Anti-integrin therapies that target specific mechanisms of tumor neovascularization and invasion present difficult problems in assessing their relative efficacy. Since the anti-angiogenesis effect may result in a significantly delayed or clinically inapparent anti-tumor effect when compared with that seen in therapies that target tumor cells directly, the most appropriate methods to assess an anti-angiogenesis effect need to be identified and validated. In patients with malignant brain tumors, it is procedurally high-risk, infeasible and unethical to obtain routine multiple tissue biopsies on a longitudinal basis to verify, at histopathological, cellular and molecular levels, that tumor vasculature is being appropriately targeted and adversely affected. The overall objective of this project will be to evaluate the capacity of several different non-invasive mechanisms and assays to correlate changes in vascularization of recurrent malignant gliomas in patients who will be treated with a novel anti-angiogenic drug, cyclic RGD (EMD121974). Our hypothesis is that specific non-invasive methodologies can be used to visualize and quantify the responses of tumor vasculature to an anti-angiogenesis therapy that focuses on a specific molecular target on activated endothelial cells. Under the auspices of the New Approaches to Brain Tumor Therapy (NABTT) consortium, we will conduct a dose-escalating Phase 1 Clinical Trial of EMD121974 (IND #59,073) using a novel anti-integrin drug supplied by CTEP. We propose to (1) determine the ability of dynamic contrast susceptibility (DCS) MR imaging to assess and quantify neovascularization responses to EMD121974 therapy at specific time points during the course of therapy; (2) perform specific in vitro assays on patient biofluids (blood, csf, urine, etc.) at these imaging timepoints that will assess antiangiogenic activity against endothelial cell function required for neovascularization (proliferation, migration, apoptosis) or glioma cells for invasion; and, (3) explore the utility of a labeled, targeted nanoparticle to quantify tumor and tumor-vascular burden in a mouse brain tumor model. Data from these studies will be critically important in developing, refining and validating non-invasive methodologies for timely assessment of specific anti-angiogenic therapies for malignant brain tumors in patients.
| Pike, M M; Stoops, C N; Langford, C P et al. (2009) High-resolution longitudinal assessment of flow and permeability in mouse glioma vasculature: Sequential small molecule and SPIO dynamic contrast agent MRI. Magn Reson Med 61:615-25 |
| Nabors, L Burt; Mikkelsen, Tom; Rosenfeld, Steven S et al. (2007) Phase I and correlative biology study of cilengitide in patients with recurrent malignant glioma. J Clin Oncol 25:1651-7 |
| Akella, N Shastry; Ding, Qiang; Menegazzo, Ingrid et al. (2006) A novel technique to quantify glioma tumor invasion using serial microscopy sections. J Neurosci Methods 153:183-9 |
| Akella, N Shastry; Twieg, Donald B; Mikkelsen, Tom et al. (2004) Assessment of brain tumor angiogenesis inhibitors using perfusion magnetic resonance imaging: quality and analysis results of a phase I trial. J Magn Reson Imaging 20:913-22 |
