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: 7663342
• 负责人: ELIZABETH A REPASKY
• 金额: $ 35.48万
• 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 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7663342
• 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; Neoplasms in Vascular Tissue; 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，用于肿瘤放射增敏的热疗通常在相对较高的温度下在肿瘤部位进行局部施用。此外，由于技术应用困难，第一加热剂量通常在第一辐射剂量之后递送，并且与辐射分数相比施用频率较低。然而，越来越多的证据表明局部高温热疗的生物学原理是错误的。此外，对于物理学家、放射治疗师和患者来说，即使持续时间很短，维持和监测局部的强烈高热状态也具有挑战性。相比之下，我们断言，根据我们探索热应激对宿主组织和肿瘤影响的经验，用温和的、生理相关的高温（38.5 - 39.5oC）对正常器官和组织进行局部或全身治疗可以导致对肿瘤有显着的放射增敏作用。我们观察到，轻度全身高热会选择性地长期增加肿瘤血管灌注，我们认为这是正常脉管系统中强大（且快速可逆）温度调节机制的结果，最终迫使位于正常下游的非功能性肿瘤血管塌陷。接受血液的血管床。具体来说，我们有强有力的证据表明，轻度全身加热可以在相对较长的时间内显着且选择性地增加肿瘤血管灌注，降低肿瘤间质液压力并显着提高肿瘤对后续放疗的敏感性。这项新拨款提案的总体目标是解决我们初步数据中出现的机制和临床前问题。具体来说，我们将测试总体假设，即可以利用正常的温度调节机制选择性地增加肿瘤脉管系统的灌注，从而大大增强肿瘤氧合，而无需进一步增加正常组织的氧合。该提案的具体目标是：1) 检验温和的全身热应激选择性增加肿瘤血管灌注和氧合同时降低间质液压力的假设，2) 检验用温和的全身热疗法预处理动物将显着增强肿瘤血管灌注和氧合的假设。放射治疗在不增加正常组织敏感性的情况下的抗肿瘤功效，以及 3) 比较不同临床相关动物肿瘤模型（包括自发性肿瘤、患者源性肿瘤）中先进行轻度热应激预处理，然后进行放射治疗的短期和长期疗效肿瘤，以及原位和转移性肿瘤。我们的研究团队具有进行这项研究的独特资格，我们设计这些目标是为了支持快速实施合理设计的临床试验，这些临床试验基于新定义的使用热疗作为本提案中定义的辐射增敏剂的生物学基础。 公共卫生相关性：我们提出了一种可行的新策略，可以显着增强实体瘤对放射治疗的敏感性，并产生立竿见影的临床影响。这种方法（不需要局部热量传递的复杂物理过程）取决于正常脉管系统对温和温度变化（即温度调节）的反应，我们假设这将增加肿瘤下游血管的灌注，从而增加氧合。该提案将解决利用接受放射治疗的患者的体温调节特性来优化设计新临床试验时必须解决的关键问题。