Tejaswini Reddy

 Introduction: Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults and the current standard of treatment of care is surgical resection of tumor(s) followed by external beam irradiation and taking cytotoxic agent temozolomide orally [1-6]. However, many tumors develop resistance to temozolomide, which is why targeted therapies such as a monoclonal antibody against vascular endothelial growth factor (VEGF), known as bevacizumab,  have been incorporated into combination therapy regimens [7-10]. Unfortunately, bevacizumab in combination with radiotherapy and temozolomide did not improve overall survival in newly diagnosed GBM patients and patients developed resistance to bevacizumab [2, 7]. Preclinical studies have suggested that the angiopoietin-2 (Ang-2)/TEK receptor kinase 2 (Tie2) pathway plays a role in the developed resistance to VEGF inhibition[7, 8, 10-14]. Clinical studies found that in GBM patients treated with bevacizumab, there were increased levels of Ang-2 in circulation[11]. In murine glioblastoma models, ectopic expression of Ang-2 in combination with bevacizumab treatment destabilized blood vessels and compromised the survival benefit of VEGF inhibition, leading to increased vascular permeability and cerebral edema [11, 15]. Hypothesis: The hypothesis is that dual inhibition of Ang-2 and VEGF could induce vessel normalization, improve survival, and promote antitumor activity in murine models of glioblastoma [7, 16, 17]. Methods: Two orthotopic murine GBM models, G1261 and U87 were utilized. The mice were treated with control IgG, anti-Ang2 neutralizing monoclonal (MEDI3617), pan-VEGF receptor inhibitor (Cediranib), or MEDI3617+Cediranib dual therapy. The effects of the dual therapy on survival, tumor growth, vascular normalization, and tumor associated macrophage (TAM) phenotype were studied [7, 8]. Results: Murine glioblastoma models treated with dual Anti-Ang2/Anti-VEGF treatment had extended survival, decreased tumor growth and decreased tumor volume in comparison to Anti-VEGF or Anti-Ang2 monotherapy alone [7]. Dual Anti-Ang2/Anti-VEGF therapy also promoted increased microvascular density, increased perivascular cell coverage, and significantly higher basement membrane coverage, which are all indicators of improved   vascular structure and normalization [7, 15]. Dual inhibition of Ang2 and VEGF also resulted in increased M1 macrophages (anti-tumor phenotype) than M2 macrophages (pro-tumor phenotype)[7, 8, 18-22]. Conclusions: Dual inhibition of Ang2 and VEGF may be an effective combination therapy for GBM due to this synergistic ability to improve survival, vascular normalization, and reprogram GBM-associated TAMs from a M2, protumor phenotype to a M1, antitumor phenotype.

1. Sandmann, , et al., Patients With Proneural Glioblastoma May Derive Overall Survival Benefit From the Addition of Bevacizumab to First-Line Radiotherapy and Temozolomide: Retrospective Analysis of the AVAglio Trial. J Clin Oncol, 2015. 33(25): p. 2735-44.
2. Chinot, L., et al., Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med, 2014. 370(8): p. 709-22.
3. Alifieris, and D.T. Trafalis, Glioblastoma multiforme: Pathogenesis and treatment.Pharmacol Ther, 2015. 152: p. 63-82.
4. Polivka, , Jr., et al., Advances in Experimental Targeted Therapy and Immunotherapy for Patients with Glioblastoma Multiforme. Anticancer Res, 2017. 37(1): p. 21-33.
5. Urbanska, , et al., Glioblastoma multiforme – an overview. Contemp Oncol (Pozn), 2014.18(5): p. 307-12.
6. Verhaak, G., et al., Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell, 2010. 17(1): p. 98-110.
7. Peterson, E., et al., Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages. Proc Natl Acad Sci U S A, 2016. 113(16): p. 4470-5.
8. Kloepper, , et al., Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival. Proc Natl Acad Sci U S A, 2016. 113(16): p. 4476-81.
9. Field, M., et al., Bevacizumab and glioblastoma: scientific review, newly reported updates, and ongoing controversies. Cancer, 2015. 121(7): p. 997-1007.
10. Batchelor, T., et al., Antiangiogenic therapy for glioblastoma: current status and future prospects. Clin Cancer Res, 2014. 20(22): p. 5612-9.
11. Chae, S., et al., Angiopoietin-2 interferes with anti-VEGFR2-induced vessel normalization and survival benefit in mice bearing gliomas. Clin Cancer Res, 2010. 16(14): p. 3618-27.
12. Daly, , et al., Angiopoietin-2 functions as a Tie2 agonist in tumor models, where it limits the effects of VEGF inhibition. Cancer Res, 2013. 73(1): p. 108-18.
13. Huang, , et al., Targeting the ANGPT-TIE2 pathway in malignancy. Nat Rev Cancer, 2010.10(8): p. 575-85.
14. Maisonpierre, C., et al., Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science, 1997. 277(5322): p. 55-60.
15. Yancopoulos, D., et al., Vascular-specific growth factors and blood vessel formation. Nature, 2000. 407(6801): p. 242-8.
16. Park, S., et al., Normalization of Tumor Vessels by Tie2 Activation and Ang2 Inhibition Enhances Drug Delivery and Produces a Favorable Tumor Microenvironment. Cancer Cell, 2017. 31(1): p. 157-158.
17. Biel, M. and D.W. Siemann, Targeting the Angiopoietin-2/Tie-2 axis in conjunction with VEGF signal interference. Cancer Lett, 2016. 380(2): p. 525-33.
18. Canton, , D. Neculai, and S. Grinstein, Scavenger receptors in homeostasis and immunity.Nat Rev Immunol, 2013. 13(9): p. 621-34.
19. Sica, and A. Mantovani, Macrophage plasticity and polarization: in vivo veritas. J Clin Invest, 2012. 122(3): p. 787-95.
20. Grenga, , et al., Inhibition of the angiopoietin/Tie2 axis induces immunogenic modulation, which sensitizes human tumor cells to immune attack. J Immunother Cancer, 2015. 3: p. 52.
21. Lu-Emerson, , et al., Increase in tumor-associated macrophages after antiangiogenic therapy is associated with poor survival among patients with recurrent glioblastoma. Neuro Oncol, 2013. 15(8): p. 1079-87.
22. Brown, L., et al., A human monoclonal anti-ANG2 antibody leads to broad antitumor activity in combination with VEGF inhibitors and chemotherapy agents in preclinical models. Mol Cancer Ther, 2010. 9(1): p. 145-56.