D.; Zhou, S.; Halatsch, M.E.; Debatin, K.M.; Westhoff, M.A. The effects of PI3K-mediated signalling on glioblastoma cell behaviour. Oncogenesis, 2017, 6(11), 398. doi: 10.1038/s41389-017-0004-8 PMID: 29184057Zhang, Y.; Dube, C.; Gibert, M., Jr; Cruickshanks, N.; Wang, B.; Coughlan, M.; Yang, Y.; Setiady, I.; Deveau, C.; Saoud, K.; Grello, C.; Oxford, M.; Yuan, F.; Abounader, R. The p53 pathway in glioblastoma. Cancers., 2018, 10(9), 297. doi: 10.3390/cancers10090297 PMID: 30200436Cantley, L.C. The phosphoinositide 3-kinase pathway. Science, 2002, 296(5573), 1655-1657. doi: 10.1126/science.296.5573.1655 PMID: 12040186Westhoff, M.A.; Karpel-Massler, G.; Brühl, O.; Enzenmüller, S.; La Ferla-Brühl, K.; Siegelin, M.D.; Nonnenmacher, L.; Debatin, K.M. A critical evaluation of PI3K inhibition in glioblastoma and neuroblastoma therapy. Mol. Cell. Ther., 2014, 2(1), 32. doi: 10.1186/2052-8426-2-32 PMID: 26056598Shahcheraghi, S.H.; Tchokonte-Nana, V.; Lotfi, M.; Lotfi, M.; Ghorbani, A.; Sadeghnia, H.R. Wnt/beta-catenin and PI3K/Akt/mTOR signaling pathways in glioblastoma: Two main targets for drug design: A review. Curr. Pharm. Des., 2020, 26(15), 1729-1741. doi: 10.2174/1381612826666200131100630 PMID: 32003685Petővári, G.; Hujber, Z.; Krencz, I.; Dankó, T.; Nagy, N.; Tóth, F.; Raffay, R.; Mészáros, K.; Rajnai, H.; Vetlényi, E.; Takács-Vellai, K.; Jeney, A.; Sebestyén, A. Targeting cellular metabolism using rapamycin and/or doxycycline enhances anti-tumour effects in human glioma cells. Cancer Cell Int., 2018, 18(1), 211. doi: 10.1186/s12935-018-0710-0 PMID: 30574020Chen, Z.X.; Wallis, K.; Fell, S.M.; Sobrado, V.R.; Hemmer, M.C.; Ramsköld, D.; Hellman, U.; Sandberg, R.; Kenchappa, R.S.; Martinson, T.; Johnsen, J.I.; Kogner, P.; Schlisio, S. RNA helicase A is a downstream mediator of KIF1Bβ tumor-suppressor function in neuroblastoma. Cancer Discov., 2014, 4(4), 434-451. doi: 10.1158/2159-8290.CD-13-0362 PMID: 24469107Ströbele, S.; Schneider, M.; Schneele, L.; Siegelin, M.D.; Nonnenmacher, L.; Zhou, S. A potential role for the inhibition of PI3K signaling in glioblastoma therapy. Castresana JS, editor. PLOS ONE., 2015, 10(6), e0131670.Felsberg, J.; Hentschel, B.; Kaulich, K.; Gramatzki, D.; Zacher, A.; Malzkorn, B.; Kamp, M.; Sabel, M.; Simon, M.; Westphal, M.; Schackert, G.; Tonn, J.C.; Pietsch, T.; von Deimling, A.; Loeffler, M.; Reifenberger, G.; Weller, M. Epidermal growth factor receptor variant III (EGFRvIII) positivity in EGFR -amplified glioblastomas: Prognostic role and comparison between primary and recurrent tumors. Clin. Cancer Res., 2017, 23(22), 6846-6855. doi: 10.1158/1078-0432.CCR-17-0890 PMID: 28855349Xie, S.; Ni, J.; McFaline-Figueroa, J.R.; Wang, Y.; Bronson, R.T.; Ligon, K.L.; Wen, P.Y.; Roberts, T.M.; Zhao, J.J. Divergent roles of PI3K isoforms in PTEN-deficient glioblastomas. Cell Rep., 2020, 32(13), 108196. doi: 10.1016/j.celrep.2020.108196 PMID: 32997991Wang, H.; Xu, T.; Jiang, Y.; Xu, H.; Yan, Y.; Fu, D.; Chen, J. The challenges and the promise of molecular targeted therapy in malignant gliomas. Neoplasia, 2015, 17(3), 239-255. doi: 10.1016/j.neo.2015.02.002 PMID: 25810009Le Rhun, E.; Preusser, M.; Roth, P.; Reardon, D.A.; van den Bent, M.; Wen, P.; Reifenberger, G.; Weller, M. Molecular targeted therapy of glioblastoma. Cancer Treat. Rev., 2019, 80, 101896. doi: 10.1016/j.ctrv.2019.101896 PMID: 31541850Ou, A.; Yung, W.K.A.; Majd, N. Molecular mechanisms of treatment resistance in glioblastoma. Int. J. Mol. Sci., 2020, 22(1), 351. doi: 10.3390/ijms22010351 PMID: 33396284Li, 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, 7(22), 33440-33450. doi: 10.18632/oncotarget.7961 PMID: 26967052Yang, J.; Nie, J.; Ma, X.; Wei, Y.; Peng, Y.; Wei, X. Targeting PI3K in cancer: Mechanisms and advances in clinical trials. Mol. Cancer., 2019, 18(1), 26. doi: 10.1186/s12943-019-0954-x PMID: 30782187Sami, A.; Karsy, M. Targeting the PI3K/AKT/mTOR signaling pathway in glioblastoma: novel therapeutic agents and advances in understanding. Tumour Biol., 2013, 34(4), 1991-2002. doi: 10.1007/s13277-013-0800-5 PMID: 23625692Shergalis, A.; Bankhead, A.; Luesakul, U.; Muangsin, N.; Neamati, N. Current challenges and opportunities in treating glioblastoma. Pharmacol Rev., 2018, 70(3), 412-445. doi: 10.1124/pr.117.014944Hughes, J.P.; Rees, S.; Kalindjian, S.B.; Philpott, K.L. Principles of early drug discovery. Br. J. Pharmacol., 2011, 162(6), 1239-1249. doi: 10.1111/j.1476-5381.2010.01127.x PMID: 21091654Ediriweera, M.K.; Tennekoon, K.H.; Samarakoon, S.R. In vitro assays and techniques utilized in anticancer drug discovery. J. Appl. Toxicol., 2019, 39(1), 38-71. doi: 10.1002/jat.3658 PMID: 30073673Kotecki, N.; Kindt, N.; Krayem, M.; Awada, A. New horizons in early drugs development in solid cancers. Curr. Opin. Oncol., 2021, 33(5), 513-519. doi: 10.1097/CCO.0000000000000766 PMID: 34310410Atanasov, A.G.; Waltenberger, B.; Pferschy-Wenzig, E.M.; Linder, T.; Wawrosch, C.; Uhrin, P.; Temml, V.; Wang, L.; Schwaiger, S.; Heiss, E.H.; Rollinger, J.M.; Schuster, D.; Breuss, J.M.; Bochkov, V.; Mihovilovic, M.D.; Kopp, B.; Bauer, R.; Dirsch, V.M.; Stuppner, H. Discovery and resupply of pharmacologically active plant-derived natural products: A review. Biotechnol. Adv., 2015, 33(8), 1582-1614. doi: 10.1016/j.biotechadv.2015.08.001 PMID: 26281720Yao, W.; Gong, H.; Mei, H.; Shi, L.; Yu, J.; Hu, Y. Taxifolin targets PI3K and mTOR and inhibits glioblastoma multiforme. J. Oncol., 2021, 20(2021), 1-12.Thuan, N.H.; Shrestha, A.; Trung, N.T.; Tatipamula, V.B.; Van Cuong, D.; Canh, N.X.; Van Giang, N.; Kim, T.S.; Sohng, J.K.; Dhakal, D. Advances in biochemistry and the biotechnological production of taxifolin and its derivatives. Biotechnol. Appl. Biochem., 2022, 69(2), 848-861. doi: 10.1002/bab.2156 PMID: 33797804Das, A.; Baidya, R.; Chakraborty, T.; Samanta, A.K.; Roy, S. Pharmacological basis and new insights of taxifolin: A comprehensive review. Biomed. Pharmacother., 2021, 142, 112004. doi: 10.1016/j.biopha.2021.112004 PMID: 34388527Xie, J.; Pang, Y.; Wu, X. Taxifolin suppresses the malignant progression of gastric cancer by regulating the AhR/CYP1A1 signaling pathway. Int. J. Mol. Med., 2021, 48(5), 197. doi: 10.3892/ijmm.2021.5030 PMID: 34490474Wang, R.; Zhu, X.; Wang, Q.; Li, X.; Wang, E.; Zhao, Q.; Wang, Q.; Cao, H. The anti-tumor effect of taxifolin on lung cancer via suppressing stemness and epithelial-mesenchymal transition in vitro and oncogenesis in nude mice. Ann. Transl. Med., 2020, 8(9), 590-0. doi: 10.21037/atm-20-3329 PMID: 32566617Butt, S.S.; Khan, K.; Badshah, Y.; Rafiq, M.; Shabbir, M. Evaluation of pro-apoptotic potential of taxifolin against liver cancer. PeerJ, 2021, 9, e11276. doi: 10.7717/peerj.11276 PMID: 34113483Li, J.; Hu, L.; Zhou, T.; Gong, X.; Jiang, R.; Li, H.; Kuang, G.; Wan, J.; Li, H. Taxifolin inhibits breast cancer cells proliferation, migration and invasion by promoting mesenchymal to epithelial transition via β-catenin signaling. Life Sci., 2019, 232, 116617. doi: 10.1016/j.lfs.2019.116617 PMID: 31260685Su, R.Y.; Hsueh, S.C.; Chen, C.Y.; Hsu, M.J.; Lu, H.F.; Peng, S.F.; Chen, P.Y.; Lien, J.C.; Chen, Y.L.; Chueh, F.S.; Chung, J.G.; Yeh, M.Y.; Huang, Y.P. Demethoxycurcumin suppresses proliferation, migration, and Invasion of Human Brain Glioblastoma Multiforme GBM 8401 Cells via PI3K/Akt Pathway. Anticancer Res., 2021, 41(4), 1859-1870. doi: 10.21873/anticanres.14952 PMID: 33813391Han, G.; Bi, R.; Le, Q.; Zhao, L.L.; Dong, Y.; Lin, Q.H. Study on effect of demethoxycurcumin in Curcuma long on stability of curcumin. Zhong Yao Cai, 2008, 31(4), 592-594. PMID: 18661836Hatamipour, M.; Ramezani, M.; Tabassi, S.A.S.; Johnston, T.P.; Ramezani, M.; Sahebkar, A. Demethoxycurcumin: A naturally occurring curcumin analogue with antitumor properties. J. Cell. Physiol., 2018, 233(12), 9247-9260. doi: 10.1002/jcp.27029 PMID: 30076727Hoxhaj, G.; Manning, B.D. The PI3K–AKT network at the interface of oncogenic signalling and cancer metabolism. Nat. Rev. Cancer, 2020, 20(2), 74-88. doi: 10.1038/s41568-019-0216-7 PMID: 31686003Jiang, H.; Shang, X.; Wu, H.; Gautam, S.C.; Al-Holou, S.; Li, C.; Kuo, J.; Zhang, L.; Chopp, M. Resveratrol downregulates PI3K/Akt/mTOR signaling pathways in human U251 glioma cells. J. Exp. Ther. Oncol., 2009, 8(1), 25-33. PMID: 19827268Clark, P.A.; Bhattacharya, S.; Elmayan, A.; Darjatmoko, S.R.; Thuro, B.A.; Yan, M.B.; van Ginkel, P.R.; Polans, A.S.; Kuo, J.S. Resveratrol targeting of AKT and p53 in glioblastoma and glioblastoma stem-like cells to suppress growth and infiltration. J. Neurosurg., 2017, 126(5), 1448-1460. doi: 10.3171/2016.1.JNS152077 PMID: 27419830Debinski, W.; Tatter, S.B. Convection-enhanced delivery for the treatment of brain tumors. Expert Rev. Neurother., 2009, 9(10), 1519-1527. doi: 10.1586/ern.09.99 PMID: 19831841Florean, C.; Dicato, M.; Diederich, M. Immune-modulating and anti-inflammatory marine compounds against cancer. Semin. Cancer Biol., 2022, 80, 58-72. doi: 10.1016/j.semcancer.2020.02.008 PMID: 32070764Yao, Y.; Sun, S.; Cao, M.; Mao, M.; He, J.; Gai, Q.; Qin, Y.; Yao, X.; Lu, H.; Chen, F.; Wang, W.; Luo, M.; Zhang, H.; Huang, H.; Ju, J.; Bian, X.W.; Wang, Y. Grincamycin B functions as a potent inhibitor for glioblastoma stem cell via targeting RHOA and PI3K/AKT. ACS Chem. Neurosci., 2020, 11(15), 2256-2265. doi: 10.1021/acschemneuro.0c00206 PMID: 32584547Wang, Z.; Li, Z.; Zhao, W.; Huang, H.; Wang, J.; Zhang, H.; Lu, J.; Wang, R.; Li, W.; Cheng, Z.; Xu, W.; Di Zhu; Zhou, L.; Jiang, W.; Yu, L.; Liu, J.; Luo, C.; Zhu, H.; Dan Ye; Pan, W.; Ju, J.; Dang, Y. Identification and characterization of isocitrate dehydrogenase 1 (IDH1) as a functional target of marine natural product grincamycin B. Acta Pharmacol. Sin., 2021, 42(5), 801-813. doi: 10.1038/s41401-020-0491-6 PMID: 32796956Calvert, A.E.; Chalastanis, A.; Wu, Y.; Hurley, L.A.; Kouri, F.M.; Bi, Y.; Kachman, M.; May, J.L.; Bartom, E.; Hua, Y.; Mishra, R.K.; Schiltz, G.E.; Dubrovskyi, O.; Mazar, A.P.; Peter, M.E.; Zheng, H.; James, C.D.; Burant, C.F.; Chandel, N.S.; Davuluri, R.V.; Horbinski, C.; Stegh, A.H. Cancer-associated IDH1 promotes growth and resistance to targeted therapies in the absence of mutation. Cell Rep., 2017, 19(9), 1858-1873. doi: 10.1016/j.celrep.2017.05.014 PMID: 28564604Pan, L.; Chai, H.; Kinghorn, A.D. The continuing search for antitumor agents from higher plants. Phytochem. Lett., 2010, 3(1), 1-8. doi: 10.1016/j.phytol.2009.11.005 PMID: 20228943Gairola, K.; Gururani, S.; Bahuguna, A.; Garia, V.; Pujari, R.; Dubey, S.K. Natural products targeting cancer stem cells: Implications for cancer chemoprevention and therapeutics. J. Food Biochem., 2021, 45(7), e13772. doi: 10.1111/jfbc.13772 PMID: 34028051Lathia, J.D.; Mack, S.C.; Mulkearns-Hubert, E.E.; Valentim, C.L.L.; Rich, J.N. Cancer stem cells in glioblastoma. Genes Dev., 2015, 29(12), 1203-1217. doi: 10.1101/gad.261982.115 PMID: 26109046Biserova, K.; Jakovlevs, A.; Uljanovs, R.; Strumfa, I. Cancer stem cells: Significance in origin, pathogenesis and treatment of glioblastoma. Cells, 2021, 10(3), 621. doi: 10.3390/cells10030621 PMID: 33799798Sonabend, A.M.; Carminucci, A.S.; Amendolara, B.; Bansal, M.; Leung, R.; Lei, L.; Realubit, R.; Li, H.; Karan, C.; Yun, J.; Showers, C.; Rothcock, R.; O, J.; Califano, A.; Canoll, P.; Bruce, J.N. Convection-enhanced delivery of etoposide is effective against murine proneural glioblastoma. Neuro-oncol., 2014, 16(9), 1210-1219. doi: 10.1093/neuonc/nou026 PMID: 24637229Wang, Z.; Liang, P.; He, X.; Wu, B.; Liu, Q.; Xu, Z.; Wu, H.; Liu, Z.; Qian, Y.; Wang, S.; Zhu, R. Etoposide loaded layered double hydroxide nanoparticles reversing chemoresistance and eradicating human glioma stem cells in vitro and in vivo. Nanoscale, 2018, 10(27), 13106-13121. doi: 10.1039/C8NR02708K PMID: 29961791Needle, M.N.; Molloy, P.T.; Geyer, J.R.; Herman-Liu, A.; Belasco, J.B.; Goldwein, J.W.; Sutton, L.; Phillips, P.C. Phase II study of daily oral etoposide in children with recurrent brain tumors and other solid tumors. Med. Pediatr. Oncol., 1997, 29(1), 28-32. doi: 10.1002/(SICI)1096-911X(199707)29:13.0.CO;2-U PMID: 9142202Gimple, R.C.; Bhargava, S.; Dixit, D.; Rich, J.N. Glioblastoma stem cells: Lessons from the tumor hierarchy in a lethal cancer. Genes Dev., 2019, 33(11-12), 591-609. doi: 10.1101/gad.324301.119 PMID: 31160393Wang, J.B.; Pan, H.X.; Tang, G.L. Production of doramectin by rational engineering of the avermectin biosynthetic pathway. Bioorg. Med. Chem. Lett., 2011, 21(11), 3320-3323. doi: 10.1016/j.bmcl.2011.04.008 PMID: 21514826Gao, A.; Wang, X.; Xiang, W.; Liang, H.; Gao, J.; Yan, Y. Reversal of P-glycoprotein-mediated multidrug resistance in vitro by doramectin and nemadectin. J. Pharm. Pharmacol., 2010, 62(3), 393-399. doi: 10.1211/jpp.62.03.0016 PMID: 20487225Chen, C.; Liang, H.; Qin, R.; Li, X.; Wang, L.; Du, S.; Chen, Z.; Meng, X.; Lv, Z.; Wang, Q.; Meng, J.; Gao, A. Doramectin inhibits glioblastoma cell survival via regulation of autophagy in vitro and in vivo. Int. J. Oncol., 2022, 60(3), 29. doi: 10.3892/ijo.2022.5319 PMID: 35137919Wang, J.; Liu, X.; Hong, Y.; Wang, S.; Chen, P.; Gu, A.; Guo, X.; Zhao, P. Ibrutinib, a Bruton’s tyrosine kinase inhibitor, exhibits antitumoral activity and induces autophagy in glioblastoma. J. Exp. Clin. Cancer Res., 2017, 36(1), 96. doi: 10.1186/s13046-017-0549-6 PMID: 28716053Nadeem Abbas, M.; Kausar, S.; Wang, F.; Zhao, Y.; Cui, H. Advances in targeting the epidermal growth factor receptor pathway by synthetic products and its regulation by epigenetic modulators as a therapy for glioblastoma. Cells., 2019, 8(4), 350. doi: 10.3390/cells8040350 PMID: 31013819Charmsaz, S.; Prencipe, M.; Kiely, M.; Pidgeon, G.; Collins, D. Innovative technologies changing cancer treatment. Cancers., 2018, 10(6), 208. doi: 10.3390/cancers10060208 PMID: 29921753Bittlinger, M.; Bicer, S.; Peppercorn, J.; Kimmelman, J. Ethical considerations for phase I trials in oncology. J. Clin. Oncol., 2022, 40(30), 3474-3488. doi: 10.1200/JCO.21.02125 PMID: 35275736Minneci, P.C.; Deans, K.J. Clinical trials. Semin. Pediatr. Surg., 2018, 27(6), 332-337. doi: 10.1053/j.sempedsurg.2018.10.003 PMID: 30473036Mokhtari, R.B.; Homayouni, T.S.; Baluch, N.; Morgatskaya, E.; Kumar, S.; Das, B.; Yeger, H. Combination therapy in combating cancer. Oncotarget., 2017, 8(23), 38022-38043. doi: 10.18632/oncotarget.16723 PMID: 28410237Lah, T.T.; Novak, M.; Pena Almidon, M.A.; Marinelli, O.; Žvar Baškovič, B.; Majc, B.; Mlinar, M.; Bošnjak, R.; Breznik, B.; Zomer, R.; Nabissi, M. Cannabigerol is a potential therapeutic agent in a novel combined therapy for glioblastoma. Cells, 2021, 10(2), 340. doi: 10.3390/cells10020340 PMID: 33562819Ghosh, D.; Nandi, S.; Bhattacharjee, S. Combination therapy to checkmate Glioblastoma: Clinical challenges and advances. Clin. Transl. Med., 2018, 7(1), 33. doi: 10.1186/s40169-018-0211-8 PMID: 30327965Yang, J.; Shi, Z.; Liu, R.; Wu, Y.; Zhang, X. Combined-therapeutic strategies synergistically potentiate glioblastoma multiforme treatment via nanotechnology. Theranostics., 2020, 10(7), 3223-3239. doi: 10.7150/thno.40298 PMID: 32194864Speranza, M.C.; Nowicki, M.O.; Behera, P.; Cho, C.F.; Chiocca, E.A.; Lawler, S.E. BKM-120 (Buparlisib): A Phosphatidyl- inositol-3 kinase inhibitor with anti-invasive properties in glioblastoma. Sci. Rep., 2016, 6(1), 20189. doi: 10.1038/srep20189 PMID: 26846842Chakravarti, A.; Zhai, G.; Suzuki, Y.; Sarkesh, S.; Black, P.M.; Muzikansky, A.; Loeffler, J.S. The prognostic significance of phosphatidylinositol 3-kinase pathway activation in human gliomas. J. Clin. Oncol., 2004, 22(10), 1926-1933. doi: 10.1200/JCO.2004.07.193 PMID: 15143086Wachsberger, P.R.; Lawrence, Y.R.; Liu, Y.; Rice, B.; Feo, N.; Leiby, B.; Dicker, A.P. Hsp90 inhibition enhances PI-3 kinase inhibition and radiosensitivity in glioblastoma. J. Cancer Res. Clin. Oncol., 2014, 140(4), 573-582. doi: 10.1007/s00432-014-1594-6 PMID: 24500492Hainsworth, J.D.; Becker, K.P.; Mekhail, T.; Chowdhary, S.A.; Eakle, J.F.; Wright, D.; Langdon, R.M.; Yost, K.J.; Padula, G.D.A.; West-Osterfield, K.; Scarberry, M.; Shaifer, C.A.; Shastry, M.; Burris, H.A., III; Shih, K. Phase I/II study of bevacizumab with BKM120, an oral PI3K inhibitor, in patients with refractory solid tumors (phase I) and relapsed/refractory glioblastoma (phase II). J. Neurooncol., 2019, 144(2), 303-311. doi: 10.1007/s11060-019-03227-7 PMID: 31392595Wen, P.Y.; Rodon, J.A.; Mason, W.; Beck, J.T.; DeGroot, J.; Donnet, V.; Mills, D.; El-Hashimy, M.; Rosenthal, M. Phase I, open-label, multicentre study of buparlisib in combination with temozolomide or with concomitant radiation therapy and temozolomide in patients with newly diagnosed glioblastoma. ESMO Open, 2020, 5(4), e000673. doi: 10.1136/esmoopen-2020-000673 PMID: 32661186Heffron, T.P.; Ndubaku, C.O.; Salphati, L.; Alicke, B.; Cheong, J.; Drobnick, J.; Edgar, K.; Gould, S.E.; Lee, L.B.; Lesnick, J.D.; Lewis, C.; Nonomiya, J.; Pang, J.; Plise, E.G.; Sideris, S.; Wallin, J.; Wang, L.; Zhang, X.; Olivero, A.G. Discovery of clinical development candidate GDC-0084, a brain penetrant inhibitor of PI3K and mTOR. ACS Med. Chem. Lett., 2016, 7(4), 351-356. doi: 10.1021/acsmedchemlett.6b00005 PMID: 27096040Salphati, L.; Alicke, B.; Heffron, T.P.; Shahidi-Latham, S.; Nishimura, M.; Cao, T.; Carano, R.A.; Cheong, J.; Greve, J.; Koeppen, H.; Lau, S.; Lee, L.B.; Nannini-Pepe, M.; Pang, J.; Plise, E.G.; Quiason, C.; Rangell, L.; Zhang, X.; Gould, S.E.; Phillips, H.S.; Olivero, A.G. Brain distribution and efficacy of the brain penetrant PI3K inhibitor GDC-0084 in orthotopic mouse models of human glioblastoma. Drug Metab. Dispos., 2016, 44(12), 1881-1889. doi: 10.1124/dmd.116.071423 PMID: 27638506Wen, P.Y.; De Groot, J.F.; Battiste, J.D.; Goldlust, S.A.; Garner, J.S.; Simpson, J.A.; Kijlstra, J.; Olivero, A.; Cloughesy, T.F. Escalation portion of phase II study to evaluate the safety, pharmacokinetics, and clinical activity of the PI3K/mTOR inhibitor paxalisib (GDC-0084) in glioblastoma (GBM) with unmethylated O6-methylguanine-methyltransferase (MGMT) promotor status. J. Clin. Oncol., 2020, 38(S15), 2550-0. doi: 10.1200/JCO.2020.38.15_suppl.2550Przystal, J.M.; Cianciolo Cosentino, C.; Yadavilli, S.; Zhang, J.; Laternser, S.; Bonner, E.R.; Prasad, R.; Dawood, A.A.; Lobeto, N.; Chin Chong, W.; Biery, M.C.; Myers, C.; Olson, J.M.; Panditharatna, E.; Kritzer, B.; Mourabit, S.; Vitanza, N.A.; Filbin, M.G.; de Iuliis, G.N.; Dun, M.D.; Koschmann, C.; Cain, J.E.; Grotzer, M.A.; Waszak, S.M.; Mueller, S.; Nazarian, J. Imipridones affect tumor bioenergetics and promote cell lineage differentiation in diffuse midline gliomas. Neuro-oncol., 2022, 24(9), 1438-1451. doi: 10.1093/neuonc/noac041 PMID: 35157764Chan, H.Y.; Choi, J.; Jackson, C.; Lim, M. Combination immunotherapy strategies for glioblastoma. J. Neurooncol., 2021, 151(3), 375-391. doi: 10.1007/s11060-020-03481-0 PMID: 33611705Hörnschemeyer, J.; Kirschstein, T.; Reichart, G.; Sasse, C.; Venus, J.; Einsle, A.; Porath, K.; Linnebacher, M.; Köhling, R.; Lange, F. Studies on biological and molecular effects of small-molecule kinase inhibitors on human glioblastoma cells and organotypic brain slices. Life., 2022, 12(8), 1258. doi: 10.3390/life12081258 PMID: 36013437Sweeney, C.; Bracarda, S.; Sternberg, C.N.; Chi, K.N.; Olmos, D.; Sandhu, S.; Massard, C.; Matsubara, N.; Alekseev, B.; Parnis, F.; Atduev, V.; Buchschacher, G.L., Jr; Gafanov, R.; Corrales, L.; Borre, M.; Stroyakovskiy, D.; Alves, G.V.; Bournakis, E.; Puente, J.; Harle-Yge, M.L.; Gallo, J.; Chen, G.; Hanover, J.; Wongchenko, M.J.; Garcia, J.; de Bono, J.S. Ipatasertib plus abiraterone and prednisolone in metastatic castration-resistant prostate cancer (IPATential150): A multicentre, randomised, double-blind, phase 3 trial. Lancet., 2021, 398(10295), 131-142. doi: 10.1016/S0140-6736(21)00580-8 PMID: 34246347Dent, R.; Oliveira, M.; Isakoff, S.J.; Im, S.A.; Espié, M.; Blau, S.; Tan, A.R.; Saura, C.; Wongchenko, M.J.; Xu, N.; Bradley, D.; Reilly, S.J.; Mani, A.; Kim, S.B.; Lee, K.S.; Sohn, J.H.; Kim, J.H.; Seo, J.H.; Kim, J.S.; Park, S.; Velez, M.; Dakhil, S.; Hurvitz, S.; Valero, V.; Vidal, G.; Figlin, R.; Allison, M.A.K.; Chan, D.; Cobleigh, M.; Hansen, V.; Iannotti, N.; Lawler, W.; Salkini, M.; Seigel, L.; Romieu, G.; Debled, M.; Levy, C.; Hardy-Bessard, A.; Guiu, S.; Estevez, L.G.; Villanueva, R.; Martin, A.G.; Rovira, P.S.; Montaño, A.; Plaza, M.I.C.; Saenz, J.A.G.; Garau, I.; Bermejo, B.; Alonso, E.V.; Wang, H-C.; Huang, C-S.; Chen, S-C.; Chen, Y-H.; Tseng, L-M.; Wong, A.; Ang, C.S.P.; De Laurentiis, M.; Conte, P.F.; De Braud, F.; Montemurro, F.; Gianni, L.; Dirix, L. Final results of the double-blind placebo-controlled randomized phase 2 LOTUS trial of first-line ipatasertib plus paclitaxel for inoperable locally advanced/metastatic triple-negative breast cancer. Breast Cancer Res. Treat., 2021, 189(2), 377-386. doi: 10.1007/s10549-021-06143-5 PMID: 34264439Kaley, T.J.; Panageas, K.S.; Pentsova, E.I.; Mellinghoff, I.K.; Nolan, C.; Gavrilovic, I.; DeAngelis, L.M.; Abrey, L.E.; Holland, E.C.; Omuro, A.; Lacouture, M.E.; Ludwig, E.; Lassman, A.B. Phase I clinical trial of temsirolimus and perifosine for recurrent glioblastoma. Ann. Clin. Transl. Neurol., 2020, 7(4), 429-436. doi: 10.1002/acn3.51009 PMID: 32293798Galanis, E.; Buckner, J.C.; Maurer, M.J.; Kreisberg, J.I.; Ballman, K.; Boni, J.; Peralba, J.M.; Jenkins, R.B.; Dakhil, S.R.; Morton, R.F.; Jaeckle, K.A.; Scheithauer, B.W.; Dancey, J.; Hidalgo, M.; Walsh, D.J. Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: A North Central Cancer Treatment Group Study. J. Clin. Oncol., 2005, 23(23), 5294-5304. doi: 10.1200/JCO.2005.23.622 PMID: 15998902Almeida Pachioni, J.D.; Magalhães, J.G.; Cardoso Lima, E.J.; Moura Bueno, L.D.; Barbosa, J.F.; Malta de Sá, M.; Rangel-Yagui, C.O. Alkylphospholipids - a promising class of chemotherapeutic agents with a broad pharmacological spectrum. J. Pharm. Pharm. Sci., 2013, 16(5), 742-759. doi: 10.18433/J3CW23 PMID: 24393556Pitter, K.L.; Galbán, C.J.; Galbán, S.; Saeed-Tehrani, O.; Li, F.; Charles, N. Perifosine and CCI 779 co-operate to induce cell death and decrease proliferation in PTEN-Intact and PTEN-Deficient PDGF-Driven Murine Glioblastoma. PLoS ONE., 2011, 6(1), e14545.Kaley, T.J.; Panageas, K.S.; Mellinghoff, I.K.; Nolan, C.; Gavrilovic, I.T.; DeAngelis, L.M.; Abrey, L.E.; Holland, E.C.; Lassman, A.B. Phase II trial of an AKT inhibitor (perifosine) for recurrent glioblastoma. J. Neurooncol., 2019, 144(2), 403-407. doi: 10.1007/s11060-019-03243-7 PMID: 31325145Chinnaiyan, P.; Won, M.; Wen, P.Y.; Rojiani, A.M.; Wendland, M.; Dipetrillo, T.A.; Corn, B.W.; Mehta, M.P. RTOG 0913: A phase 1 study of daily everolimus (RAD001) in combination with radiation therapy and temozolomide in patients with newly diagnosed glioblastoma. Int. J. Radiat. Oncol. Biol. Phys., 2013, 86(5), 880-884. doi: 10.1016/j.ijrobp.2013.04.036 PMID: 23725999Chinnaiyan, P.; Won, M.; Wen, P.Y.; Rojiani, A.M.; Werner-Wasik, M.; Shih, H.A.; Ashby, L.S.; Michael Yu, H.H.; Stieber, V.W.; Malone, S.C.; Fiveash, J.B.; Mohile, N.A.; Ahluwalia, M.S.; Wendland, M.M.; Stella, P.J.; Kee, A.Y.; Mehta, M.P. A randomized phase II study of everolimus in combination with chemoradiation in newly diagnosed glioblastoma: Results of NRG Oncology RTOG 0913. Neuro-oncol., 2018, 20(5), 666-673. doi: 10.1093/neuonc/nox209 PMID: 29126203O’Reilly, K.E.; Rojo, F.; She, Q.B.; Solit, D.; Mills, G.B.; Smith, D.; Lane, H.; Hofmann, F.; Hicklin, D.J.; Ludwig, D.L.; Baselga, J.; Rosen, N. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res., 2006, 66(3), 1500-1508. doi: 10.1158/0008-5472.CAN-05-2925 PMID: 16452206Luchman, H.A.; Stechishin, O.D.M.; Nguyen, S.A.; Lun, X.Q.; Cairncross, J.G.; Weiss, S. Dual mTORC1/2 blockade inhibits glioblastoma brain tumor initiating cells in vitro and in vivo and synergizes with temozolomide to increase orthotopic xenograft survival. Clin. Cancer Res., 2014, 20(22), 5756-5767. doi: 10.1158/1078-0432.CCR-13-3389 PMID: 25316808Lapointe, S.; Mason, W.; MacNeil, M.; Harlos, C.; Tsang, R.; Sederias, J.; Luchman, H.A.; Weiss, S.; Rossiter, J.P.; Tu, D.; Seymour, L.; Smoragiewicz, M. A phase I study of vistusertib (dual mTORC1/2 inhibitor) in patients with previously treated glioblastoma multiforme: A CCTG study. Invest. New Drugs, 2020, 38(4), 1137-1144. doi: 10.1007/s10637-019-00875-4 PMID: 31707687Osuka, S.; Van Meir, E.G. Overcoming therapeutic resistance in glioblastoma: the way forward. J. Clin. Invest., 2017, 127(2), 415-426. doi: 10.1172/JCI89587 PMID: 28145904Arrillaga-Romany, I.; Chi, A.S.; Allen, J.E.; Oster, W.; Wen, P.Y.; Batchelor, T.T. A phase 2 study of the first imipridone ONC201, a selective DRD2 antagonist for oncology, administered every three weeks in recurrent glioblastoma. Oncotarget, 2017, 8(45), 79298-79304. doi: 10.18632/oncotarget.17837 PMID: 29108308Mecca, C; Giambanco, I; Donato, R; Arcuri, C. Targeting mTOR in glioblastoma: Rationale and preclinical/clinical evidence. Dis Markers, 2018, 2018, 9230479.