Project 3: Direct & Repeated Measurement of pO2 in Deep-seated Tumors using EPR O

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A number of strategies to improve oxygen levels in tumors by oxygen enriched gases or modulation of tumor vasculature (e.g. ARCON, avastin) have failed to show efficacy in clinical trials despite promising pre-clinical results. A major caveat in these studies is the lack of techniques for monitoring oxygen levels in the tumors and therefore it is not known if the therapy indeed was effective in reducing tumor hypoxia. It is imperative to monitor tumor pO2 to understand treatment responses in future clinical trials. In project 3, we will implement a novel implantable deep-tissue oxygen sensor approach with improved versatility to be used in tumors located at depths > 10 mm from the patient's skin. This approach will use OxyChip (Project 2), but with the addition of a thin (<0.2 mm wire gauge) non-magnetic wire to transduce the microwave energy from deep-tissue to the spectrometer for the acquisition of EPR spectra. The implantable deep-tissue oxygen sensors has been designed and rigorously tested for pO2 measurements at 2-4 sites simultaneously, MRI compatibility, and biocompatibility in experimental animal models. We will first perform a safety and feasibility study in patients, and then proceed with a two institutional (Dartmouth and Emory) study to measure oxygen levels at baseline, temporal fluctuations and response to hyperoxygenation with carbogen (2% CO2 + 98% O2) breathing. Importantly, we will measure oxygen levels in recurrent gliomas being treated with an anti-angiogenic agent, avastin. This study will contribute to our understanding of the effect of avastin on tumor pO2 in patients and determine how best to administer avastin with radiation therapy for improving treatment outcomes. These studies will provide a paradigm to measure tumor oxygen levels during therapy and will be the first step in disseminating this technology to the broader radiation oncology community. We propose the following specific aims to meet the objective of this project and the overall goals of the PPG: (1) Establish the efficacy and safety of implantable deep-tissue oxygen sensors and investigate pre-treatment oxygen profiles of patients with deep-seated head and neck, sarcoma and brain tumors; (2) Determine the response and change in pO2 induced by hyperoxygenation and anti-angiogenic treatment in human tumors, and (3) Determine tumor oxygen levels during concurrent treatment with radiation and subsequently evaluate the effects of oxygen-modifying interventions during radiotherapy. Project 3 will fulfill the unmet need for monitoring pO2 in deep-seated tumors, which will provide clinicians crucial diagnostic, therapeutic, and prognostic information to improve the treatment outcome of patients.