Identification of alternative protein targets of glutamate-ureido-lysine associated with PSMA tracer uptake in prostate cancer cells
Martin Bakht, John J. Hayward, Farsheed Shahbazi‐Raz, Magdalena Skubal, Ryo Tamura, Keith Stringer, Daniel Meister, Varadha Balaji Venkadakrishnan, Hui Xue, Adam Pillon, Mathew Stover, Adam Tronchin, Bre‐Anne Fifield, Lavleen Mader, Sheng‐Yu Ku, Gi Jeong Cheon, Keon Wook Kang, Yuzhuo Wang, Xuesen Dong, Himisha Beltran, Jan Grimm, Lisa A. Porter, John F. Trant
Abstract
Prostate-specific membrane antigen (PSMA) is highly overexpressed in most prostate cancers and is clinically visualized using PSMA-specific probes incorporating glutamate-ureido-lysine (GUL). PSMA is effectively absent from certain high-mortality, treatment-resistant subsets of prostate cancers, such as neuroendocrine prostate cancer (NEPC); however, GUL-based PSMA tracers are still reported to have the potential to identify NEPC metastatic tumors. These probes may bind unknown proteins associated with PSMA-suppressed cancers. We have identified the up-regulation of PSMA-like aminopeptidase NAALADaseL and the metabotropic glutamate receptors (mGluRs) in PSMA-suppressed prostate cancers and find that their expression levels inversely correlate with PSMA expression and are associated with GUL-based radiotracer uptake. Furthermore, we identify that NAALADaseL and mGluR expression correlates with a unique cell cycle signature. This provides an opportunity for the future study of the biology of NEPC and potential therapeutic directions. Computationally predicting that GUL-based probes bind well to these targets, we designed and synthesized a fluorescent PSMA tracer to investigate these proteins in vitro, where it shows excellent affinity for PSMA, NAALADaseL, and specific mGluRs associated with poor prognosis.