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显著的潜力 方法来增强对PDT的治疗反应。使用此方法时结果的改善 将明确包括分子靶向剂对肿瘤微环境的影响。理论上，分子 靶向可以有利地改变PDT前的肿瘤环境，从而增强PDT期间的细胞毒性; 也可以增强PDT后的血管效应和肿瘤破坏。因此，分子生物学的时机 与PDT相关的治疗值得仔细考虑。可翻译协议的合理开发 结合PDT和分子靶向将必然从这项研究中发展出来。 采用的方法包括我们经验丰富的定制设计技术。 将使用化学染色切片的定量图像分析来确定治疗效果 对肿瘤氧合、血管结构和相关组织学的影响。扩散光学光谱学将用于 纵向监测肿瘤的生理过程，如氧合和血流，在整个过程中， 治疗 我们假设AKT信号通路的靶向分子治疗将选择性地调节 肿瘤微环境，增强PDT肿瘤反应而不增加正常组织毒性。 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指导 实现以下三个目标。 具体目标1.为了量化VEGF、EGFR和EGFR的微环境和治疗后果， 和/或PDT后的AKT信号抑制。 具体目标2.评价结合PDT前使用靶向药物的联合治疗方案， 分子治疗和/或在PDT过程中增加氧气以产生更有利的PDT 微环境 具体目标3.确定VEGF、EGFR和/或AKT信号抑制如何影响正常组织毒性 到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.