Surgery is the most common treatment for all types of solid tumors. A successful cancer surgery is to
completely remove cancer cells and maximally preserve normal structures. To improve cancer surgery
outcomes, fluorescent molecular probes have been developed and increasingly used for guiding tumor
removal during surgery. Fluorescence emitted from these intraoperative molecular probes enables
surgeons to visualize tumor tissues in real time and perform fluorescence-guided tumor resection. It has
been well demonstrated that fluorescence-guided tumor resection enables more complete tumor resection
and enhances treatment outcomes. Aminolevulinic acid (ALA) is one of a few FDA-approved intraoperative
fluorescent probes. Although ALA itself is not fluorescent, it is metabolized in the heme biosynthesis
pathway to a fluorescent and photosensitizing metabolite protoporphyrin IX (PpIX), enabling fluorescence
detection and photodynamic therapy (PDT). ALA-PpIX has been clinically used for guiding the resection of
various types of tumors. However, clinical applications of ALA are limited by issues such as low PpIX tumor
production, PpIX fluorescence heterogeneity, and low tumor/normal fluorescence contrast. Our goal is to
optimize ALA-based modalities by addressing tumor phenotypic and genotypic characteristics that affect
tumor PpIX fluorescence. Two optimization strategies are proposed in this research. Specific Aim 1 is to
optimize ALA-PpIX fluorescence-guided tumor resection and treatment by suppressing PpIX efflux. We
have found that triple negative breast cancer (TNBC) cell lines show reduced ALA-PpIX fluorescence and
are resistant to ALA-PDT due to elevated ABCG2 transporter activity. We have searched for clinical ABCG2
transporter inhibitors and will use them to improve ALA-PpIX fluorescence-guided resection and treatment
of TNBC tumors with increased ABCG2 transporter activity. Specific Aim 2 is to optimize the dose of ALA
for PpIX fluorescence-guided resection and treatment of tumors with genetic alterations in heme
biosynthesis enzymes. We have found that pancreatic cancers exhibit genetic alterations in heme
biosynthesis enzymes, which change ALA-PpIX production profile. We will optimize ALA dose to increase
PpIX fluorescence contrast between tumor and normal tissues to improve fluorescence-guided resection of
pancreatic cancers. Through this research, we hope to demonstrate that ALA protocols optimized to fit
tumor phenotype and genotype offer better surgical outcomes than applying it based on one-size-fits-all
approach.
