Time Domian Electron Paramagnetic Resonance Imaging

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a) Multi-modal metabolic and physiologic assessment of tumor microenvironment: Tumor microenvironment is an important determinant in the choice of treatments and treatment outcomes. Molecular imaging approaches for metabolic and physiologic imaging of tumors have become important for treatment planning and response monitoring. However, the relationship between the physiologic and metabolic aspects of tumors is not fully understood. Positron Emission Tomography using 18F-depxyglucose (18FDG) is widely used to identify hypermetabolic regions in vivo. 18FDG is transported in cells with high expression of GLT transporters typical in malignancies and trapped in cells using hexokinase. This is one of the widely used clinical method to identify malignancies relying on GLT transporters and hexokinase activity. Tumors also have high levels of LDHA activity. 13C MRI using hyperpolarized 13C labeled pyruvate is used to detect malignancies by monitoring its conversion rates to lactate. Thus this method relies on monocarboxylate transporters and LDHA activity. In this study, using well defined pancreatic ductal adenocarcinoma xenograft models Here, we used hyperpolarized MRI and electron paramagnetic resonance imaging procedures that allow more direct assessment of tumor glycolysis and oxygenation status quantitatively. We investigated the spatial relationship between hypoxia, glucose uptake, and glycolysis in three human pancreatic ductal adenocarcinoma tumor xenografts with differing physiologic and metabolic characteristics. At the bulk tumor level, there was a strong positive correlation between 18F-FDG-PET and lactate production, while pO2 was inversely related to lactate production and 18F-2-fluoro-2-deoxy- D-glucose (18F-FDG) uptake. However, metabolism was not uniform throughout the tumors, and the whole tumor results masked different localizations that became apparent while imaging. 18F-FDG uptake negatively correlated with pO2 in the center of the tumor and positively correlated with pO2 on the periphery. In contrast to pO2 and 18F-FDG uptake, lactate dehydrogenase activity was distributed relatively evenly throughout the tumor. The heterogeneity revealed by each measure suggests a multi- modal molecular imaging approach can improve tumor characterization, potentially leading to better prognostics in cancer treatment. b) The hypoxia activated prodrug Evofosfamide improves tumor oxygenation. Tumors have regions with low. Levels of oxygen called hypoxic zones, These regions are resistant to radiation therapy and chemotherapy. Hypoxia activated prodrugs such as Evofosfamide are developed to specifically kill cells in hypoxic regions. In hypoxic tumor microenvironments, the strongly reducing redox state converts evofosfamide (TH-302) to a reduced form and releases a cytotoxic bromo-isophosphoramide (Br-IPM) moiety. This drug therefore preferentially attacks hypoxic regions in tumors where other standard anti-cancer treatments such as chemotherapy and radiation therapy are often ineffective. Various combination therapies with evofosfamide have been proposed and tested in preclinical and clinical settings. However, the treatment effect of evofosfamide monotherapy on tumor hypoxia has not been fully understood, partly due to the lack of quantitative methods to assess tumor pO2 in vivo. Here, we use quantitative pO2 imaging by EPR to evaluate the change in tumor hypoxia in response to evofosfamide treatment using two pancreatic ductal adenocarcinoma xenograft models; MIA Paca-2 tumors responding to evofosfamide and Su.86.86 tumors which do not respond. EPR imaging showed oxygenation improved globally after evofosfamide treatment in hypoxic MIA Paca-2 tumors, in agreement with the ex vivo results obtained from hypoxia staining by pimonidazole and in apparent contrast to the decrease in Ktrans observed in DCE MRI. The observation that evofosfamide not only kills the hypoxic region of the tumor but also improves oxygenation in the residual tumor regions provides a rationale for combination therapies using radiation and anti-proliferatives post evofosfamide for improved outcomes.