The L-type amino acid transporter-1 (LAT1, SLC7A5) is an outstanding target for both imaging and therapy of prostate cancer because it is upregulated in many primary and metastatic prostate cancers and is strongly negatively correlated with overall survival. The current paradigm for imaging LAT1 uses radiolabeled amino acids that are transported into tumor cells to a greater extent than normal tissues. However, these substrate-based approaches for imaging LAT1 in tumors outside of the brain have met with limited success. LAT1 can mediate both influx and efflux of its substrates, leading to relatively low and transient uptake in tumors with poor tumor visualization. The specificity of anti-LAT1 antibodies will provide a more accurate measure of LAT1 protein density than the currently available system L transport substrates, which are not entirely selective for LAT1. This increased selectivity is important because LAT1 is the transporter that provides the greatest prognostic and predictive values. The overall goal of this project is to develop and evaluate radiolabeled antibody constructs selective for LAT1 as positron emission tomography (PET) and therapeutic agents that overcome the substantial limitations of currently available tracers. The development of these new agents is essential to realizing the full potential of LAT1-based imaging and treatment strategies. The long-term goal of this work is to develop clinically applicable imaging and therapeutic agents targeting LAT1 that possess optimal biological properties, are robust markers of prostate tumor aggressiveness, predict response to therapies targeting LAT1, and can be used for radio immunotherapy (RIT). Building on our previous work, we aim to investigate the tumor uptake of the anti-LAT1 immunoPET agent [89Zr] DFO-Ab2 in relevant prostate cancer models. Next, we will compare the uptake of these novel agents to the radiolabeled amino acids [18F] FET and [18F] FACBC. Finally, we will develop a theranostic strategy to visualize LAT1 levels through immunoPET followed by therapy with the anti-LAT1 antibody constructs labeled with 90Y, a therapeutic radionuclide. In addition to providing clinically relevant immunoPET and RIT agents, this work will lead to powerful and well characterized new tools for investigating the role of LAT1 in cancer biology that cannot be performed with currently available radiolabeled amino acids. Thus, the immunoPET and RIT agents developed through this proposal are highly innovative, have great potential for clinical impact, and can help investigators around the world answer clinical and basic research questions regarding the role of LAT1 in cancer biology that cannot be currently addressed with existing technologies.
The expression of the neutral amino acid transporter LAT1 expression is negatively correlated with overall survival in prostate cancer. A method to accurately measure the levels of LAT1 in cancer will help identify patients at high risk for poor outcome and select the most appropriate therapeutic approach. The overall goal of this project is to develop and evaluate radiolabeled antibody constructs selective for LAT1 as imaging and therapeutic agents that overcome the substantial limitations of currently available compounds.
