Lessons from anti-vascular endothelial growth factor and anti-vascular endothelial growth factor receptor trials in patients with glioblastoma

Abstract

Treatment of glioblastoma (GBM), the most common primary malignant brain tumor in adults, remains a significant unmet need in oncology. Historically, cytotoxic treatments provided little durable benefit, and tumors recurred within several months. This has spurred a substantial research effort to establish more effective therapies for both newly diagnosed and recurrent GBM. In this context, antiangiogenic therapy emerged as a promising treatment strategy because GBMs are highly vascular tumors. In particular, GBMs overexpress vascular endothelial growth factor (VEGF), a proangiogenic cytokine. Indeed, many studies have demonstrated promising radiographic response rates, delayed tumor progression, and a relatively safe profile for anti-VEGF agents. However, randomized phase III trials conducted to date have failed to show an overall survival benefit for antiangiogenic agents alone or in combination with chemoradiotherapy. These results indicate that antiangiogenic agents may not be beneficial in unselected populations of patients with GBM. Unfortunately, biomarker development has lagged behind in the process of drug development, and no validated biomarker exists for patient stratification. However, hypothesis-generating data from phase II trials that reveal an association between increased perfusion and/or oxygenation (ie, consequences of vascular normalization) and survival suggest that early imaging biomarkers could help identify the subset of patients who most likely will benefit from anti-VEGF agents. In this article, we discuss the lessons learned from the trials conducted to date and how we could potentially use recent advances in GBM biology and imaging to improve outcomes of patients with GBM who receive antiangiogenic therapy.

Fig 1.

Resistance to anti–vascular endothelial growth factor (VEGF)/anti–VEGF receptor (VEGFR) strategies in glioblastoma (GBM): (1) Angiogenesis is a critical process in GBM progression, which is accompanied by endothelial cell hyperproliferation and abnormal vascular structure and function. (2) VEGF is overexpressed in GBM and is a validated target for antiangiogenic therapy. (3) Anti-VEGF/anti-VEGFR therapy induces high rates of radiographic response and reduces vasogenic edema in GBM, but these benefits do not translate into increased overall survival in all patients. (4) An increase in survival will likely require patient stratification based on biomarkers, and promising circulating and imaging biomarkers have emerged from small phase II studies. (5) Identifying escape biomarkers may help in designing trials that combine antiangiogenic agents with agents targeting these evasion pathways. (6) These biomarkers should be prospectively tested in large clinical studies. Potential mechanisms of resistance to targeted VEGF therapy in cancer. Different mechanisms underlie the resistance to VEGF blockade seen in some patients with cancer. These mechanisms are not exclusive, and it is likely that several occur simultaneously in a single tumor: (1) vessel co-option: tumor cell migration and growth along the existing vasculature without generation of new vessels; (2) vascular intussusception: vascular network expansion through enlargement of existing vessels; (3) vasculogenic mimicry: incorporation of tumor cells into the endothelial lining of the vasculature, potentially via endothelial differentiation from putative tumor stem cells; (4) pericyte-covered vessels: persistence of more mature vessels characterized by coverage by pericytes of mesenchymal origin or differentiated from putative tumor stem cells; (5) bone marrow–derived cell (BMDCs) and cancer associated fibroblast (CAF) activation: paracrine support of tumor vascularization through increased recruitment of angiogenic BMDCs and CAFs; and (6) hypoxia-driven production of angiogenic factors: in established tumors, VEGF blockade aggravates hypoxia, which upregulates the production of other angiogenic factors. Figure courtesy of Giorgio Seano, PhD, Massachusetts General Hospital and Harvard Medical School, Boston, MA.