Hypoxia and Radiotherapy: Evaluation and Mitigation in Tumors

描述(由申请人提供)： 我们将开发、演示和评估一种评估肿瘤氧合的新方法，以期快速转化到临床。我们认为这将与前列腺癌等疾病的大剂量低分割放射治疗最为相关。DOCUNT(由核磁共振T1和T2*评估的动态氧气挑战)利用BOLD(血氧水平依赖)和TELD(组织氧水平依赖)，与使用质子MRI非侵入性检测肿瘤氧合变化形成对比。我们建议开发一种强有力的预后检测方法来揭示肿瘤的缺氧情况。自从格雷等人的经典研究以来。50年前，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，但移植到临床上显示出微效。低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扩展的分割方案，要求患者在数周内每天接受治疗。这是基于避免正常组织损伤的需要。高聚焦射束和立体定向全身放射治疗(SBRT)的发展允许重新考虑更高剂量和少数部分的放射治疗。低氧可能在少量的高剂量照射中发挥更大的作用，因为在每日低剂量照射之间遇到的组间复氧机会较少。我们之前基于19F磁共振血氧测定仪已经证明了单次高剂量照射后的肿瘤生长延迟与大鼠前列腺癌生长中的pO2直接相关，但这需要一个外源报告分子。我们相信，氧敏感的1H磁共振成像将使我们能够仅根据组织水松弛来识别缺氧性肿瘤，并最终对患者进行个体化的低氧依赖治疗。虽然这里建议的研究完全是临床前的，但我们相信它们将证明在患者身上快速实施的强大理由。目的1通过与19F磁共振血氧测定仪的比较，严格证明DOUMENT将肿瘤分类为低氧(耐药或敏感)或氧化的能力。目的2将检查DONCENT是否确实能预测皮下生长的前列腺癌对低分割放射治疗的反应。AIM 3将把研究扩展到原位前列腺癌。AIM 4将寻求通过包括辐射增强来克服缺氧肿瘤的治疗阻力。这项建议回应了最近由NCI赞助的一次研讨会的结论，该研讨会旨在评估低氧成像的现状。人们一致认为，需要一种强有力的实用方法来识别缺氧性肿瘤患者。必要的标准涉及侵袭性、辐射暴露、分辨率、安全性和潜在临床实施的时间。一种大胆的方法被认为是特别实际的，加上TELD评估可以使其更加有用。

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.