Microenvironmental Effects of PDT Combined with Targeted Molecular Theraphy

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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.