Microenvironmental Effects of PDT Combined with Targeted Molecular Theraphy

AKT信号通路中的分子靶向作为一种组合方式显示出巨大的潜力 提高光动力疗法疗效的途径。使用此方法时，结果会有所改善 将明确包括分子靶向剂对肿瘤微环境的影响。从理论上讲，分子 靶向可以有利地改变光动力疗法前的肿瘤环境，从而增强光动力疗法中的细胞毒性；它 还可以增强PDT后的血管效应和肿瘤破坏。因此，分子的时间 与PDT相关的治疗值得慎重考虑。可翻译协议的合理发展 将光动力疗法和分子靶向结合起来将必然从这项研究中演变出来。 要采用的方法包括我们经验丰富的定制设计技术。 免疫组织化学染色切片的定量图像分析将用于确定治疗效果 肿瘤氧合、血管结构及相关组织学。漫反射光谱学将用于 在整个过程中，纵向监测肿瘤的生理过程，如氧合和血流 治疗。 我们假设AKT信号通路中的靶向分子治疗将选择性地调节 肿瘤微环境，在不增加正常组织毒性的情况下增强PDT肿瘤反应。 在肺癌和卵巢癌的原位和异位肿瘤模型中进行的研究将被定向 朝向以下三个目标。 具体目的1.量化血管内皮生长因子、表皮生长因子受体对微环境和治疗的影响 和/或光动力疗法后AKT信号抑制。 具体目的2.评估结合PDT前使用靶向治疗的组合模式方案 在光动力疗法中进行分子治疗和/或增氧，以产生更有利的光动力疗法 微环境。 特异性目的3.确定血管内皮生长因子、表皮生长因子受体和/或AKT信号抑制如何影响正常组织毒性 致PDT。

Molecular targeting in the AKT signaling pathway demonstrates significant potential as a combined modality approach to enhancing therapeutic response to PDT. Improvements in outcome when using this approach will clearly include the effect of molecular targeting agents on tumor microenvironment. In theory, molecular targeting could favorably modify the pre-PDT tumor environment so as to enhance cytotoxicity during PDT; it could also augment post-PDT vascular effects and tumor destruction. Consequently, the timing of molecular therapy relative to PDT deserves careful consideration. The rational development of translatable protocols incorporating PDT and molecular targeting will necessarily evolve from this research. Methods to be employed include custom-designed technologies in which we are well-experienced. Quantitative image analysis of immunohistochemically-stained sections will be used to define therapy effects on tumor oxygenation, vascular structure, and related histology. Diffuse optical spectroscopy will be used to longitudinally monitor tumor physiological processes, such as oxygenation and blood flow, over the course of treatment. We hypothesize that targeted molecular therapy in the AKT signaling pathway will selectively modulate tumor microenvironment, augmenting PDT tumor response without increasing normal tissue toxicity. Investigations conducted in orthotopic and ectopic tumor models of lung and ovarian cancer will be directed toward the following three aims. SPECIFIC AIM 1. To quantify the microenvironmental and therapeutic consequences of VEGF, EGFR and/or AKT signal inhibition after PDT. SPECIFIC AIM 2. To evaluate combined modality protocols that incorporate pre-PDT use of targeted molecular therapy and/or oxygen augmentation during PDT in order to produce a more favorable PDT microenvironment. SPECIFIC AIM 3. To determine how VEGF, EGFR and/or AKT signal inhibition affect normal tissue toxicity to PDT.