Effects of Photodynamic Therapy on Tumor Oxygenation and Blood Flow

描述（由申请人提供）：在上一次资助期间，我们成功完成了关于光动力疗法（PDT）对肿瘤氧合和血流影响的研究，重点是光照期间PDT触发的血管反应性的治疗改变后果。这些研究已经确定了微环境特征，如血管大小和与细胞外基质的关系，以改变PDT的反应。我们提出的研究将建立在这些发现的基础上，以更具体地描述细胞外基质（ECM）在肿瘤和血管对PDT反应中的作用，并在临床前和临床上评估其他治疗干预如何改变肿瘤血管系统，从而可能创造一种新的治疗方法。 更有PDT反应的微环境。我们假设肿瘤ECM是PDT结果的效应物，可以调节以改善治疗反应性。在针对这一假设的研究中，目标1将采用在基质包被的培养皿上生长的内皮细胞或肿瘤细胞的体外培养物，以及动物肿瘤中的确证性研究，以确定ECM的PDT增加治疗诱导的细胞毒性的机制-将特别考虑ECM相关细胞的PDT后粘附依赖性存活信号的变化，ECM的PDT的抗血管生成/血管生成作用也是如此。目标2将测试有前途的方法，以有利地改变ECM沉积在肿瘤前的PDT。我们将确定是否可以应用抗血管生成药物或其他血管修饰药物作为血管正常化剂，以增加肿瘤血管对PDT的敏感性。此外，在另一种方法中，我们将评估由辐射刺激的ECM沉积的增加是否可以被PDT利用来治疗放射治疗失败的肿瘤。目标3将基于临床样本，用于研究人类恶性肿瘤中的辐射效应和PDT对肿瘤ECM的依赖性。我们将确定放射复发性疾病的ECM特征，特别关注IV型胶原沉积（基于临床前结果选择）。使用来自已完成的腹膜恶性肿瘤PDT试验的库存组织，我们将证实ECM沉积（包括IV型胶原）与PDT结果的临床相关性。 在这方面，初步数据确定，在肿瘤表达更多胶原蛋白的患者中，PDT后的复发时间更长。总之，我们建议的总体目标是确定肿瘤ECM，特别是血管基底膜的胶原蛋白影响PDT结果的机制，以开发通过调节ECM水平“引发”肿瘤进行PDT的临床相关方法，并确认ECM沉积与PDT临床反应的相关性。我们将研究放射复发性肿瘤的ECM，因为我们的临床前和临床数据显示这些肿瘤中IV型胶原沉积增加，并且增加PDT作为放射复发的二线治疗可能是一种直接和高效的方法，以利用PDT中的ECM依赖性，从而使治疗选择有限的患者受益。

DESCRIPTION (provided by applicant): During the previous grant, we successfully completed research on the effects of photodynamic therapy (PDT) on tumor oxygenation and blood flow, with a focus on the treatment-altering consequences of PDT- triggered vasoreactivity during illumination. These studies have identified microenvironmental characteristics such as vessel size and association with extracellular matrix to be response-altering in PDT. Our proposed investigations will build on these findings to more specifically delineate the role of extracellula matrix (ECM) in tumor and vessel responses to PDT, and to assess, both pre-clinically and clinically, how other therapeutic interventions can alter tumor vasculature, potentially creating a more PDT-responsive microenvironment. We hypothesize that tumor ECM is an effector of PDT outcome that can be modulated to improve treatment responsiveness. In studies directed toward this hypothesis, Aim 1 will employ in vitro cultures of endothelial or tumor cells grown on matrix-coated dishes, together with confirmatory studies in animal tumors, to define the mechanisms by which PDT of ECM increases treatment-induced cytotoxicity~ changes in adhesion-dependent survival signaling upon PDT of ECM-associated cells will specifically be considered, as will the anti- angiogenic/angiogenic effect of PDT of ECM. Aim 2 will test promising approaches to favorably alter ECM deposition in tumors prior to PDT. We will determine if anti-angiogenics or other vessel-modifying drugs can be applied as vascular normalizing agents to increase the sensitivity of tumor vessels to PDT. Also, in another approach, we will evaluate if increases in ECM deposition stimulated by radiation can be exploited by PDT to treat tumors that failed radiation therapy. Aim 3 will be based in clinical samples for the purposes of studying radiation effects and PDT dependencies on tumor ECM in human malignancies. We will determine the ECM characteristics of radiation-recurrent disease, with a particular focus on collagen IV deposition (chosen based pre-clinical results). Using banked tissue from a completed trial of PDT for peritoneal malignancies, we will confirm the clinical relevance of ECM deposition (including collagen IV) to PDT outcome. In this regard, preliminary data identify the time-to-recurrence after PDT to be longer in patients whose tumors expressed more collagen. In summary, the overall goals of our proposal are to define the mechanisms by which tumor ECM, and in particular the collagen of vascular basement membrane affects outcome to PDT~ to develop clinically-relevant approaches toward "priming" tumors for PDT through modulation of ECM levels~ and to confirm the relevance of ECM deposition to clinical response to PDT. We will study the ECM of radiation- recurrent tumors because our pre-clinical and clinical data show increased collagen IV deposition in these tumors, and the addition of PDT as second-line therapy for radiation recurrences could be a straightforward and highly effective approach to exploit ECM dependencies in PDT responsive for the benefit of patients who otherwise have limited therapy choices.