Abstract 5234: Sequential multi-modality imaging to detect metabolic changes during tumor growth

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC The expression and activity of lactate dehydrogenase A (LDH-A) in malignant tissue is considered a prognostic marker of poor outcome in many tumors. A limitation of tissue LDH-A measurements is the requirement of tissue for assay. The development of new non-invasive methods is highly demanded for clinical evaluation. One mechanistic link between tumor cell metabolism and the activity of lactate dehydrogenase A (LDH-A) is based on the HIF-1 transcription factor and its upregulation in tumors. HIF-1 binds to the LDH-A promoter and increases LDH-A expression; this in turn results in increased lactic acid production. The objective of this study was to detect the metabolic changes during tumor growth using a multi-modality imaging approach. To monitor HIF-1 pathway activity by bioluminescence imaging (BLI), we cloned an external Gaussia luciferase (exGLuc) reporter gene into an -IRES-GFP cassette, and placed the cassette in a self-inactivated retroviral vector under the control of an enhancer, containing multiple copies of the binding sites for the HIF-1 transcription factor. 18F-fluorodeoxyglucose (FDG)/microPET imaging was used for the detection of glucose metabolism in tumors, while lactate production was measured by proton magnetic resonance spectroscopic imaging (MRI/S). To validate this multi-modality imaging approach, human glioblastoma U87MG cells were transduced with the HIF-1 reporter vector and the HIF-1 reporter response was validated in vitro by exposure cells to hypoxia (1% O2) and to CoCl2 or DFO (deferoxamine mesylate). Despite a high basal level of HIF-1 transcriptional activity in the U87MG reporter cells, a strong correlation between oxygen deprivation and the level of exGLuc/GFP expression (indicating HIF-1 transcriptional activation) was detected, and this increase corresponded with a significant increase in LDH-A expression, assessed by immunoblotting. In vivo experiments using U87 reporter-xenografts also demonstrated a correspondence between the levels of HIF-1 expression and lactate production assessed by MRI/S. The measurement of lactate production using MRI/S with consecutive BLI imaging of HIF-1 activity and 18F fluorodeoxyglucose (FDG)/microPET confirmed the feasibility of a multi-modality imaging approach to study the link between the HIF-1 activity and a lactate production, as well as the level of glucose (FDG) uptake in growing xenografts. This multi-modal imaging paradigm can provide new and relevant information, and the opportunity to initiate and monitor more effective treatment strategies to arrest tumor growth. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5234.