|
Aminolevulinic acid (ALA) is a prodrug that is converted in the heme biosynthesis pathway to protoporphyrin IX (PpIX) for photodynamic therapy (PDT) and fluorescence-guided tumor detection and resection. Although ALA-based therapy has been clinically used for the treatment of various types of tumors, clinical outcomes of ALA applications are not satisfactory due to issues such as low tumor PpIX production, high PpIX fluorescence heterogeneity, and low tumor to normal fluorescence contrast. We argue that a personalized ALA-based therapy would overcome these limitations and result in enhanced therapeutic outcomes. Since PpIX is endogenously produced in the complex heme biosynthesis pathway composed of 4 cytoplasmic and 4 mitochondrial enzymes and subject to cell membrane transporters, ALA-based therapy needs to be tailored to tumor phenotypic and genotypic characteristics that affect tumor PpIX production and accumulation. We found that genetic alterations in heme biosynthesis enzymes in tumor cells could cause significant changes in ALA-PpIX production. In these tumors, a low dose of ALA was able to achieve better PpIX fluorescence contrast between tumor and normal cells than a high dose of ALA that is commonly used. For tumors with elevated transporter activity, combination of ALA and a clinical transporter inhibitor is necessary for increasing ALA-PpIX fluorescence and reducing PpIX fluorescence heterogeneity. Overall we hope to demonstrate that a personalized ALA protocol optimized to fit tumor phenotype and genotype offers better treatment outcomes than applying ALA based on a one-size-fits-all approach.
|
