One-shot morphologic, hemodynamic and metabolic MR imaging of brain tumors

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PROJECT SUMMARY/ABSTRACT: The goal of this project is to validate a clinically feasible, one-shot contrast-enhanced, multiparametric MRI approach for mapping the morphologic, hemodynamic and metabolic features of brain tumors using a single contrast agent. Contrast-enhanced (CE) MRI is the clinical imaging standard for guiding nearly all aspects of brain tumor management, including surgical biopsy/resection, radiation treatment planning, and post-treatment surveillance for response assessment. Dynamic susceptibility contrast (DSC) MRI is a complementary technique that leverages the dynamic passage of the contrast agents utilized for CE-MRI in order to provide maps of tumor perfusion. An unmet clinical need in the assessment of tumor pathophysiology is the ability to routinely detect hypoxia and its evolution. Brain tumors exhibit considerable hypoxia which leads to therapy resistance, triggers more aggressive and invasive phenotypes, is considered a potential therapeutic target, and is prognostic of overall survival. The most widely used method for interrogating hypoxia in the clinic relies on PET radiotracers, which, in the context of brain tumors, necessitates multiple scans and injections in addition to routine CE-MRI and DSC-MRI. This limitation increases costs, dose and patient discomfort, while reducing efficiency and the likelihood of widespread use, particularly in non-academic community hospitals where patients are unlikely to undergo multi-modality imaging. Consequently, an MRI-based hypoxia imaging approach could significantly enhance the metabolic characterization and therapeutic management of brain tumor patients. We have developed a GdDOTA monoamide conjugate of 2-nitroimidazole (a well-established hypoxia binding moiety), termed GdDO3NI, that enables detection of regional hypoxia. We hypothesize that CE-MRI, DSC-MRI and hypoxia data can be acquired in brain tumors in a single imaging session following a single-injection of GdDO3NI and can help predict outcome of hypoxia targeted therapy. We anticipate that optimal acquisition and analysis protocols for dynamic GdDO3NI MRI will provide hypoxia maps that regionally colocalize with pimonidazole IHC and FMISO PET and will provide congruous estimates of hypoxic tumor fraction between the various techniques. Towards this end we propose to 1) validate GdDO3NI based CE-MRI and DSC-MRI in orthotopic, human-derived glioma preclinical models, 2) establish optimal GdDO3NI based hypoxia mapping protocols and validate using immunohistochemistry (IHC) and clinically comparable PET markers and 3) demonstrate the potential of GdDO3NI to predict response to a hypoxia activated prodrug, evofosfamide. Our innovative, one-shot, multi-parametric strategy represents a transformational shift in brain tumor imaging that could enable personalized therapy based on lesion morphology, regional perfusion and metabolic heterogeneity. The proposed one-shot strategy could also be translated to cancers outside the brain, increasing the range of patients impacted by this research and feasibility of translating GdDO3NI to the clinic.