The prognosis for patients with malignant gliomas remains dismal in spite of many advances in surgical, chemotherapeutic and radiotherapeutic modalities. Treatment options are determined mostly empirically, and therefore new approaches based on tumor physiology or genetics are needed to improve outcome for patients with this highly malignant tumor. Brain tumors are treated with a spectrum of fractionation regimens based on the clinical and anatomical characteristics of the tumor but are rarely based on the molecular or physiological characteristics of the individual tumor. Hypoxia is a known factor in radioresistance. Radiotherapy is expected to change oxygenation in tumors, this effect is likely to vary with the dose per fraction and interval between doses, and therefore may significantly alter the effectiveness of the treatment. Establishing the presence of hypoxia and particularly the possibility of exploiting post-irradiation reoxygenation in gliomas offers the promise of developing individualized RT regimens that might improve the response of radioresistant glioma cells to therapy. We hypothesize that the therapeutic outcome of hypofractionated radiotherapy of gliomas can be significantly enhanced if radiotherapy is used at times of optimal tumor oxygenation and the use of hyperoxic therapies in conjunction with hypofractionated radiotherapy can 'be optimized by the use of information on oxygen levels in the tumors. This would be a highly significant development for gliomas due to their poor radiotherapy prognosis. We will measure partial pressure of oxygen (pO2) using multi-site EPR (Electron Paramagnetic Resonance) oximetry in experimental intracranial 9L tumors undergoing hypofractionated radiotherapy and relate hypoxia and changes in hypoxia to outcome in terms of tumor growth delay. This has not been possible previously due to a lack of suitable in vivo techniques for repeated non-invasive pO2 measurements in the same tumor during the entire course of therapy. MRI and histology will be used to determine tumor tissue characteristics that may be related to the mechanism of the changes in oxygen, at time points during therapy and in relation to measured tumor pO2. We also will determine the relationship between radiation-induced changes in tumor oxygenation and the extent of tumor pO2 increases during hyperoxygenation with hyperbaric oxygen therapy (100% oxygen at 2-4 ATA) and carbogen (95%O2/5%CO2). This study will provide a rationale basis for the application of hypofractionated stereotactic radiotherapy so that it can be used with optimal effectiveness, and establish methodology that can be used to enhanced therapeutic outcome of gliomas in particular but also for tumors in general.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Radiation Therapeutics and Biology Study Section (RTB)
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Bernhard, Eric J
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Dartmouth College
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Hou, Huagang; Krishnamurthy Nemani, Venkata; Du, Gaixin et al. (2015) Monitoring oxygen levels in orthotopic human glioma xenograft following carbogen inhalation and chemotherapy by implantable resonator-based oximetry. Int J Cancer 136:1688-96
Hou, Huagang; Mupparaju, Sriram P; Lariviere, Jean P et al. (2013) Assessment of the changes in 9L and C6 glioma pO2 by EPR oximetry as a prognostic indicator of differential response to radiotherapy. Radiat Res 179:343-51
Hou, Huagang; Dong, Ruhong; Li, Hongbin et al. (2012) Dynamic changes in oxygenation of intracranial tumor and contralateral brain during tumor growth and carbogen breathing: a multisite EPR oximetry with implantable resonators. J Magn Reson 214:22-8
Khan, Nadeem; Mupparaju, Sriram; Hou, Huagang et al. (2012) Repeated assessment of orthotopic glioma pO(2) by multi-site EPR oximetry: a technique with the potential to guide therapeutic optimization by repeated measurements of oxygen. J Neurosci Methods 204:111-117
Hou, Huagang; Dong, Ruhong; Lariviere, Jean P et al. (2011) Synergistic combination of hyperoxygenation and radiotherapy by repeated assessments of tumor pO2 with EPR oximetry. J Radiat Res 52:568-74
Khan, Nadeem; Blinco, James P; Bottle, Steven E et al. (2011) The evaluation of new and isotopically labeled isoindoline nitroxides and an azaphenalene nitroxide for EPR oximetry. J Magn Reson 211:170-7
Mupparaju, Sriram; Hou, Huagang; Lariviere, Jean P et al. (2011) Tumor pO? as a surrogate marker to identify therapeutic window during metronomic chemotherapy of 9L gliomas. Adv Exp Med Biol 701:107-13
Mupparaju, Sriram; Hou, Huagang; Lariviere, Jean P et al. (2011) Repeated tumor oximetry to identify therapeutic window during metronomic cyclophosphamide treatment of 9L gliomas. Oncol Rep 26:281-6
Abramovic, Zrinka; Hou, Huagang; Julijana, Kristl et al. (2011) Modulation of tumor hypoxia by topical formulations with vasodilators for enhancing therapy. Adv Exp Med Biol 701:75-82
Khan, Nadeem; Mupparaju, Sriram; Hekmatyar, Shahryar K et al. (2010) Effect of hyperoxygenation on tissue pO2 and its effect on radiotherapeutic efficacy of orthotopic F98 gliomas. Int J Radiat Oncol Biol Phys 78:1193-200

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