Exploiting thermoregulatory mechanisms to improve radiation therapy of cancer

描述（由申请人提供）：目前，用于肿瘤放射增敏的热疗通常在肿瘤部位以相对较高的温度局部施用。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，并且与辐射部分相比很少施用。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，维持和监测局部强烈高热状态，即使持续时间短，对于物理学家，放射治疗师和患者来说也是一个挑战。相反，根据我们探索热应激对宿主组织和肿瘤的影响的经验，我们认为，对正常器官和组织进行温和的、生理相关的高温（38.5 - 39.5 ℃）的局部或全身治疗可导致肿瘤的显著放射增敏。我们已经观察到，轻度全身热疗诱导肿瘤血管灌注的选择性和长期增加，我们认为这是正常血管系统中强大的（和快速可逆的）温度调节机制的结果，最终迫使塌陷的非功能性肿瘤血管位于正常血管床的下游接受血液。具体来说，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。这项新的拨款提案的总体目标是解决我们的初步数据中出现的机械和临床前问题。具体来说，我们将测试的总体假设，正常的温度调节机制可以被利用来选择性地增加肿瘤血管系统的灌注，从而大大提高肿瘤氧合，而不进一步增加正常组织的氧合。该提案的具体目标是：1）检验以下假设：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，2）检验以下假设：用温和的全身热疗法预处理动物将显著增强放射疗法的抗肿瘤功效而不增加正常组织敏感性，以及3）比较短期和长期热疗法。在不同的临床相关动物肿瘤模型中，包括自发性肿瘤、患者源性肿瘤以及原位和转移性肿瘤，用轻度热应激预处理后进行放射治疗的长期有效性。我们的研究团队是唯一有资格进行这项研究的，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，这些临床试验基于本提案中定义的使用热疗作为辐射敏化剂的新定义的生物学基础。 公共卫生相关性：我们正在提出一种可行的新策略，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（其不需要复杂的局部热传递物理学）取决于正常脉管系统对温和温度变化的响应（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。该提案将解决关键问题，必须解决的新的临床试验的最佳设计，利用体温调节的性质，在病人谁将接受放射治疗。

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.