For over a century, resistance of radiation to living tissues has been associated with hypoxia, a local lack of molecular oxygen, or low pO?. 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 pO?, voxels less than 10 torr, hypoxia boosts, would improve tumor curability. This research grant has used Electron Paramagnetic Resonance (EPR) imaging to provide absolute pO? images in volume elements or voxels of murine tumors with 1 torr pO? resolution and 0.5 mm spatial resolution in FSa carcinomas in the legs of C?H mice. The voxel pO? correlates with local Oxylite measurements. EPR pO? image based hypoxic fractions, HF10 (fraction of tumor voxels with pO? less than 10 torr) correlates with hypoxia proteins VEGF, CAIX, and HIF1?, and with the curability of tumors given a dose of radiation sufficient to cure 50% of 450 l tumors (TCD50). This established EPR pO? imaging as a reliable locator of relevant radiobiologically relevant hypoxia. To determine if pO? based dose painting improves tumor cure, we implemented the XRAD???Cx 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 pO? 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 ?F-nitroimidazole PET images. We propose the following program investigating the systematics of EPR pO? image based dose painting: 1) Determine the in vivo hypoxic and separate normally oxygenated tumor tissue pO? control doses (TCD??Hypox and TCD??Ox), 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 (?fTCD??Hypox, ?fTCD??Ox: ?fOER) 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.
This grant application includes recent, novel data demonstrating increased tumor cure rate by targeting hypoxic (low oxygen) tumor volumes in live animals for the first time since the discovery of hypoxia induced radiation resistance over a century ago. Hypoxia was measured with novel spin lattice rate pO? sensitive electron paramagnetic resonance imaging and treated with novel high precision conformal radiation to cover 100% of hypoxic tumor volumes. This work will quantify the difference in radiation response between well- and poorly oxygenated tissue to guide hypoxic tumor boost radiation treatment for both single dose and fractionated clinical radiation therapy to focus radiation treatment on resistant tumor areas, allowing lower dose to well-oxygenated tumor and with that, reducing radiation complications.
| Rinard, George A; Quine, Richard W; Buchanan, Laura A et al. (2017) Resonators for In Vivo Imaging: Practical Experience. Appl Magn Reson 48:1227-1247 |
| Sundramoorthy, Subramanian V; Epel, Boris; Halpern, Howard J (2017) A Pulse EPR 25 mT magnetometer with 10ppm resolution. Appl Magn Reson 48:805-811 |
| Nakagawa, Kouichi; Epel, Boris (2017) Investigating the Distribution of Stable Paramagnetic Species in an Apple Seed Using X-Band EPR and EPR Imaging. J Oleo Sci 66:315-319 |
| Eaton, Sandra S; Shi, Yilin; Woodcock, Lukas et al. (2017) Rapid-scan EPR imaging. J Magn Reson 280:140-148 |
| Epel, Boris; Maggio, Matt; Pelizzari, Charles et al. (2017) Electron Paramagnetic Resonance pO2 Image Tumor Oxygen-Guided Radiation Therapy Optimization. Adv Exp Med Biol 977:287-296 |
| Rahimi, Robabeh; Halpern, Howard J; Takui, Takeji (2017) In Vivo EPR Resolution Enhancement Using Techniques Known from Quantum Computing Spin Technology. Adv Exp Med Biol 977:335-339 |
| Kuzhelev, Andrey A; Tormyshev, Victor M; Rogozhnikova, Olga Yu et al. (2017) Triarylmethyl Radicals: EPR Study of 13C Hyperfine Coupling Constants. Z Phys Chem (N F) 231:777-794 |
| Shi, Yilin; Quine, Richard W; Rinard, George A et al. (2017) Triarylmethyl Radical: EPR Signal to Noise at Frequencies between 250 MHz and 1.5 GHz and Dependence of Relaxation on Radical and Salt Concentration and on Frequency. Z Phys Chem (N F) 231:923-937 |
| Boris, Epel; Sundramoorthy, Subramanian V; Halpern, Howard J (2017) 250 MHz passive Q-modulator for reflection resonators. Concepts Magn Reson Part B Magn Reson Eng 47B: |
| Epel, Boris; Sundramoorthy, Subramanian V; Krzykawska-Serda, Martyna et al. (2017) Imaging thiol redox status in murine tumors in vivo with rapid-scan electron paramagnetic resonance. J Magn Reson 276:31-36 |
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