The Only Way Out is in: A Deeper Understanding of Anti-VEGF Therapy Escape Mechanisms Offers Possibilities for More Effective Antiangiogenic Treatment

Ottenhausen, Malte; Bodhinayake, Imithri; Boockvar, John A.

doi: 10.1227/NEU.0000000000000210
Science Times

Preliminary data presented at the American Society for Clinical Oncology meeting earlier this year disappointed expectations that the addition of bevacizumab would increase overall survival in patients with newly diagnosed glioblastoma (GBM). Current research suggests that anti-VEGF therapy with drugs such as bevacizumab may promote a more aggressive phenotype. Therefore, an investigation of potential escape pathways remains important.

Recent work by Chung et al (Nature Medicine, September 2013) contributes to an understanding of antiangiogenic therapy escape mechanisms by investigating tumor stroma-mediated resistance to VEGF inhibition in multiple tumor models. The authors place the cytokine interleukin 17 (IL-17), secreted from infiltrating T helper 17 cells (Th-17), at the core of a paracrine network that mediates tumor resistance through the expression of proinflammatory cytokines. The paper shows that anti-VEGF resistant cancer cells secrete significantly more IL-17, leading to an upregulation of G-CSF, IL-6, Bv8, and VEGF in a mouse lymphoma model. Cancer-associated fibroblasts and immature myeloid cells play a crucial role in the pathways revealed by the article.

Although the exact consequences of these changes remain unclear, the authors additionally discovered that anti-VEGF treatment was more effective in combination with blockade of IL-17 in a mouse model (Figure). These results are an interesting foundation for future experiments.

The article highlights the important role of the tumor microenvironment in mediating therapy resistance in lung cancer, colon cancer, and lymphoma. These studies on IL-17 may be well worth extending to malignant glioma where escape from anti-VEGF takes away an important therapeutic option. Further studies on the complex regulation of tumor angiogenesis are needed to help prevent drug resistance and improve the clinical efficacy of antiangiogenic treatment.

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