Predictive Markers of Glioblastoma Response to VEGF Trap

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DESCRIPTION (provided by applicant): Glioblastoma is the most common type of primary brain tumor and carries a grave prognosis. Despite maximal therapy including surgery and combination radiation with chemotherapy median survival is 14 months with less than 5% of patients remaining alive at 5 years. New treatment approaches are needed to halt progression of this devastating disease. Endothelial proliferation is a pathologic hallmark of glioblastoma and studies have shown that the expression of pro-angiogenic factors such as vascular endothelial growth factor (VEGF) is one mechanism by which tumors induce the formation of new blood vessels. VEGF is a specific endothelial cell mitogen, permeability and survival factor, and is overexpressed in virtually all human tumors including glioblastoma. VEGF Trap is a recombinantly-produced fusion protein which scavenges free VEGF and placental growth factor (PlGF) removing important ligands for the VEGF family receptors. In preclinical studies, VEGF Trap significantly increased survival of mice bearing intracranial glioma xenografts. Anti-VEGF therapy is known to alter contrast enhancement patterns on MRI, but it is not known if this accurately reflects changes in tumor biology or will be predictive of long-term outcome. We are proposing to study biomarkers of response in patients with temozolomide-resistant glioblastoma enrolled in the North American Brain Tumor Consortium (NABTC) VEGF Trap phase II clinical trial. To assess the biologic activity of VEGF Trap and to develop predictive biomarkers of response, we will incorporate the measurement of multiple pharmacokinetic and pharmacodynamic parameters. Plasma and urine levels of free VEGF and PlGF and VEGF Trap pharmacology will be correlated with outcome as measured by 6-month progression free survival (PFS). Samples from patients who progress or do not respond will be evaluated for circulating growth factors mediating "tumor escape." Pre-treatment tumor tissue will be examined for molecular markers and vascularity and circulating endothelial cells will be measured as potential determinants of response. Biomarkers will be evaluated before treatment and at serial time points after initiation of therapy with the goal of determining the association between tumor-specific and circulating biomarkers of activity against endothelial cells and patient outcome. Based on dynamic contrast enhanced MRI changes, we will use statistical and pharmacodynamic modeling to incorporate these measures into a predictive model of response. These studies are critical to establish which biomarkers are useful in predicting response and monitoring treatment progress, as well as for forming a baseline for biomarker studies for future trials with anti-VEGF therapies. Incorporation of biomarker measurements into this phase II study represent unique strengths of our institution and the NABTC and will enhance our ability to assess the potential efficacy of VEGF Trap in a multidimensional manner. This research is significant because no study has explored the dynamic trend of blood and urine biomarkers in relation to the pharmacology of VEGF Trap and DCE-MRI pharmacodynamic changes though a course of anti- VEGF monotherapy in glioma, explored its possible predictive significance, or evaluated which methodology is the most powerful for defining trends. These studies are critical for establishing which biomarkers are useful in predicting patient response and monitoring treatment progress, as well as forming a baseline for biomarker studies for future trials with anti-VEGF therapies.