Antiangiogenic therapy for glioblastoma: current status and future prospects

Abstract

Glioblastoma is characterized by high expression levels of proangiogenic cytokines and microvascular proliferation, highlighting the potential value of treatments targeting angiogenesis. Antiangiogenic treatment likely achieves a beneficial impact through multiple mechanisms of action. Ultimately, however, alternative proangiogenic signal transduction pathways are activated, leading to the development of resistance, even in tumors that initially respond. The identification of biomarkers or imaging parameters to predict response and to herald resistance is of high priority. Despite promising phase II clinical trial results and patient benefit in terms of clinical improvement and longer progression-free survival, an overall survival benefit has not been demonstrated in four randomized phase III trials of bevacizumab or cilengitide in newly diagnosed glioblastoma or cediranib or enzastaurin in recurrent glioblastoma. However, future studies are warranted. Predictive markers may allow appropriate patient enrichment, combination with chemotherapy may ultimately prove successful in improving overall survival, and novel agents targeting multiple proangiogenic pathways may prove effective.

Figure 1

Normalization of tumor vasculature. (A) Tumor vasculature is structurally and functionally abnormal. One potential mechanism of action for antiangiogenic therapies is transient improvement in both the structure and the function of tumor vessels. However, sustained antiangiogenic treatment may eventually result in a vasculature that is both resistant to further treatment and inadequate for the delivery of drugs or oxygen. (B) Vessel structural patterns before, during and with sustained VEGFR2 blockade. (C) Diagram depicting the concomitant changes in pericyte coverage (green) and basement membrane thickness (blue) before, during and with sustained VEGFR2 blockage. (D) Changes in the balance of pro- and antiangiogenic factors leading to the phenotypic changes noted above. Reprinted from Jain (99).