Exploiting thermoregulatory mechanisms to improve radiation therapy of cancer

描述(申请人提供)：目前，用于肿瘤放射增敏的热疗通常是在相对较高的温度下在肿瘤部位进行局部热疗。此外，由于技术应用上的困难，第一次加热剂量通常在第一次辐射剂量之后提供，与辐射部分相比，使用次数较少。然而，越来越多的证据表明，局部应用的高温热疗的生物学原理是错误的。此外，对物理学家、放射治疗师和患者来说，维持和监测局部强烈高温的状态，即使是短期的，也是具有挑战性的。相反，根据我们探索热应激对宿主组织和肿瘤影响的经验，我们断言，对正常器官和组织进行局部或全身治疗时，采用温和的、生理上相关的热疗(38.5-39.5oC之间)可以导致显著的肿瘤放射增敏。我们观察到，轻度全身热疗导致肿瘤血管血流选择性和长期增加，我们认为这是正常血管强大(且快速可逆)温度调节机制的结果，这种机制最终迫使位于正常血管床下游的坍塌的无功能肿瘤血管接受血液。具体地说，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著和选择性地增加肿瘤血管的灌注量，降低肿瘤间质液体压力，并显著提高肿瘤对后续放射治疗的敏感性。这项新拨款提案的总体目标是解决从我们的初步数据中产生的机械性和临床前问题。具体地说，我们将检验这一总体假设，即可以利用正常的体温调节机制选择性地增加肿瘤血管的灌注量，从而大大增强肿瘤的氧合能力，而不会进一步增加正常组织的氧合。该建议的具体目的是：1)测试温和的全身热应激选择性地增加肿瘤血管的灌注和氧合，同时降低间质液体压力的假说；2)测试温和的全身热疗预处理动物将在不增加正常组织敏感性的情况下显著增强放射治疗的抗肿瘤效果的假说；3)比较不同临床相关的动物肿瘤模型，包括自发性肿瘤、患者来源的肿瘤以及原位和转移性肿瘤，在预热应激后进行放射治疗的短期和长期疗效。我们的研究团队是唯一有资格进行这项研究的人，我们设计这些目标是为了支持根据本提案中定义的使用热疗作为辐射敏感剂的新定义的生物学基础，快速实施合理设计的临床试验。 与公共卫生相关：我们正在提出一种可行的新策略，该策略可以显著提高实体肿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传递物理学)依赖于正常血管对轻微温度变化(即体温调节)的反应，我们假设这将增加肿瘤下游血管的灌注量，从而增加氧合。这项提案将解决必须解决的关键问题，以便利用将接受放射治疗的患者的体温调节特性来优化设计新的临床试验。

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.