Exploiting thermoregulatory mechanisms to improve radiation therapy of cancer

利用温度调节机制改善癌症放射治疗

• 批准号: 8065893
• 负责人: ELIZABETH A REPASKY
• 金额: $ 35.29万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8065893
• 关键词: Address; Affect; Animals; Applications Grants; Biological; Blood; Blood Vessels; Clinic; Clinical; Clinical Trials; Clinical Trials Design; Complex; Contrast Media; Data; Dose; Dose Fractionation; Effectiveness; Exercise; Fever; Goals; Heating; Hemoglobin; High temperature of physical object; Immunity; Implant; Induced Hyperthermia; Intercellular Fluid; Link; Local Hyperthermia; Magnetic Resonance Imaging; Modeling; Monitor; Mus; Neoplasm Metastasis; Normal tissue morphology; Organ; Oxygen saturation measurement; Patients; Perfusion; Physics; Physiologic Thermoregulation; Physiological; Property; Published Comment; Qualifying; Radiation; Radiation therapy; Radiation-Sensitizing Agents; Radio; Radiosensitization; Research; SCID Mice; Schedule; Scheme; Site; Solid Neoplasm; Temperature; Testing; Therapeutic; Time; Tissues; Translations; Treatment Efficacy; Tumor Oxygenation; Tumor Tissue; Tumor-Derived; Work; base; blood oxygen level dependent; cancer radiation therapy; clinical application; clinically relevant; compare effectiveness; design; experience; improved; in vivo; pre-clinical; pressure; public health relevance; research clinical testing; research study; response; thermal stress; tumor; tumor growth; vascular bed

DESCRIPTION (provided by applicant): Currently, hyperthermia used for radiosensitization of tumors is usually administered locally at the site of the tumor, at relatively high temperatures. Moreover, because of technical application difficulties, the first heating dose is usually delivered after the first radiation dose, and is administered infrequently in comparison to radiation fractions. However, there is growing evidence that the biological rationale for locally applied, high temperature hyperthermia is faulty. Moreover, maintaining and monitoring a state of intense hyperthermia locally, even for short durations, has been challenging for the physicist, radio-therapist and the patient. In contrast, we assert, based on our experience exploring the effects of thermal stress on host tissues and tumors, that regional or systemic treatment of normal organs and tissues with a mild, physiologically relevant, hyperthermia (between 38.5 - 39.5oC) can result in significant radiosensitization of tumors. We have observed that mild systemic hyperthermia induces selective and long term increases in tumor vascular perfusion and we propose that this is the result of powerful (and rapidly reversible) thermoregulatory mechanisms in normal vasculature which eventually force collapsed non-functional tumor vessels lying downstream of normal vascular beds to receive blood. Specifically, we have strong evidence that mild systemic heating can significantly and selectively increase tumor vascular perfusion over a relatively long period of time, decrease tumor interstitial fluid pressure and significantly sensitize tumors to subsequent radiotherapy. The overall goal of this new grant proposal is to address the mechanistic and pre-clinical questions that arise from our preliminary data. Specifically, we will test the overall hypothesis that normal thermoregulatory mechanisms can be exploited to selectively increase perfusion of tumor vasculature, thus greatly enhancing tumor oxygenation without further increasing oxygenation of normal tissues. The Specific Aims of this proposal are to: 1) Test the hypothesis that mild, systemic thermal stress selectively increases tumor vascular perfusion and oxygenation while decreasing interstitial fluid pressure, 2) Test the hypothesis that pretreatment of animals with mild systemic thermal therapy will significantly enhance the anti-tumor efficacy of radiation therapy without increasing normal tissue sensitivity and 3) Compare short and long-term effectiveness of pre-treatment with mild thermal stress followed by radiation therapy among different clinically relevant animal tumor models, including spontaneous tumors, patient-derived tumors, and orthotopic and metastatic tumors. Our research team is uniquely qualified to conduct this research and we have designed these aims to support rapid implementation of rationally designed clinical trials based upon the newly defined biological basis for the use of hyperthermia as a radiation sensitizer defined in this proposal. PUBLIC HEALTH RELEVANCE: We are proposing a feasible new strategy that can significantly enhance the sensitivity of solid tumors to radiation therapy and result in immediate clinical impact. This approach (which does not require complex physics of local heat delivery) depends upon the response of normal vasculature to mild temperature shifts (i.e., thermoregulation), which we hypothesize will increase the perfusion of downstream blood vessels in tumors, thus increasing oxygenation. This proposal will address critical issues which must be addressed for the optimal design of new clinical trials utilizing the property of thermoregulation in patients who will receive radiation therapy.

描述（由申请人提供）：目前，用于肿瘤放射敏化的高温通常在相对较高的温度下在肿瘤部位局部给药。此外，由于技术应用困难，第一个加热剂量通常是在第一次辐射剂量后输送，并且与辐射级分相比很少给药。但是，越来越多的证据表明，局部应用的生物学原理，高温高温是错误的。此外，对于物理学家，放射治疗师和患者，即使在短时间内，在本地维护和监测强烈的高温状态也是在挑战。相比之下，我们根据探索热应激对宿主组织和肿瘤的影响的经验认为，对具有轻度，生理上相关的，高温（38.5-39.5OC）的正常器官和组织的区域或全身治疗可以导致肿瘤的明显放射辐射。我们已经观察到，轻度的全身性高温诱导肿瘤血管灌注的选择性和长期增加，我们建议这是正常血管中强大（且迅速可逆的）热调节机制的结果，这些机制最终迫使正常血管床下方的非功能性肿瘤容器崩溃，以接收血液。具体而言，我们有强有力的证据表明，温和的全身加热可以在相对较长的时间内显着，有选择地增加肿瘤血管灌注，减少肿瘤间质液压，并显着使肿瘤对随后的放疗。这项新赠款提案的总体目标是解决我们初步数据引起的机械和临床前问题。具体而言，我们将检验总体假设，即可以利用正常的温度调节机制来选择性地增加肿瘤脉管系统的灌注，从而大大增强肿瘤的氧合，而无需进一步增加正常组织的氧合。该提案的具体目的是：1）检验以下假说：轻度，全身热应激有选择地增加肿瘤血管灌注和氧合，同时降低室内液压，2）检验以下假说，即预处理动物对轻度全身热治疗的动物预处理，而无需显着增强持续的抗肿瘤疗法的抗肿瘤疗法，并增强抗肿瘤的效果，使得抗肿瘤的效果效率是正常的效果。在不同临床相关的动物肿瘤模型（包括自发性肿瘤，患者衍生的肿瘤以及矫形和转移性肿瘤）之间进行轻度热应激的预处理，然后进行放射治疗。我们的研究团队具有独特的资格来进行这项研究，我们设计了这些目的，旨在支持基于新定义的生物学基础的合理设计临床试验的快速实施，该试验将高温用作在本提案中定义的放射线敏感器。 公共卫生相关性：我们提出了一种可行的新策略，可以显着提高实体瘤对放射治疗的敏感性，并立即产生临床影响。这种方法（不需要复杂的局部热量递送物理学）取决于正常脉管系统对轻度温度转移的反应（即温度调节），我们假设这将增加肿瘤中下游血管的灌注，从而增加氧合作用。该提案将解决关键问题，这些问题必须解决，以最佳的设计，利用将接受放射治疗的患者中热管的特性进行新的临床试验。