Moving Toward the Next Steps in Angiogenesis Therapy? (2008)

The clinical approach of using antibodies that sequester molecules in the bloodstream is an elegant solution to the drug-uptake problem in neuro-oncology. Our recent editorial, “Bevacizumab—News from the Fast Lane?”1 highlighted the progress and some of the concerns regarding antiangiogenesis therapy for brain tumors; there, we commented on some encouraging results from clinical trials using the humanized antivascular endothelial growth factor (VEGF) antibody bevacizumab that indicated increased patient response rates. Preclinical and clinical data support the benefits of antiangiogenic therapies for cancer; however, the observed benefit is no more than temporary, suggesting the emergence of a resistant phenotype.

A new anti-VEGF agent, VEGF Trap/aflibercept, has been developed by incorporating domains of both VEGFR-1 and VEGFR-2 fused to the constant region of human IgG1, which acts as a soluble decoy receptor for VEGF. In the current issue of Neuro-Oncology (see page 940), Gomez-Manzano and colleagues have assessed the role of this new anti-VEGF antibody in a well-established intracranial glioma animal model.2 Using different treatment schedules and initiating treatment at different times following glioma cell implantation, they conclude that VEGF Trap treatment was efficacious in both initial and advanced phases of tumor development. This antitumor effect was enhanced in animals treated with more prolonged regimens. However, long-term treatment with VEGF Trap resulted in a modified pattern of tumor growth, characterized by the presence of satellitosis consisting of aggregations of glioma cells in the perivascular regions, suggesting acquisition of an invasive phenotype in response to anti-VEGF therapy. Those results seem to coincide with preliminary data from MRI studies of glioblastoma patients treated with bevacizumab, showing the development of multifocal recurrence and strongly indicating the presence of an infiltrative/invasive pattern.3,4 In this regard, Bergers and Hanahan recently proposed several hypothetical mechanisms that might underlie the evasive resistance to antiangiogenic therapy.5 These models include an increased capability of the tumor cells to develop an invasive phenotype without promoting angiogenesis. In fact, there is strong evidence that malignant glioma cells adapt to pathological conditions (such as necrosis) or to therapies that challenge angiogenesis, by migrating more aggressively into normal tissue. Collectively, these observations indicate that the clinical success of antiangiogenic therapy, including VEGF Trap, might depend on the establishment of combined therapies aiming to induce tumor regression by inhibiting angiogenesis and to prevent multifocal recurrence by inhibiting tumor infiltration.

Preclinical and clinical data have established the effectiveness of antiangiogenic therapies for human malignant gliomas. However, more studies need to be undertaken, with a special focus on identification of the mechanisms of the resistant phenotype and, ultimately, the testing of combined therapies. The establishment of animal models suitable for these goals and the search for reliable biomarkers of response and resistance to therapy are urgent priorities in the drive to advance the promising field of antiangiogenic therapy. Timely results from a multicenter phase II clinical trial of VEGF Trap in patients with recurrent gliomas will soon be available, and therefore, critical information on these evasive resistant phenotypes and progression patterns might soon be available.6