Hypoxia and Radiotherapy: Evaluation and Mitigation in Tumors

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DESCRIPTION (provided by applicant): We will develop, demonstrate, and evaluate a novel approach to assessing tumor oxygenation with a view to rapid translation to the clinic. We believe it will be most pertinent to high dose hypofractionated radiotherapy in diseases such as prostate cancer. DOCENT (Dynamic Oxygen Challenge Evaluated by NMR T1 and T2*) exploits BOLD (blood oxygen level dependent) and TOLD (tissue oxygen level dependent) contrast to non- invasively detect changes in tumor oxygenation using proton MRI. We propose to develop DOCENT as a robust prognostic test to reveal tumor hypoxia. Ever since the classic studies of Gray et al. fifty years ago, it has been appreciated that hypoxia can influence the efficacy of radiotherapy. There have been many attempts to modulate tumor hypoxia, but translation to the clinic has shown marginal efficacy. Hypoxia has been confirmed in human tumors and correlated with therapeutic outcome, but the current biopsy/histology, electrodes, and nuclear medicine imaging approaches are neither convenient nor widely used. Current radiotherapy uses extended fractionation regimens requiring patients to attend daily for many weeks. This is predicated on the need to avoid normal tissue damage. The development of highly focused beams and stereotactic body radiation therapy (SBRT) allows higher doses with a few fractions to be considered again. Hypoxia is likely to play a greater role for small numbers of high dose irradiations, since there is less opportunity for the inter fraction reoxygenation encountered between daily low doses. We have shown direct correlations between tumor growth delay following single high dose irradiation and pO2 in prostate tumors growing in rats based on 19F MR oximetry previously, but this required an exogenous reporter molecule. We believe that oxygen sensitive 1H MRI will allow us to identify hypoxic tumors based on tissue water relaxation alone and ultimately stratify patients for individualized hypoxia-dependant therapy. While the investigations proposed here are entirely pre-clinical, we believe they will demonstrate a strong rationale for rapid implementation in patients. Aim 1 will rigorously demonstrate the ability of DOCENT to categorize tumors as hypoxic (resistant or responsive) or oxic by comparison with 19F MR oximetry. Aim 2 will examine whether DOCENT does indeed predict response to hypofractionated radiation in subcutaneously growing prostate tumors. Aim 3 will extend studies to orthotopic prostate tumors. Aim 4 will seek to overcome therapeutic resistance of hypoxic tumors by including a radiation boost. This proposal responds to conclusions of a recent NCI-sponsored workshop to assess the current status of hypoxia imaging. There was consensus that a robust practical method is needed to identify patients with hypoxic tumors. Requisite criteria relate to invasiveness, radiation exposure, resolution, safety, and time to potential clinical implementation. A BOLD approach was considered to be particularly practical and the addition of the TOLD assessment can make it even more useful. PUBLIC HEALTH RELEVANCE: We will develop, demonstrate, and evaluate a novel approach to assessing tumor oxygenation. DOCENT (Dynamic Oxygen Challenge Evaluated by NMR T1 and T2*) exploits BOLD (blood oxygen level dependent) and TOLD (tissue oxygen level dependent) approaches to non-invasively detect changes in tumor oxygenation using proton MRI. We propose to develop this as a robust prognostic test to reveal tumor hypoxia, which could become a valuable tool in stratifying patients for personalized therapy planning in diseases such as prostate cancer.