Optimization of aminolevulinic acid-protoporphyrin IX for fluorescence-guided tumor resection and treatment

点击翻译按钮获取中文摘要

The long-term goal of our research is to determine tumor phenotypic and genotypic characteristics that reduce tumor protoporphyrin IX fluorescence and design mechanism-based approaches to overcome these limiting factors – this first renewal builds on progress made in our initial funding period. Surgery is the most common treatment for all types of solid tumors. A successful cancer surgery is to completely remove tumor tissues and maximally preserve normal structures. To improve cancer surgery accuracy and precision, fluorescent molecular probes have been developed and are being increasingly used in the oncological surgery. Fluorescence from intraoperative molecular probes enables surgeons to visualize tumor tissues in real time and perform fluorescence-guided resection (FGR). It has been well demonstrated that FGR leads to more complete tumor resection and better surgical outcomes than conventional surgery under white light. Aminolevulinic acid (ALA) is one of a few FDA-approved intraoperative fluorescent probes and the only molecular probe based on the metabolic alterations in tumor cells. ALA has no fluorescence on its own and needs to be metabolized in the heme biosynthesis pathway in tumor cells to produce a fluorescent and photosensitizing metabolite protoporphyrin IX (PpIX), which enables tumor fluorescence imaging and photodynamic therapy (PDT). Although ALA-PpIX has been clinically used for tumor FGR, its applications are limited by low tumor PpIX fluorescence, high tumor fluorescence heterogeneity, and low tumor-to-normal tissue fluorescence contrast. Studies in the initial funding period of this award have led to the identification of ABCG2 transporter activity as a critical factor in reducing tumor PpIX fluorescence. Importantly, we have identified clinically used agents to suppress ABCG2 activity to enhance tumor PpIX fluorescence. In this renewal, we will use an FDA-approved drug lapatinib (Lap), the most potent one we have identified for the enhancement of tumor PpIX fluorescence, and hypothesize that lapatinib improves the use of ALA for FGR and PDT of gliomas. We chose to study this enhancement strategy in gliomas because ALA is now primarily used for guiding the resection of gliomas and, more importantly, ABCG2 expression elevation is a common feature in human gliomas. To this end, we will evaluate Lap in combination with ALA for the enhancement of PpIX fluorescence and PDT response in human glioma cell lines with different genotype and phenotype (Aim 1) and glioma tumor models (Aim 2). Through this research, we hope to demonstrate that Lap in combination with ALA enhances tumor PpIX fluorescence and PDT response. The successful completion of this research will lead to an optimized use of ALA for FGR and PDT treatment of gliomas.