Effects of Photodynamic Therapy on Tumor Oxygenation and Blood Flow

描述（由申请人提供）：光动力疗法（PDT）已被批准或在临床试验中用于多种类型恶性肿瘤的局部治疗。在上一个资助周期中，对啮齿动物肿瘤进行了详细的空间分析，以确定PDT与肿瘤生理特性（包括氧合和血流）之间的相互作用。这些数据表明，PDT的结果可以预测的基础上个性化监测肿瘤血氧或血流，从而确认肿瘤间和肿瘤内异质性的治疗相关性。在本申请的更新中，将研究组织脉管系统（血管微环境）的结构和功能特性对PDT的细胞、血管和分子反应的影响。研究旨在验证血管微环境及其伴随的血管反应性是肿瘤对PDT反应的效应子这一假设。血管微环境影响PDT结果的能力为改变特定血管类型（例如成熟血管）中的血管反应的方法打开了大门，以提高治疗效果。因此，PDT将与成熟血管功能的药理学修饰剂相结合，以改善结局。在临床研究中，将针对PDT临床试验患者的非小细胞肺癌和卵巢癌活检，研究血管成熟度与PDT结局之间的相关性。本文提出的研究将使用许多标准生物测定法以及我们拥有丰富经验的定制设计技术进行。将使用化学染色切片的定量图像分析来确定血管微环境和PDT对肿瘤氧合和血管损伤的空间分布的影响。非侵入性光谱学（扩散光谱学）将用于纵向监测肿瘤生理过程，如治疗过程中的氧合和血流。使用这些技术，将解决以下具体目标：具体目标1。明确血管微环境如何影响肿瘤对PDT的生理和细胞毒性反应。具体目标2。明确PDT期间血管反应性的调节如何影响肿瘤和正常组织的反应。具体目标3。探讨PDT治疗患者血管微环境与治疗结果之间的关系。公共卫生解放：本提案中生成的数据将定义血管微环境对血管、细胞和光动力治疗（PDT）的治疗反应的影响，并确定治疗结果如何受益于照明期间血管反应的调节。PDT期间成熟血管的血管反应性将使用常见的临床药理学试剂改变，这使得这种治疗优化方法具有高度临床相关性。与临床前研究平行，临床研究将解决血管微环境如何影响患者对PDT反应的问题，从而为设计PDT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.