Glioblastoma multiform (GBM) is the most common and lethal intracranial cancer, and highly resists to conventional multimodal therapies. These tumors are characterized by profound angiogenesis, disrupted blood-brain-barrier (BBB), vasogenic edema, as well as regions of hypoxia and necrosis, which have been shown to correlate negatively with local tumor control, disease free survival and overall survival. There is considerable anecdotal evidence that intra-tumoral hypoxia confers radiation resistance. However, in the absence of a reliable method of monitoring, in vivo, the dynamic intra-tumoral oxygen status, has remained untested in GBM. We have developed a genetic strategy to monitor intra-tumoral hypoxia using a bioluminescence reporter system. By introducing the Hypoxia-inducible-factor1a-firefly luciferase (HIF-1a-ODD-luc) to various GBM cells including the cells isolated from fresh GBM tumors of patient and enriched for the cell surface marker CD133, we will be able to monitor real-time tumor hypoxia in orthotopic GBM model by bioluminescent imaging (BLI). We also propose to develop MRI techniques based on an interleaved T2- (BOLD, blood oxygen level dependent) and T1- (tissue oxygen level dependent) weighted sequence for assessing tumor oxygenation, including baseline hypoxia, spatial heterogeneity and dynamics of response to interventions in orthotopic GBM model. Moreover, correlation of vascular perfusion, BBB status with hypoxia will be evaluated by dynamic susceptibility contrast (DSC) and Dynamic contrast enhanced (DCE) MRI. Recent gains in overall survival as well as progression free survival of GBM patients have been reported following adjuvant treatment with antiangiogenic and chemotherapeutic agents. However, the underlying mechanisms remain unclear. We hypothesize that in vivo multimodal imaging of tumor hypoxia and vasculature will enhance our understanding of pathophysiological mechanisms of effective antiangiogenesis and further facilitate optimization of combined radiotherapy or chemotherapy. The major goal of this project is to integrate multiple parameters of tumor hypoxia and vasculature acquired by multimodal imaging to correlate with tumor aggressiveness and understand pathophysiological mechanism underlying the clinical benefits from antiangiogenic treatment. The imaging findings will be correlated with histological and immunohistochemical studies of perfusion, vascular density and hypoxia, as well as pharmacological study of drug. Successful accomplishment of the goals of this project will enhance our understanding of clinical glioblastoma and lay the foundation for future novel clinical treatment regimens towards chemotherapy in combination with radiotherapy.

PUBLIC HEALTH RELEVANCE: Glioblastoma multiform (GBM) is the most common and lethal intracranial cancer, and highly resists to conventional multimodal therapies. These tumors are characterized by profound angiogenesis, disrupted blood-brain-barrier, vasogenic edema, as well as regions of hypoxia and necrosis, which have been shown to correlate negatively with clinical outcome. We propose to apply bioluminescent imaging (BLI), based on a hypoxia reporter gene, and a novel MRI approach to assessing dynamic change of intra-tumor hypoxia and vascular characteristics in orthotopic GBM models, and to further understand pathophysiological mechanisms underlying the clinical benefits from antiangiogenic agents such as bevacizumab.

R21CA141348

2010-01-01

2012-12-31