Molecular and Metabolic Mechanisms Underlying Selective 5-Aminolevulinic Acid-Induced Fluorescence in Gliomas

SIMPLE SUMMARY: 5-aminolevulinic acid (5-ALA) is a medication that produces fluorescence in certain cancers, which enables surgeons to visualize tumor margins during surgery. Gliomas are brain tumors that can be difficult to fully resect due to their infiltrative nature. In this review we explored what is known about the mechanism of 5-ALA, recent discoveries that increase our understanding of that mechanism, and potential targets to increase fluorescence in lower grade gliomas. ABSTRACT: 5-aminolevulinic acid (5-ALA) is a porphyrin precursor in the heme synthesis pathway. When supplied exogenously, certain cancers consume 5-ALA and convert it to the fluorogenic metabolite protoporphyrin IX (PpIX), causing tumor-specific tissue fluorescence. Preoperative administration of 5-ALA is used to aid neurosurgical resection of high-grade gliomas such as glioblastoma, allowing for increased extent of resection and progression free survival for these patients. A subset of gliomas, especially low-grade tumors, do not accumulate PpIX intracellularly or readily fluoresce upon 5-ALA administration, making gross total resection difficult to achieve in diffuse lesions. We review existing literature on 5-ALA metabolism and PpIX accumulation to explore potential mechanisms of 5-ALA-induced glioma tissue fluorescence. Targeting the heme synthesis pathway and understanding its dysregulation in malignant tissues could aid the development of adjunct therapies to increase intraoperative fluorescence after 5-ALA treatment.