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Table of Contents
Year : 2019  |  Volume : 2  |  Issue : 4  |  Page : 182-184

Anti-angiogenic therapy for glioma: Puzzle and hope

Department of Neurosurgery/Neuro-Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong Province, China

Date of Submission18-Dec-2019
Date of Acceptance27-Dec-2019
Date of Web Publication23-Jan-2020

Correspondence Address:
Prof. Zhong-ping Chen
Department of Neurosurgery/Neuro.Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, Guangdong Province
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/glioma.glioma_27_19

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Glioma is one of the most common primary malignant tumors in the central nervous system and glioblastoma (GBM) is the deadly disease. Excessive angiogenesis and adequate blood supply result in rapid proliferation and invasion in GBM. Therefore, targeting angiogenesis may be an effective way to inhibit glioma progression. Currently, there are two categories in targeting angiogenesis in GBM: vascular endothelial growth factor monoclonal antibody and vascular endothelial growth factor receptor tyrosine kinase inhibitors. Unfortunately, none of these ways yield efficient overall survival improvement in GBM, implying that it is difficult to really block the tumor angiogenesis by blocking a single pathway. Expectantly, there are some clinical trials showing that a combination of antiangiogenesis and immunotherapy may exert synergism on suppressing glioma growth and improving patients' prognosis.

Keywords: Angiogenesis, anti-angiogenic therapy, glioblastoma, glioma, regulatory factor, survival, targeting therapy

How to cite this article:
Chen Zp. Anti-angiogenic therapy for glioma: Puzzle and hope. Glioma 2019;2:182-4

How to cite this URL:
Chen Zp. Anti-angiogenic therapy for glioma: Puzzle and hope. Glioma [serial online] 2019 [cited 2023 Oct 2];2:182-4. Available from: http://www.jglioma.com/text.asp?2019/2/4/182/276700

Glioma is one of the most common primary malignant tumors in the central nervous system, but currently, the therapeutic effect is not yet satisfactory. It has been documented that the highest grade glioblastoma (GBM) is the highly vascular proliferative tumor, and neovascularization is an important factor in the growth and poor prognosis of GBM. Therefore, anti-angiogenic therapy for high-grade glioma has naturally aroused much concern.[1] In recent years, the exploration and attempt of antitumor angiogenesis therapy “Let tumor starve to death” has shown an obvious clinical effect in a variety of tumors. Anti-angiogenic therapy should also play an important role in the treatment of GBM.[2]

Tumor angiogenesis is a complex process regulated by a series of multisignal pathways. Key regulatory pathways (factors) currently recognized are vascular endothelial growth factor (VEGF), platelet-derived growth factor, and fibroblast growth factor. The exploration in gliomas suggested that in GBM, the increase of VEGF will promote neovascularization, leading to the destruction of the blood-brain barrier, and GBM stem cell proliferation, thereby aggravating brain edema, and abnormality of tumor vascular structure and function, local tumor hypoxia and increased inter-tissue pressure, which can lead to drug resistance, invasion, and spread of the tumor.[3],[4],[5],[6],[7],[8],[9],[10] Therefore, anti-VEGF could block the progression of GBM through various mechanisms. Currently, the anti-angiogenic drugs for glioma that have been explored clinically are mainly aimed at VEGF pathway, which can be divided into two categories: VEGF monoclonal antibodies (for example, bevacizumab) and VEGF receptor tyrosine kinase inhibitors (for example, apatinib, and regorafenib). Among them, bevacizumab is the most deeply investigated in the treatment of GBM. Bevacizumab has shown significant progression-free survival (PFS) benefits in clinical practice in recurrent GBM. It can improve the quality of life of patients, reduce corticosteroids use for GBM patients, and has been recommended by many guidelines as the treatment for recurrent gliomas. Unfortunately, AVAglio study has proved that when bevacizumab is added to the standard Stupp protocol for treating the newly diagnosed GBM, although the PFS can be significantly prolonged, there are no overall survival (OS) benefits. Therefore, it has not been recommended as a first-line treatment of GBM.[11]

In recent years, VEGF receptor tyrosine kinase inhibitor drugs such as apatinib and regorafenib have also been preliminarily explored in the treatment of GBM.[12],[13] A single-arm phase II study of apatinib plus temozolomide in the treatment of adult patients with recurrent GBM was reported at the last year Society for NeuroOncology meeting. The mean PFS was 6.1 months and the mean OS was 8.4 months. However, the efficacy results need to be further verified by randomized controlled trials. Encouragingly, according to the findings of the REMOGA study, a phase II randomized controlled study of regorafenib in the treatment of recurrent GBM published in Lancet Oncology at the beginning of this year, the disease control rate in the regorafenib arm was significantly better, and OS and PFS were significantly longer, but the baseline characteristics of the patients in the two arms were significantly different in age, corticosteroids use, and median time from the last chemotherapy. Therefore, the findings should be referred to with care, and large sample phase III clinical studies are needed to confirm the efficacy of regorafenib. In fact, so far, although anti-angiogenic therapy has achieved some exploration results in the treatment of GBM, it has no clinical effect of really extending the survival time of patients as that in the treatment of colorectal cancer, lung cancer, breast cancer, and other solid tumors. Therefore, there are quite a lot of puzzles that need to be solved.[2]

Studies suggested that tumor angiogenesis pathways and mechanisms are complex. In 1999, Maniotis et al.[14] found a new vascular channel with circulatory function formed by tumor cells in a melanoma research, which is called vasculogenic mimicry (VM). We first reported that VM also exists in gliomas and found that VM persists during GBM xenograft growth.[15] In 2017, we published the findings of a study in Neuro-Oncology in which we explored the correlation between VM and endothelium-dependent blood vessels and found that glioma stem cells could differentiate into epithelial cells, which plays a key role in the angiogenesis of GBM.[16] Rupp et al.[17] found that tenascin-C (TNC) was closely related to abnormal blood vessel function in GBM. In a recent study, we found that TNC expression was related to the poor prognosis of patients with glioma and related to tumor VM. TNC knockout can reduce tumor VM, suggesting that TNC may be used as a potential anti-angiogenic target, which may bring more opportunities for patients with GBM.[18]

In fact, the patterns and signal pathways of tumor angiogenesis are complicated. Therefore, it is difficult to really block the tumor angiogenesis by blocking a single pathway. Theoretically, the multichannel (multitarget) blocking will have a better anti-angiogenic effect. However, considering the biological characteristics of tumor cells, blocking the existing signal pathways will certainly induce the activation of other bypasses so that why the targeted therapy will lead to drug resistance (failure) even if it is effective at the beginning.

In recent years, immunotherapy has brought great clinical benefits in the treatment of many tumor types, and there are also related explorations in GBM. However, no clinical studies with a large size of samples have been carried out to prove its positive effect in the treatment of GBM. Due to the failure of immunotherapy alone, we have begun to search the application of immunotherapy combined with anti-angiogenic drugs in the treatment of GBM. Vascular abnormalities lead to the tumor microenvironment of immunosuppression, while the use of anti-angiogenic drugs normalizes the blood vessels, which may change the tumor microenvironment from immunosuppression to immune active. The efficacy of this combination mode has been verified in the treatment of lung cancer, liver cell cancer, breast cancer, and other tumors.[9] In addition, the findings of some studies suggested that the use of corticosteroids at the initial stage of immunotherapy may hinder the proliferation of CD8+ cells and diminish the efficacy of immunocheckpoint inhibitors.[19] Bevacizumab can reduce the use of corticosteroids in GBM patients and may enhance benefits of immunotherapy. At present, bevacizumab combined with immunosuppressive checkpoint inhibitors has been preliminarily explored in the treatment of GBM. A phase I study of using pembrolizumab combined with bevacizumab plus hypofractionation radiotherapy for treatment of recurrent GBM showed a 12-month OS rate of 64% with good tolerance. Then, a phase II study was carried out to evaluate the efficacy and safety of pembrolizumab plus bevacizumab in patients with recurrent GBM. The results showed that the PFS benefits of the patients in the pembrolizumab plus bevacizumab arm were better than those in the bevacizumab arm, but the efficacy was comparable to that of bevacizumab alone. Although the anti-angiogenic therapy combined with immunosuppressive checkpoint inhibitors has slight benefits in the treatment of GBM in general, the combination mechanism is still in the initial stage of exploration.[20]

  Conclusion Top

The investigation of the anti-angiogenic therapy for glioma should be promising, but there is still a long way to go. The mechanism of angiogenesis, especially the molecular process of angiogenesis in individual tumor and different stages of tumor growth, needs to be deeply clarified. The stratagem adopting multitarget blocking and dynamic target blocking could be challenging. The regulation of glioma microenvironment, especially combined with immune regulation, is expected to be a breakthrough.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Ameratunga M, Pavlakis N, Wheeler H, Grant R, Simes J, Khasraw M. Anti-angiogenic therapy for high-grade glioma. Cochrane Database Syst Rev 2018;11:CD008218.  Back to cited text no. 1
Anthony C, Mladkova-Suchy N, Adamson DC. The evolving role of antiangiogenic therapies in glioblastoma multiforme: Current clinical significance and future potential. Expert Opin Investig Drugs 2019;28:787-97.  Back to cited text no. 2
Casanovas O, Hicklin DJ, Bergers G, Hanahan D. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 2005;8:299-309.  Back to cited text no. 3
Mthembu NN, Mbita Z, Hull R, Dlamini Z. Abnormalities in alternative splicing of angiogenesis-related genes and their role in HIV-related cancers. HIV AIDS (Auckl) 2017;9:77-93.  Back to cited text no. 4
Argaw AT, Gurfein BT, Zhang Y, Zameer A, John GR. VEGF-mediated disruption of endothelial CLN-5 promotes blood-brain barrier breakdown. Proc Natl Acad Sci U S A 2009;106:1977-82.  Back to cited text no. 5
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Ferretti S, Allegrini PR, Becquet MM, McSheehy PM. Tumor interstitial fluid pressure as an early-response marker for anticancer therapeutics. Neoplasia 2009;11:874-81.  Back to cited text no. 7
Jain RK. Antiangiogenesis strategies revisited: From starving tumors to alleviating hypoxia. Cancer Cell 2014;26:605-22.  Back to cited text no. 8
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Turley RS, Fontanella AN, Padussis JC, Toshimitsu H, Tokuhisa Y, Cho EH, et al. Bevacizumab-induced alterations in vascular permeability and drug delivery: A novel approach to augment regional chemotherapy for in-transit melanoma. Clin Cancer Res 2012;18:3328-39.  Back to cited text no. 10
Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med 2014;370:709-22.  Back to cited text no. 11
Zhang H, Chen F, Wang Z, Wu S. Successful treatment with apatinib for refractory recurrent malignant gliomas: A case series. Onco Targets Ther 2017;10:837-45.  Back to cited text no. 12
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Maniotis AJ, Folberg R, Hess A, Seftor EA, Gardner LM, Pe'er J, et al. Vascular channel formation by human melanoma cells in vivo and in vitro: Vasculogenic mimicry. Am J Pathol 1999;155:739-52.  Back to cited text no. 14
Li C, Chen YS, Zhang QP, Chen JL, Wang J, Chen FR, et al. Vasculogenic mimicry persists during glioblastoma xenograft growth. Glioma 2018;1:16-21.  Back to cited text no. 15
Mei X, Chen YS, Chen FR, Xi SY, Chen ZP. Glioblastoma stem cell differentiation into endothelial cells evidenced through live-cell imaging. Neuro Oncol 2017;19:1109-18.  Back to cited text no. 16
Rupp T, Langlois B, Koczorowska MM, Radwanska A, Sun Z, Hussenet T, et al. Tenascin-C orchestrates glioblastoma angiogenesis by modulation of pro-and anti-angiogenic signaling. Cell Rep 2016;17:2607-19.  Back to cited text no. 17
Cai HP, Wang J, Xi SY, Ni XR, Chen YS, Yu YJ, et al. Tenascin-cmediated vasculogenic mimicry formation via regulation of MMP2/MMP9 in glioma. Cell Death Dis 2019;10:879.  Back to cited text no. 18
Arbour KC, Mezquita L, Long N, Rizvi H, Auclin E, Ni A, et al. Impact of baseline steroids on efficacy of programmed cell death-1 and programmed death-ligand 1 blockade in patients with non-small-cell lung cancer. J Clin Oncol 2018;36:2872-8.  Back to cited text no. 19
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