Effects of Photodynamic Therapy on Tumor Oxygenation and Blood Flow

描述(申请人提供)：光动力疗法(PDT)被批准或正在进行临床试验，用于多种类型的恶性肿瘤的局部治疗。在之前的资助周期中，对啮齿动物肿瘤进行了详细的空间分析，以确定光动力疗法与肿瘤生理特性之间的相互作用，包括氧合和血流。这些数据表明，基于对肿瘤血氧或血流的个体化监测，可以预测PDT的结果，从而证实肿瘤间和肿瘤内异质性的治疗相关性。在这一应用的更新中，将研究组织血管系统(血管微环境)的结构和功能特性，以了解它们对PDT的细胞、血管和分子反应的影响。研究旨在验证这样一种假设，即血管微环境及其伴随的血管反应性是肿瘤对光动力疗法反应的效应因子。血管微环境影响PDT结果的能力为改变特定血管类型的血管反应的方法打开了大门，例如成熟血管，以提高治疗效果。因此，PDT将与成熟血管功能的药理调节剂相结合，以努力改善结果。在临床研究中，将从PDT临床试验患者的非小细胞肺癌和卵巢癌患者的活检组织中调查血管成熟度与PDT结果之间的关系。这里提出的研究将使用许多标准的生物分析以及定制设计的技术来进行，我们在这些技术上有丰富的经验。免疫组织化学染色切片的定量图像分析将用于确定血管微环境和PDT对肿瘤氧合和血管损伤的空间分布的影响。无创光谱学(漫反射光谱学)将被用来纵向监测治疗过程中的肿瘤生理过程，如氧合和血流。使用这些技术将解决以下特定目标：特定目标1。明确血管微环境如何影响肿瘤对光动力疗法的生理和细胞毒性反应。明确PDT过程中血管反应性的调节如何影响肿瘤和正常组织的反应。具体目的3.探讨PDT治疗患者血管微环境与疗效的关系。公共卫生研究进展：这项提案中产生的数据将定义血管微环境对光动力疗法(PDT)的血管、细胞和治疗反应的影响，并确定在光照过程中调节血管反应可能如何使治疗结果受益。在PDT过程中，成熟血管的血管反应性将使用常见的临床药理药物来改变，这使得这种优化治疗的方法具有高度的临床意义。在临床前研究的同时，临床研究将解决血管微环境如何影响患者对光动力疗法的反应的问题，从而为设计将光动力疗法与改变成熟血管反应性的药物相结合的临床试验提供必要的基础。

DESCRIPTION (provided by applicant): Photodynamic therapy (PDT) is approved or in clinical trials for the local treatment of numerous types of malignancies. In the previous funding cycle, detailed spatial analyses of rodent tumors were performed to define the interaction between PDT and tumor physiological properties, including oxygenation and blood flow. These data demonstrate that PDT outcome can be predicted based on individualized monitoring of tumor blood oxygenation or blood flow and thus serve to confirm the therapeutic relevance of intertumor and intratumor heterogeneity. In the renewal of this application, the structural and functional properties of tissue vasculature (vascular microenvironment) will be studied for their effect on cellular, vascular, and molecular responses to PDT. Studies are designed to test the hypothesis that the vascular microenvironment and its accompanying vasoreactivity are effectors of tumor response to PDT. The ability of vascular microenvironment to affect PDT outcome opens the door to methods of altering vascular response in specific vessel types, such as mature vessels, in order to improve treatment efficacy. Accordingly, PDT will be combined with pharmacological modifiers of mature vascular function in an effort to benefit outcome. In clinical studies, the association between vascular maturity and PDT outcome will be investigated for biopsies of non-small cell lung cancer and ovarian cancer from the patients of PDT clinical trials. The studies proposed herein will be performed using many standard biological assays, as well as custom-designed technologies, of which we have substantial experience. Quantitative image analysis of immunohistochemically-stained sections will be used to define vascular microenvironment and PDT effect on spatial distributions of tumor oxygenation and vascular damage. Noninvasive optical spectroscopy (diffuse optical spectroscopy) will be used to longitudinally monitor tumor physiological processes such as oxygenation and blood flow over the course of treatment. Using these techniques the following specific aims will be addressed: Specific Aim 1. To define how vascular microenvironment affects tumor physiological and cytotoxic responses to PDT. Specific Aim 2. To define how modulation of vasoreactivity during PDT affects tumor and normal tissue responses. Specific Aim 3. To explore the association between vascular microenvironment and therapeutic outcome in patients treated with PDT. PUBLIC HEALTH RELEVENCE: The data generated in this proposal will define the effect of vascular microenvironment on vascular, cellular, and therapeutic responses to photodynamic therapy (PDT), and determine how therapeutic outcome may be benefited by modulation of vasoresponse during illumination. The vascular reactivity of mature blood vessels during PDT will be altered using common clinical pharmacological agents, which makes this approach toward therapy optimization highly clinically relevant. In parallel with the preclinical studies, clinical investigation will address the question of how vascular microenvironment affects patient response to PDT, thus providing necessary groundwork for the design of a clinical trial combining PDT with drugs that alter mature vessel reactivity.