Exploiting thermoregulatory mechanisms to improve radiation therapy of cancer

描述（由申请人提供）：目前，用于肿瘤放射致敏的热疗通常在相对较高的温度下局部施用于肿瘤部位。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给予，与辐射分量相比，给予的频率较低。然而，越来越多的证据表明，局部应用高温热疗的生物学原理是错误的。此外，维持和监测局部的高温状态，即使是短时间，对物理学家、放射治疗师和患者来说都是一个挑战。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，用轻度的、生理相关的热疗（38.5 - 39.5℃）对正常器官和组织进行局部或全身治疗可导致肿瘤的显著放射致敏。我们观察到，轻度全身热疗诱导肿瘤血管灌注选择性和长期增加，我们认为这是正常血管中强大（且快速可逆）的温度调节机制的结果，该机制最终迫使位于正常血管床下游的塌陷的无功能肿瘤血管接受血液。具体而言，我们有强有力的证据表明，轻度全身加热可以在较长时间内显著和选择性地增加肿瘤血管灌注，降低肿瘤间质液压力，并显著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从我们的初步数据中产生的机制和临床前问题。具体而言，我们将验证正常的体温调节机制可以选择性地增加肿瘤血管的灌注，从而在不进一步增加正常组织氧合的情况下大大增强肿瘤氧合的总体假设。本建议的具体目标是：1)验证轻度全身热应激选择性地增加肿瘤血管灌注和氧合，同时降低间质液压力的假设；2)在不增加正常组织敏感性的情况下，对动物进行轻度全身热应激预处理，可显著增强放射治疗的抗肿瘤疗效。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、原位和转移性肿瘤）进行轻度热应激预处理后再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，我们设计了这些目标，以支持快速实施合理设计的临床试验，该试验基于新定义的生物学基础，使用热疗作为本提案中定义的辐射致敏剂。

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.