New Directions in Anti-Angiogenic Therapy for Glioblastoma

Abstract

Anti-angiogenic therapy has become an important component in the treatment of many solid tumors given the importance of adequate blood supply for tumor growth and metastasis. Despite promising preclinical data and early clinical trials, anti-angiogenic agents have failed to show a survival benefit in randomized controlled trials of patients with glioblastoma. In particular, agents targeting vascular endothelial growth factor (VEGF) appear to prolong progression free survival, possibly improve quality of life, and decrease steroid usage, yet the trials to date have demonstrated no extension of overall survival. In order to improve duration of response and convey a survival benefit, additional research is still needed to explore alternative pro-angiogenic pathways, mechanisms of resistance, combination strategies, and biomarkers to predict therapeutic response.

Keywords: Angiogenesis; Bevacizumab; Glioblastoma; Glioma; VEGF.

Fig. 1

Mechanisms of angiogenesis and resistance to anti-VEGF therapy. Resistance to anti-VEGF therapy is thought to occur through the following mechanisms: (1) Vessel co-option: tumor cell migration and growth along native vasculature without new blood vessel formation. (2) Vascular intussusception: enlargement and bifurcation of existing vessels. (3) Vascular mimicry: incorporation of tumor cells into the endothelial lining, possibly through endothelial differentiation of tumor stem cells. (4) Peri-cyte covered vessels may be inherently more resistant to VEGF signaling. (5) Recruitment of bone marrow-derived cells and cancer associated fibroblasts which provide paracrine support. (6) Hypoxia-driven release of alternate angiogenic factors. Reprinted with permission from Lu-Emerson et al, J Clin Oncol 2015 [19]

Fig. 2

Radiographic response to bevacizumab. Magnetic resonance imaging of a patient with left parietal glioblastoma before (A, B) and after (C, D) bevacizumab. There is decreased enhancement (A, C) and decreased T2/FLAIR hyperintensity (B, D) two months after initiating treatment

Fig 3

Disease progression on bevacizumab. Magnetic resonance imaging from a patient with glioblastoma who progressed on bevacizumab. Panels A and B show T1 post-contrast and T2/FLAIR sequences, respectively, of a patient with glioblastoma involving the splenium of the corpus callosum. Panels C and D show post-contrast and T2/FLAIR sequences after one month with notable increase in patchy enhancement and corresponding increase in T2 hyperintensity

Fig. 4

Anti-angiogenic therapy and the immune microenvironment. Abnormal tumor vasculature creates a hypoxic tumor microenvironment, thereby decreasing tumor oxygenation, tumor perfusion, reducing the number of immune effector cells in the microenvironment, increasing myeloid-derived stem cells, and polarizing tumor associated macrophages to the immune inhibitory M2-like phenotype. Low dose anti-VEGF therapy is thought to normalize blood vessels and have the opposite effect. Reprinted with permission from Huang et al, Cancer Res [112]