Exploring SGLTs as Theranostic Targets for Cancer Metastasis - Project Summary/Abstract: Exploring SGLTs as Theranostic Targets for Cancer Metastasis Cancer requires substantial energy that is commonly provided by increased glucose transport and metabolism. Clinically, this is evaluated using Positron Emission Tomography (PET) imaging of the18F-labeled glucose analog 2-fluoro-2-deoxy-D-glucose ([18F]FDG). [18F]FDG enters cells primarily via facilitative glucose transporters known as GLUTs, which are overexpressed in some human cancers. [18F]FDG cannot be used to probe the sodium-dependent glucose transporters (SGLTs), the other different family of transporters, in cancers. In fact, the role of SGLTs in breast, prostate, lung, head/neck, brain, pancreas, colon, cervix, and ovary is only now starting to be recognized. Given that SGLT expression is even higher in metastasis than in primary tumors, we propose they could be theranostic targets for metastatic disease as SGLTs are able to concentrate glucose and its analogs intracellularly many fold their extracellular concentration. To evaluate this we created a brand new compound called 6FIGA (Fluorescent Iodinated Glucose Analog, modified at the 6 position carbon) which is selectively transported by SGLTs. It can be made with the therapeutic radionuclide 131I to deliver lethal radiation to cancer cells while having a low systemic concentration that minimizes toxicities. Further, SGLT function and therapy planning could be informed by PET imaging using the chemically-identical agent made with the 124I isotope. In addition, we have made it with stable iodine for fluorescent assays and imaging spanning from microscopy to murine in vivo studies. Herein we propose to use this novel trifunctional agent to evaluate SGLTs as a theranostic target for cancer metastasis. Significantly, targeted radionuclide therapy could solve the efficacy problem due to tumor heterogeneity. Radiation originating in SGLT-expressing cells penetrates multiple cell lengths and even kills neighboring cells that lack SGLTs. Our preliminary work shows that 6FIGA is transported selectively by SGLTs in representative metastatic breast and prostate cancer cell lines and an in vivo murine flank human prostate cancer tumor demonstrated 6FIGA concentrating with low off-target uptake. In this exploratory project we will use 6FIGA to explore SGLTs as potential theranostic targets via the aims: 1 Evaluate the time courses and biodistributions of [124I]6FIGA in in vivo metastatic models, measuring tumor and normal tissue concentration time courses and associated dosimetry. We hypothesize that [124I]6FIGA assays SGLT activity and provides different information than [18F]FDG. 2 Conduct proof-of-concept for targeted treatment using [131I]6FIGA radionuclide therapy, assessing overall survival and imaging response to therapy. Correlative studies will be performed, including immunohistochemistry and ex vivo fluorescence imaging, in order to quantify the relation between uptake and protein expression levels. Thus, we will demonstrate the potential of SGLTs as theranostic targets.