Identification of Alternative Protein Targets of Glutamate-ureido-lysine Associated with PSMA Tracer Uptake in Prostate Cancer Cells

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2022 Jan 22

PMID 35064078

Authors

Martin K Bakht

John J Hayward

Farsheed Shahbazi-Raz

Magdalena Skubal

Ryo Tamura

Keith F 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

Affiliations

Soon will be listed here.

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.

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