Hypoxia and Radiotherapy: Evaluation and Mitigation in Tumors

描述（由申请人提供）： 我们将开发，展示和评估一种新的方法来评估肿瘤氧合，以期快速转化为临床。我们相信，它将是最相关的高剂量低分割放射治疗的疾病，如前列腺癌。DOCENT（通过NMR T1和T2* 评估的动态氧挑战）利用BOLD（血氧水平依赖性）和TOLD（组织氧水平依赖性）对比度，使用质子MRI无创检测肿瘤氧合的变化。我们建议开发DOCENT作为一个强大的预后测试，以揭示肿瘤缺氧。自从五十年前Gray等人的经典研究以来，人们已经认识到缺氧会影响放射治疗的疗效。已经有许多调节肿瘤缺氧的尝试，但是转化到临床已经显示出边际功效。缺氧已在人类肿瘤中得到证实，并与治疗结果相关，但目前的活检/组织学，电极和核医学成像方法既不方便也不广泛使用。目前的放射治疗使用延长的分割方案，需要患者每天参加许多周。这是基于避免正常组织损伤的需要。高度聚焦射束和立体定向体部放射治疗（SBRT）的发展允许再次考虑使用更高剂量和几个分数。对于少量高剂量辐照，缺氧可能发挥更大的作用，因为在每日低剂量之间遇到的分次间复氧的机会较少。我们已经显示了基于19 F MR血氧测定法在大鼠中生长的前列腺肿瘤中，单次高剂量照射后肿瘤生长延迟与pO 2之间的直接相关性，但这需要外源性报告分子。我们相信，氧敏感的1H MRI将使我们能够识别缺氧肿瘤的基础上组织水松弛单独和最终分层的患者进行个性化的缺氧依赖性治疗。虽然本文提出的研究完全是临床前研究，但我们相信它们将证明在患者中快速实施的有力依据。目标1将通过与19 F MR血氧测定法进行比较，严格证明DOCENT将肿瘤分类为缺氧（耐药或反应性）或氧化的能力。目的2将检验DOCENT是否确实预测皮下生长的前列腺肿瘤对大分割放射的反应。目标3将研究扩展到原位前列腺肿瘤。目标4将寻求通过包括辐射增强来克服缺氧肿瘤的治疗抗性。该建议响应了最近由美国国家癌症研究所主办的评估缺氧成像现状的研讨会的结论。人们一致认为，需要一种强大的实用方法来识别缺氧肿瘤患者。要求标准涉及侵入性、辐射暴露、分辨率、安全性和潜在临床实施时间。BOLD方法被认为是特别实用的，增加TOLD评估可以使其更加有用。 公共卫生相关性： 我们将开发、演示和评估一种评估肿瘤氧合的新方法。DOCENT（通过NMR T1和T2* 评估的动态氧挑战）利用BOLD（血氧水平依赖性）和TOLD（组织氧水平依赖性）方法，使用质子MRI无创检测肿瘤氧合的变化。我们建议将其开发为一个强大的预后测试，以揭示肿瘤缺氧，这可能成为一个有价值的工具，在分层患者的个性化治疗计划的疾病，如前列腺癌。

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.