# Radiation Biology of EPR Oxygen Images

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2020 · $307,800

## Abstract

For over a century, resistance of radiation to living tissues has been associated with hypoxia, a local
lack of molecular oxygen, or low pO₂. The focus of the past funding cycle has been to validate the hypothesis
that has been assumed, but not proven over the past century, that treatment focused specifically on regions of
tumors with low pO₂, voxels less than 10 torr, hypoxia boosts, would improve tumor curability. This
research grant has used Electron Paramagnetic Resonance (EPR) imaging to provide absolute pO₂ images in
volume elements or voxels of murine tumors with 1 torr pO₂ resolution and 0.5 mm spatial resolution in FSa
carcinomas in the legs of C₃H mice. The voxel pO₂ correlates with local Oxylite measurements. EPR pO₂ image
based hypoxic fractions, HF10 (fraction of tumor voxels with pO₂ less than 10 torr) correlates with hypoxia
proteins VEGF, CAIX, and HIF1α, and with the curability of tumors given a dose of radiation sufficient to cure
50% of 450 µl tumors (TCD50). This established EPR pO₂ imaging as a reliable locator of relevant
radiobiologically relevant hypoxia. To determine if pO₂ based dose painting improves tumor cure, we
implemented the XRAD₂₂₅Cx system to deliver gantry based x-ray treatments to mouse tumors accurately
registered with EPR pO2 images. We implemented rapid 3D printing Tungsten loaded, conformal plastic
blocks to compare treating ~100% of hypoxic tumor voxels with hypoxia avoidance. Only then did we observe
significant (p=0.02) tumor control differences between hypoxic boosts and anti-boosts. This is the first
validation of hypoxia based dose painting in mammalian tumors. The systematics of the differences between
hypoxic and normal pO₂ tumor tissue now need to be determined in several animal models with different
immunologic conditions and with fractionation to guide eventual human use, possibly based on reductive
retention of ¹⁸F-nitroimidazole PET images. We propose the following program investigating the systematics of
EPR pO₂ image based dose painting:
1) Determine the in vivo hypoxic and separate normally oxygenated tumor tissue pO₂ control doses
(TCD₅₀Hypox and TCD₅₀Ox), an in vivo oxygen enhancement ratios (OER) for orthotopic FSa and RIF1
fibrosarcomas, MCa4 mammary carcinomas grown orthotopically and, to determine the immunogenic status
dependence, in human PC3 prostate carcinoma xenografts in athymic nude mice.
2) Determine the influence of three dose fractionation on hypoxic tumor control and oxygen enhancement
ratios (₃fTCD₅₀Hypox, ₃fTCD₅₀Ox: ₃fOER)
These experiments will provide ranges of in vivo variation from which to estimate in vivo oxygen enhancement
ratios to guide early human trials of hypoxic boost/dose painting treatment. The success of preclinical
determination of OER in multiple model tumors may suggest means by which to correct PET based human
hypoxic tumor imaging. We also show technology suggesting EPR imaging in human subjects.

## Key facts

- **NIH application ID:** 9891015
- **Project number:** 5R01CA098575-14
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** HOWARD J HALPERN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $307,800
- **Award type:** 5
- **Project period:** 2003-06-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9891015

## Citation

> US National Institutes of Health, RePORTER application 9891015, Radiation Biology of EPR Oxygen Images (5R01CA098575-14). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9891015. Licensed CC0.

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