1Stupp R, Mason WP, van den Ben MJt, Weller M, et al. (2005) Radiotherapy plus concomitant and adjuvant Temozolomide for glioblastoma. N Engl J Med 352: 987-996.

2Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, et al. (2009) Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomized phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10: 459-466.

3Louis, PerryA, Reifenberger G, vonDeimling A, Figarella-Branger D, et al. (2016) The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol 131: 803-820.

4Ohgaki H, Kleihues P (2013)The definition of primary and secondary glioblastoma Clin Cancer Res 19: 764-772.

5Rong Y, Durden DL, VanMeir EG, Brat DJ (2006) 'Pseudopalisading' necrosis in glioblastoma: a familiar morphologic feature that links vascular pathology, hypoxia, and angiogenesis. J Neuropathol Exp Neurol 65: 529-539.

6Folkman J (1971)Tumor angiogenesis: therapeutic implications. N Engl J Med 285: 1182-1186.

7Baeriswyl V, Christofori G (2009) The angiogenic switch in carcinogenesis. Semin CancerBiol 19: 329-337.

8Kerbel RS (2008) Tumor Angiogenesis. N Engl J Med 358: 2039–2049.

9Schmidt NO, Westphal M, Hagel C, Ergün S, Stavrou D, et al. (1999) Levels of vascular endothelial growth factor, hepatocyte growth factor/scatter factor and basic fibroblast growth factor in human gliomas and their relation to angiogenesis. Int J Cancer 84:10-18.

10Reiss Y, Machein MR, Plate KH (2005) The role of angiopoietins during angiogenesis in gliomas. Brain Pathol. 15: 311-317.

11Brat DJ, Bellail AC, Van Meir EG (2005) The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis. Neuro Oncol 7: 122-133.

12Shibuya M (2011) Vascular Endothelial Growth Factor (VEGF) and Its Receptor (VEGFR) Signaling in Angiogenesis: A Crucial Target for Anti- and Pro-Angiogenic Therapies. Genes Cancer 22: 1097-1105.

13Shibuya M, Claesson-Welsh L (2006) Signal transduction by VEGF receptors in the regulation of angiogenesis and lymphangiogenesis. Exp Cell Res 312: 549-560.

14Lee S, Chen TT, Barber CL, Jordan MC, Murdock J, et al. (2007) Autocrine VEGF signaling is required for vascular homeostasis. Cell 130: 691-703.

15Ferrara N1, Gerber HP, Le Couter J (2003) The biology of VEGF and its receptors. Nature Med 9: 669-676.

16Ferrara N, Kerbel RS (2005) Angiogenesis as a therapeutic target. Nature 438: 967-974.

17Plate KH, Mennel HD (1995) Vascular morphology and angiogenesis in glial tumors. Exp Toxicol Pathol 147: 89-94.

18Pacioni S, D'Alessandris QG, Buccarelli M, Boe A, Martini M, et al. (2019) Brain Invasion along Perivascular Spaces by Glioma Cells: Relationship with Blood-Brain Barrier. Cancers (Basel) 19:12 pii: E18.

19Wang GL, Jiang BH, Rue EA, and Semenza GL (1995) Hypoxia-inducible factor 1 is a basic- helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 92: 5510–5514.

20Xu C1, Wu X, Zhu J (2013) VEGF promotes the proliferation of human glioblastoma multiforme stem-like cells through VEGF receptor 2. Scientific World Journal 417413.

21Bao S, Wu Q, Sathornsumetee S, Hao Y, Li Z, et al. (2006) Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res 66: 7843-7848.

22Treps L, Perret R, Edmond S, Ricard D and Gavarda J (2017) Glioblastoma stem-like cells secrete the pro-angiogenic VEGF-A factor in extracellular vesicles. J Extra cell Vesicles 6: 1359479.

23Jain RK (2010) Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med 7: 987-989.

24Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, et al. (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N. Engl. J. Med 350: 2335-2342.

25Cohen MH, Gootenberg J, Keegan P, Pazdur R (2007) FDA drug approval summary: bevacizumab (Avastin) plus Carboplatin and Paclitaxel as first-line treatment of advanced/metastatic recurrent nonsquamous non-small cell lung cancer. Oncologist 12: 713-718.

26Summers J, Cohen MH, Keegan P, Pazdur R (2010) FDA drug approval summary :bevacizumab plus interferon for advanced renal cell carcinoma. Oncologist 15: 104-111.

27Cohen MH, Shen YL, Keegan P, Pazdur R (2009) FDA drug approval summary: bevacizumab (Avastin) as treatment of recurrent glioblastoma multiforme. Oncologist 14: 1131-1138.

28Gerstner ER, Duda DG, di Tomaso E, Ryg PA, Loeffler JS, et al. (2009) VEGF inhibitors in the treatment of cerebral edema in patients with brain cancer.Nat Rev Clin Oncol 6: 229-236.

29Hasselbalch B, Lassen U, Hansen S, Holmberg M, Sørensen M, et al. (2010) Cetuximab, bevacizumab, and irinotecan for patients with primary glioblastoma and progression after radiation therapy and temozolomide: a phase II trial. Neuro Oncol 12: 508-516.

30Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, et al. (2008) Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 27: 4733-4740.

31Kreisl TN, Kim L, Moore K, Duic P, Royce C, et al. (2009) Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 27: 740-745.

32Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, et al. (2014) A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med 370: 699-708.

33Chinot OL, Wick W, Mason W, Henriksson R, Saran F, et al. (2014) Bevacizumab plus radiotherapy temozolomide for newly diagnosed glioblastoma. N Engl J Med 370: 709-722.

34Taal W, Oosterkamp HM, Walenkamp AME, DubbinkHJ, Beerepoot LV, et al. (2014) Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOBtrial):a randomized controlled phase2trial. Lancet Oncol 15: 943–953.

35Wick W, Gorlia T, Bendszus M, Taphoorn M, Sahm F, et al. (2017) Lomustine and Bevacizumab in progressive glioblastoma. N Engl J Med 377: 1954-1963.

36Sandmann T, Bourgon R, Garcia J, Li C, Cloughesy T, et al. (2015) Patients with proneural glioblastoma may derive an overall survival benefit from the addition of bevacizumab to first-line radiotherapy and Temozolomide: retrospective analysis of the AVAglio Trial. J Clin Oncol 33: 2735-2744.

37Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, et al. (2010) Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17: 98–110.

38Erdem-Eraslan L, van den Bent MJ, Hoogstrate Y, Naz-Khan H, Stubbs A, et al. (2016) Identification of Patients with Recurrent Glioblastoma Who May Benefit from Combined Bevacizumab and CCNU Therapy: A Report from the BELOB Trial. Cancer Res 76: 525-534.

39Bergers G1 Hanahan D (2008) Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8: 592-603.

40deGroot JF, Fuller G, Kumar AJ, Piao Y, Eterovic K ,et al. (2010) Tumor invasion after treatment of glioblastoma with bevacizumab: radiographic and pathologic correlation in humans and mice. Neuro Oncol 12: 233–242.

41Gomez‐Manzano C, Holash J, Fueyo J, Xu J, Conrad CA, et al. (2008) VEGF trap induces anti-glioma effect at different stages of the disease. NeuroOncol 10: 940–945.

42Pàez‐Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, et al. (2009) Antiangiogenic therapy elicit s malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15: 220–231.

43FalchettiML, D'AlessandrisQG, Pacioni S, BuccarelliM, MorganteL, et al. (2019)Glioblastoma endothelium drives bevacizumab-induced infiltrative growth via modulation of PLXDC1. Int J Cancer 144: 1331-1344.

44Stegmayr C, Oliveira D, Niemietz N, Willuweit A, Lohmann P, et al. (2017) Influence of Bevacizumabon Blood-Brain Barrier Permeability and O-(2-18FFluoroethyl)-l-TyrosineUptake in Rat Gliomas. J Nucl Med 58: 700–705.

45Gonçalves VM, Cardoso-Carneiro D, Valbom I, Cury F. Silva VA, et al. (2017) Metabolic alterations underlying Bevacizumab therapy in glioblastoma cells. Oncotarget 8: 103657– 103670.

46Elaimy AL, Mercurio AM (2018) Convergence of VEGF and YAP/TAZ signaling: Implications for angiogenesis and cancer biology. Sci Signal. 11(552). PII: eaau1165.

47Zanconato F, Cordenonsi M, Piccolo S (2016) YAP/TAZ at the Roots of Cancer. Cancer Cell 29: 783-803.

48Kara E, Dupuy L, Bouillon C, Casteret S, and Maurel MC (2019) Modulation of gonadotropins Activity by Antibodies. Front Endocrinol (Lausanne) 10: 15.

49Schechter Y, Hernaez L, Schlessinger J & Cuatrecasas P (1979) Local aggregation of hormone-receptor complexes is required for activation by the epidermal growth factor. Nature 278: 835–838.

50Brave SR, Ratcliffe K, Wilson Z, James NH, Ashton S, et al. (2011) Assessing the activity of cediranib, a VEGFR-2/3 tyrosine kinase inhibitor, against VEGFR-1 and members of the structurally related PDGFR family. Mol Cancer Ther 10: 861–873.

51Batchelor TT, Mulholl and P,Neyns B, NaborsLB, Campone, et al. (2013) PhaseIII randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma. J Clin Oncol 31: 3212–3118.

52Stein MN, Flaherty KT (2007) CCR drug updates: Sorafenib and sunitinib in renal cell carcinoma. Clin Cancer Res 13: 3765–3770.

53Hutterer M, Nowosielski M, Haybaeck J, Embacher S, Stockhammer F, et al. (2014) A single-arm phase II Austrian/German multicenter trial on continuous daily sunitinib in primary glioblastoma at first recurrence (SURGE 01-07). Neuro Oncol 16: 92–102.

54Hassler MR, Ackerl M, Flechl B, Sax C, Wöhrer A, et al. (2014) Sorafenib for patients with pretreated recurrent or progressive high-grade glioma: A retrospective, single-institution study. Anticancer Drugs 25: 723–728.

55Zustovich F, Landi L, Lombardi G, Porta C, Galli L, et al. (2013) Sorafenib plus daily low-dose temozolomide for relapsed glioblastoma: A phase II study. Anticancer Res 33: 3487–3494.

56Iwamoto FM, Lamborn KR, Robins HI, Mehta MP, Chang SM, et al. (2010) Phase II trial of pazopanib (GW786034), an oral multi-targeted angiogenesis inhibitor, for adults with recurrent glioblastoma (North American Brain Tumor Consortium Study 06-02). Neuro Oncol 12: 855-861.

57Escudier B, GoreM (2011) Axitinib for the management of metastatic renal cell carcinoma. Drugs R D 11: 113–126.

58Klaeger S, Heinzlmeir S, Wilhelm M, Polzer H, Vick B, et al. (2017) The target landscape of clinical kinase drugs. Science 358: pii: eaan 4368.

59Hu-Lowe DD, Zou HY, Grazzini ML, Hallin ME, Wickman GR, et al. (2008) Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases1,2,3. Clin Cancer Res 14: 7272–7283.

60LuL, Saha D, Martuza RL, Rabkin SD, Wakimoto H (2015)Single agent efficacy of the VEGFR kinaseinhibitoraxitinib in preclinical models of glioblastoma. J Neurooncol 121: 91-100.

61Duerinck J, Du Four S, Vandervorst F, D'Haene N, Le Mercier M, et al. (2016) Randomized phase II study of axitinib versus physician's best alternative choice of therapy in patients with recurrent glioblastoma. J Neurooncol. 128: 147-155.

62Duerinck S, Du Four F, Bouttens C, Andre V, Verschaeve F, et al. (2017) Randomized phase II trial comparing axitinib with the combination of axitinib and lomustine in patients with recurrent glioblastoma. Journal of Neuro-Oncology 136: 115–125.

63Morelli MB, Amantini C, Santoni M, Soriani A, Nabissi M, et al. (2015) Axitinib induces DNA damage response leading to senescence, mitotic catastrophe, and increased NK cell recognition in human renal carcinoma cells. Oncotarget 6: 36245–6259.

64Morelli MB, Amantini C, Nabissi M, Cardinali C, Santoni M, et al. (2017). Axitinib induces senescence-associated cell death and necrosis in glioma cell lines: The proteasome inhibitor, bortezomib, potentiates axitinib-induced cytotoxicity in a p21(Waf/Cip1) dependent manner. Oncotarget 8: 3380-3395.

65Mongiardi MP, Radice G, Piras M, Stagni V, Pacioni S, et al (2019) Axitinib exposure triggers endothelial cells senescence through ROS accumulation and ATM activation. Oncogene 38: 5413-5424.