Angiogenesis and Its Targeting in Glioblastoma with Focus on Clinical Approaches

Document Type : Review Article

Authors

1 Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran

2 Department of Tissue Engineering and Biomaterials, School of Advanced Medical Sciences and Technologies, Hamadan University of Medical Sciences, Hamadan, Iran

3 Department of Nanotechnology and Tissue Engineering, Stem Cell Technology Research Center, Tehran, Iran;5Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

4 Medical Nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Abstract

Angiogenesis is a characteristic of glioblastoma (GBM), the most fatal and therapeutic-resistant brain tumor. Highly expressed angiogenic cytokines and proliferated microvascular system made anti-angiogenesis treatments a thoroughly plausible approach for GBM treatment. Many trials have proved to be not only as a safe but also as an effective approach in GBM retardation in a certain time window as seen in radiographic response rates; however, they have failed to implement significant improvements in clinical manifestation whether alone or in combination with radio/chemotherapy. Bevasizumab, an anti-vascular endothelial growth factor-A (VEGF-A) antibody, is the only agent that exerts meaningful clinical influence by improving progression-free survival (PFS) and partially alleviate clinical symptoms, nevertheless, it could not prolong the overall survival (OS) in patients with GBM. The data generated from phase II trials clearly revealed a correlation between elevated reperfusion, subsequent to vascular normalization induction, and improved clinical outcomes which explicitly indicates anti-angiogenesis treatments are beneficial. In order to prolong these initial benefits observed in a certain period of time after anti-angiogenesis targeting, some aspects of the therapy should be tackled: recognition of other bypass angiogenesis pathways activated following antiangiogenesis therapy, identification of probable pathways that induce insensitivity to shortage of blood supply, and classifying the patients by mapping their GBM-related gene profile as biomarkers to predict their responsiveness to therapy. Herein, the molecular basis of brain vasculature development in normal and tumoral conditions is briefly discussed and it is explained how "vascular normalization" concept opened a window to a better comprehension of some adverse effects observed in anti-angiogenesis therapy in clinical condition. Then, the most targeted angiogenesis pathways focused on ligand/receptor interactions in GBM clinical trials are reviewed. Lastly, different targeting strategies applied in anti-angiogenesis treatment are discussed.

Keywords

References

1. Carmeliet P, Jain RK. Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat Rev Drug Discov. 2011; 10(6): 417-427.
2. Fukumura D, Kloepper J, Amoozgar Z, Duda DG, Jain RK. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Rev Clin Oncol. 2018; 15(5): 325-340.
3. Hajighasemlou S, Nikbakht M, Pakzad S, Muhammadnejad S, Gharibzadeh S, Mirmoghtadaei M, et al. Sorafenib and mesenchymal stem cell therapy: a promising approach for treatment of HCC. Evid Based Complement Alternat Med. 2020: 9602728.
4. Rink C, Khanna S. Significance of brain tissue oxygenation and the arachidonic acid cascade in stroke. Antioxid Redox Signal. 2011; 14(10): 1889-1903.
5. Feeney Jr JF, Watterson RL. The development of the vascular pattern within the walls of the central nervous system of the chick embryo. J Morphol. 1946; 78(2): 231-303.
6. Lok J, Gupta P, Guo S, Kim WJ, Whalen MJ, van Leyen K, et al. Cell-cell signaling in the neurovascular unit. Neurochem Res. 2007; 32(12): 2032-2045.
7. Hogan KA, Ambler CA, Chapman DL, Bautch VL. The neural tube patterns vessels developmentally using the VEGF signaling pathway. Development. 2004; 131(7): 1503-1513.
8. Bautch VL, James JM. Neurovascular development: the beginning of a beautiful friendship. Cell Adh Migr. 2009; 3(2): 199-204.
9. Bairey D, Blickstein D, Shaklai M. Tumor angiogenesis--prognostic and therapeutic implications. Harefuah. 1997; 132(2): 117-120.
10. Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer. 2003; 3(6): 401-410.
11. Wu JB, Tang YL, Liang XH. Targeting VEGF pathway to normalize the vasculature: an emerging insight in cancer therapy. Onco Targets Ther. 2018; 11: 6901-6909.
12. Kleihues P, Louis DN, Scheithauer BW, Rorke LB, Reifenberger G, Burger PC, et al. The WHO classification of tumors of the nervous system. J Neuropathol Exp Neurol. 2002; 61(3): 215-225.
13. Jain RK, di Tomaso E, Duda DG, Loeffler JS, Sorensen AG, Batchelor TT. Angiogenesis in brain tumours. Nat Rev Neurosci. 2007; 8(8): 610-622.
14. Winkler F, Kozin SV, Tong RT, Chae SS, Booth MF, Garkavtsev I, et al. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell. 2004; 6(6): 553-563.
15. Yang J, Yan J, Liu B. Targeting VEGF/VEGFR to modulate antitumor immunity. Front Immunol. 2018; 9: 978.
16. Bayat N, Izadpanah R, Ebrahimi-Barough S, Norouzi Javidan A, Ai A, Mokhtari Ardakan MM, et al. The anti-angiogenic effect of atorvastatin in glioblastoma spheroids tumor cultured in fibrin gel: in 3D in vitro model. Asian Pac J Cancer Prev. 2018; 19(9): 2553-2560.
17. Ai J, Ebrahimi S, Ai A, Karimi R, Bahrami N. Effect of deforolimus and VEGF on angiogenesis in endometrial stromal cells following three-dimensional culture. Stem Cell Discov. 2013; 3(1): 7-12.
18. Oprita A, Baloi SC, Staicu GA, Alexandru O, Tache DE, Danoiu S, et al. Updated insights on EGFR signaling pathways in glioma. Int J Mol Sci. 2021; 22(2).
19. Korc M, Friesel RE. The role of fibroblast growth factors in tumor growth. Curr Cancer Drug Targets. 2009; 9(5): 639-651.
20. Khalid EB, Ayman EE, Rahman H, Abdelkarim G, Najda A. Natural products against cancer angiogenesis. Tumour Biol. 2016; 37(11): 14513-14536.
21. Dieci MV, Arnedos M, Andre F, Soria JC. Fibroblast growth factor receptor inhibitors as a cancer treatment: from a biologic rationale to medical perspectives. Cancer Discov. 2013; 3(3): 264-279.
22. Jimenez-Pascual A, Siebzehnrubl FA. Fibroblast growth factor receptor functions in glioblastoma. Cells. 2019; 8(7): 715.
23. Zhao Y, Adjei AA. Targeting angiogenesis in cancer therapy: moving beyond vascular endothelial growth factor. Oncologist. 2015; 20(6): 660-673.
24. Manzat Saplacan RM, Balacescu L, Gherman C, Chira RI, Craiu A, Mircea PA, et al. The role of PDGFs and PDGFRs in colorectal cancer. Mediators Inflamm. 2017; 2017: 4708076.
25. Holdhoff M, Kreuzer KA, Appelt C, Scholz R, Na IK, Hildebrandt B, et al. Imatinib mesylate radiosensitizes human glioblastoma cells through inhibition of platelet-derived growth factor receptor. Blood Cells Mol Dis. 2005; 34: 181-185.
26. Dresemann G, Weller M, Rosenthal MA, Wedding U, Wagner W, Engel E, et al. Imatinib in combination with hydroxyurea versus hydroxyurea alone as oral therapy in patients with progressive pretreated glioblastoma resistant to standard dose temozolomide. J Neurooncol. 2010; 96: 393-402.
27. Al-Abd AM, Alamoudi AJ, Abdel-Naim AB, Neamatallah TA, Ashour OM. Anti-angiogenic agents for the treatment of solid tumors: Potential pathways, therapy and current strategies - a review. J Adv Res. 2017; 8(6): 591-605.
28. Kunkel P, Muller S, Schirmacher P, Stavrou D, Fillbrandt R, Westphal M, et al. Expression and localization of scatter factor/hepatocyte growth factor in human astrocytomas. Neuro Oncol. 2001; 3(2): 82-88.
29. Cheng F, Guo D. MET in glioma: signaling pathways and targeted therapies. J Exp Clin Cancer Res. 2019; 38(1): 270.
30. Affronti ML, Jackman JG, McSherry F, Herndon JE 2nd, Massey EC Jr, Lipp E, et al. Phase II study to evaluate the efficacy and safety of rilotumumab and bevacizumab in subjects with recurrent malignant glioma. Oncologist. 2018; 23(8): 889-e898.
31. Cloughesy T, Finocchiaro G, Belda-Iniesta C, Recht L, Brandes AA, Pineda E, et al. Randomized, double-blind, placebo-controlled, multicenter phase II study of onartuzumab plus bevacizumab versus placebo plus bevacizumab in patients with recurrent glioblastoma: efficacy, safety, and hepatocyte growth factor and O(6)-methylguanine-DNA methyltransferase biomarker analyses. J Clin Oncol. 2017; 35(3): 343-351.
32. Junca A, Villalva C, Tachon G, Rivet P, Cortes U, Guilloteau K, et al. Crizotinib targets in glioblastoma stem cells. Cancer Med. 2017; 6(11): 2625-2634.
33. Jia H, Dai G, Weng J, Zhang Z, Wang Q, Zhou F, et al. Discovery of (S)-1-(1-(Imidazo[1,2-a]pyridin-6-yl)ethyl)-6-(1-methyl-1Hpyrazol- 4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (volitinib) as a highly potent and selective mesenchymal-epithelial transition factor (c-Met) inhibitor in clinical development for treatment of cancer. J Med Chem. 2014; 57(18): 7577-7589.
34. Cloughesy TF, Drappatz J, de Groot J, Prados MD, Reardon DA, Schiff D, et al. Phase II study of cabozantinib in patients with progressive glioblastoma: subset analysis of patients with prior antiangiogenic therapy. Neuro Oncol. 2018; 20(2): 259-267.
35. Genander M, Frisen J. Ephrins and Eph receptors in stem cells and cancer. Curr Opin Cell Biol. 2010; 22(5): 611-616.
36. Okada H, Kalinski P, Ueda R, Hoji A, Kohanbash G, Donegan TE, et al. Induction of CD8+ T-cell responses against novel glioma-associated antigen peptides and clinical activity by vaccinations with {alpha}-type 1 polarized dendritic cells and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose in patients with recurrent malignant glioma. J Clin Oncol. 2011; 29(3): 330-336.
37. Han J, Alvarez-Breckenridge CA, Wang QE, Yu J. TGF-beta signaling and its targeting for glioma treatment. Am J Cancer Res. 2015; 5(3): 945-955.
38. Bogdahn U, Hau P, Stockhammer G, Venkataramana NK, Mahapatra AK, Suri A, et al. Targeted therapy for high-grade glioma with the TGF-beta2 inhibitor trabedersen: results of a randomized and controlled phase IIb study. Neuro Oncol. 2011; 13(1): 132-142.
39. Rodon J, Carducci MA, Sepulveda-Sanchez JM, Azaro A, Calvo E, Seoane J, et al. First-in-human dose study of the novel transforming growth factor-beta receptor I kinase inhibitor LY2157299 monohydrate in patients with advanced cancer and glioma. Clin Cancer Res. 2015; 21(3): 553-560.
40. den Hollander MW, Bensch F, Glaudemans AWJM, Enting RH, Bunskoek S, Munnink THO, et al. zr-GC1008 PET imaging and GC1008 treatment of recurrent glioma patients. J Clin Oncol. 2013; 31(15).
41. Kim BG, Malek E, Choi SH, Ignatz-Hoover JJ, Driscoll JJ. Novel therapies emerging in oncology to target the TGF-beta pathway. J Hematol Oncol. 2021; 14(1): 55.
42. Burton ER, Libutti SK. Targeting TNF-alpha for cancer therapy. J Biol. 2009; 8(9): 85.
43. Fischer R, Kontermann RE, Pfizenmaier K. Selective targeting of TNF receptors as a novel therapeutic approach. Front Cell Dev Biol. 2020; 8: 401.
44. Lakka SS, Rao JS. Antiangiogenic therapy in brain tumors. Expert Rev Neurother. 2008; 8(10): 1457-1473.
45. Wakabayashi T, Natsume A, Hashizume Y, Fujii M, Mizuno M, Yoshida J. A phase I clinical trial of interferon-beta gene therapy for high-grade glioma: novel findings from gene expression profiling and autopsy. J Gene Med. 2008; 10(4): 329-339.
46. Colman H, Berkey BA, Maor MH, Groves MD, Schultz CJ, Vermeulen S, et al. Phase II radiation therapy oncology group trial of conventional radiation therapy followed by treatment with recombinant interferon-beta for supratentorial glioblastoma: results of RTOG 9710. Int J Radiat Oncol Biol Phys. 2006; 66(3): 818-824.
47. Aoki T, Takahashi JA, Ueba T, Oya N, Hiraoka M, Matsui K, et al. Phase II study of nimustine, carboplatin, vincristine, and interferonbeta with radiotherapy for glioblastoma multiforme: experience of the Kyoto Neuro-Oncology Group. J Neurosurg. 2006; 105(3): 385-391.
48. National Institutes of Health Clinical Center (CC). Phase II trial of peginterferon alpha-2b and thalidomide in adults with recurrent gliomas. 2002. Available from: https://clinicaltrials.gov/ct2/show/record/ NCT00047879 (31 Jul 2021).
49. Groves MD, Puduvalli VK, Gilbert MR, Levin VA, Conrad CA, Liu VH, et al. Two phase II trials of temozolomide with interferon-alpha2b (pegylated and non-pegylated) in patients with recurrent glioblastoma multiforme. Br J Cancer. 2009; 101(4): 615-620.
50. Chen Z. A phase III trial on adjuvant temozolomide with or without interferon-alpha in newly diagnosed high-grade gliomas. 2013. Available from: https://clinicaltrials.gov/ct2/show/record/NCT01765088 (31 Jul 2021).
51. Mooney J, Bernstock JD, Ilyas A, Ibrahim A, Yamashita D, Markert JM, et al. Current approaches and challenges in the molecular therapeutic targeting of glioblastoma. World Neurosurg. 2019; 129: 90-100.
52. Jackson C, Ruzevick J, Phallen J, Belcaid Z, Lim M. Challenges in immunotherapy presented by the glioblastoma multiforme microenvironment. Clin Dev Immunol. 2011; 2011: 732413.
53. Zuccarini M, Giuliani P, Ziberi S, Carluccio M, Iorio PD, Caciagli F, et al. The role of wnt signal in glioblastoma development and progression: a possible new pharmacological target for the therapy of this tumor. Genes (Basel). 2018; 9(2): 105.
54. Kofler NM, Shawber CJ, Kangsamaksin T, Reed HO, Galatioto J, Kitajewski J. Notch signaling in developmental and tumor angiogenesis. Genes Cancer. 2011; 2(12): 1106-1116.
55. Gersey Z, Osiason AD, Bloom L, Shah S, Thompson JW, Bregy A, et al. Therapeutic targeting of the Notch pathway in glioblastoma multiforme. World Neurosurg. 2019; 131: 252-263.
56. Malric L, Monferran S, Gilhodes J, Boyrie S, Dahan P, Skuli N, et al. Interest of integrins targeting in glioblastoma according to tumor heterogeneity and cancer stem cell paradigm: an update. Oncotarget. 2017; 8(49): 86947-86968.
57. Farber 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; 16(3): 277-287.
58. Beyer S, Fleming J, Meng W, Singh R, Haque SJ, Chakravarti A. The role of miRNAs in angiogenesis, invasion and metabolism and their therapeutic implications in gliomas. Cancers (Basel). 2017; 9(7): 85.
59. Catuogno S, Esposito CL. Aptamer cell-based selection: overview and advances. Biomedicines. 2017; 5(3): 49.
60. Kane JR, Miska J, Young JS, Kanojia D, Kim JW, Lesniak MS. Sui generis: gene therapy and delivery systems for the treatment of glioblastoma. Neuro Oncol. 2015; 17 Suppl 2: ii24-ii36.
61. Batchelor TT, Duda DG, di Tomaso E, Ancukiewicz M, Plotkin SR, Gerstner E, et al. Phase II study of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. J Clin Oncol. 2010; 28(17): 2817-2823.
62. Kalpathy-Cramer J, Chandra V, Da X, Ou Y, Emblem KE, Muzikansky A, et al. Phase II study of tivozanib, an oral VEGFR inhibitor, in patients with recurrent glioblastoma. J Neurooncol. 2017; 131(3): 603-610.
63. Raymond E, Brandes AA, Dittrich C, Fumoleau P, Coudert B, Clement PM, et al. Phase II study of imatinib in patients with recurrent gliomas of various histologies: a European organisation for research and treatment of cancer brain tumor group study. J Clin Oncol. 2008; 26: 4659-4565.
64. Odia Y, Sul J, Shih JH, Kreisl TN, Butman JA, Iwamoto FM, et al. A phase II trial of tandutinib (MLN 518) in combination with bevacizumab for patients with recurrent glioblastoma. CNS Oncol. 2016; 5(2): 59-67.
65. Brahm CG, van Linde ME, Labots M, Kouwenhoven MC, Aliaga ES, Enting RH, et al. A phase II/III trial of high-dose, intermittent sunitinib in patients with recurrent glioblastoma: the STELLAR study. Ann Oncol. 2019; 30: v157-8.
66. de Vries NA, Buckle T, Zhao J, Beijnen JH, Schellens JH, van Tellingen O. Restricted brain penetration of the tyrosine kinase inhibitor erlotinib due to the drug transporters P-gp and BCRP. Invest New Drugs. 2012; 30: 443-449.
67. Clavreul A, Pourbaghi-Masouleh M, Roger E, Menei P. Nanocarriers and nonviral methods for delivering antiangiogenic factors for glioblastoma therapy: the story so far. Int J Nanomedicine. 2019; 14: 2497-2513.
68. Mao G, Sampath P, Sengupta S. Updates on chimeric antigen receptor-mediated glioblastoma immunotherapy. R I Med J (2013). 2017; 100(6): 39-42.
69. Sofuni A, Iijima H, Moriyasu F, Nakayama D, Shimizu M, Nakamura K, et al. Differential diagnosis of pancreatic tumors using ultrasound contrast imaging. J Gastroenterol. 2005; 40(5): 518-525.

Files

Cited by

Share

How to cite

Statistics