Absolute quantitative oxygen-enhanced MRI for oxygen mapping and targeted radiation therapy

The National Cancer Institute awarded Trustees of Dartmouth College $100,228 on February 14, 2027, under the Cancer Research Manpower program (CFDA 93.398) to develop absolute quantitative oxygen-enhanced MRI (AQOE-MRI), a method combining an FDA-approved oxychip electron paramagnetic resonance spin probe with relaxometry measurements to generate absolute PO2 values for mapping tumor hypoxia and guiding radiation therapy dose escalation. The project runs through August 16, 2028, and is performed in Hanover, New Hampshire.

Current clinical approaches to assessing tumor oxygenation—polarographic probes that perturb tissue and consume oxygen during measurement, and FMISO PET scans requiring hours for tracer perfusion with poor spatial resolution—fail to provide the stable, absolute oxygen values needed for routine hypoxia-guided treatment. Oxygen-enhanced MRI captures broad anatomical regions with superior soft-tissue contrast but yields only relative relaxation rates. AQOE-MRI addresses this gap by using the oxychip as an internal reference calibration standard, enabling absolute quantification of tissue oxygen levels to inform targeted dose escalation in head and neck cancer and other radiation-sensitive tumors where hypoxia drives treatment resistance and recurrence.

Abstract

Tumor hypoxia remains a major unsolved challenge in radiation therapy. IT is well-known that poorly oxygenated cancer cells experience an increased resistance to radiation treatment, as much as 3 times as normoxic tissue, referred to as the oxygen enhancement ratio (OER). Despite this fact, clinicians lack dependable ways to track oxygen levels in deep tissue over a treatment regimen. This GAP in clinical application has consequences, namely, that patients treated for head and neck tumors frequently experience recurrence, leading to additional rounds of treatment. In parallel, a persistent poor oxygen environment raises chances of the cancer metastasizing and lowers overall odds of survival. Although researchers have understood the link between oxygenation and radiation effects on cells for decades, applying hypoxia markers to inform treatments is not routine. One key reason lies in the deficiencies of current methodologies, which fail to provide stable or meaningful data needed for daily clinical use. Polarographic probes (like the eppendorf electrode) perturb this tissue environment and consume oxygen during measurement with limited measurement capability. Fmiso pet scans require hours for tracers to perfuse the body, suffer from poor spatial resolution, and result in increased patient dose. Then there is oxygen-enhanced MRI (OE-MRI), which captures broad anatomical regions with superior soft-tissue contrast by detecting shifts in tissue relaxation rates due to the presence of oxygen; however, OE-MRI yields only relative relaxation rates rather than the absolute PO2 values required for hypoxia-guided dose escalation. This study introduces absolute quantitative oxygen-enhanced MRI (aqoe-MRI): a method combining the FDA-approved oxychip (an electron paramagnetic resonance (EPR) spin probe for oximetry) as an internal reference with relaxometry measurements obtained with OE-MRI to map tissue PO2 with high spatial resolution. This new method allows, for the first time, detailed oxygen mapping that can guide targeted dose escalation during MRI-guided radiation treatment (mrgrt). The central hypothesis is that aqoe-MRI will provide clinically actionable tissue oxygenation maps enabling hypoxia-directed treatment to improve tumor control without increasing normal tissue toxicity. I intend to test this hypothesis through two specific aims. Aim 1 will establish the technical foundations by characterizing the relationship between signal-to-noise ratio and oxygen measurement precision across clinically relevant field strengths, then validating aqoe-MRI-derived maps against established EPR oxygen imaging in murine tumor models. Aim 2 will demonstrate clinical-scale implementation by tracking tumor hypoxic fraction during fractionated radiation therapy in a large-animal translational cancer model using a clinical 0.35T MR-linac system and will determine whether aqoe-MRI-guided dose escalation improves tumor control compared to conventional uniform dose delivery.