Identification of alternative protein targets of glutamate-ureido-lysine associated with PSMA tracer uptake in prostate cancer cells

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.

Treatment of prostate cancer with CD46 targeted225Ac alpha particle radioimmunotherapy

“…For this study, we utilized well-characterized patient-derived xenografts (PDXs) from the Living Tumor Laboratory. 18–20 As shown in Fig 1a most of the xenografts, including all the neuroendocrine prostate models used in this experiment were PSMA-negative, but most showed high expression of CD46. Our previous study reported that PSMA-positive and PSMA-negative xenografts could be readily detected with a CD46 PET scan using [ 89 Zr]DFO-YS5 probe, including the LTL-331, LTL-331R, and LTL-545 models.…”

“…PSMA is a type II glycoprotein overexpressed on PCa cells. Currently, PSMA PET (positron emission tomography) imaging using 68 Ga-PSMA-11 or 18 F-DCFPyL is used in routine clinical care to localize and stage patients.…”

“…[18][19][20] As shown in Fig 1a most of the xenografts, including all the neuroendocrine prostate models used in this experiment were PSMA-…”

A Single Dose of Novel PSMA-Targeting Radiopharmaceutical Agent [177Lu]Ludotadipep for Patients with Metastatic Castration-Resistant Prostate Cancer: Phase I Clinical Trial

“…As could be expected from the high salivary gland uptake in the PSMA PET/CT images, xerostomia was the most frequent non-hematologic side effect in this study, though serum amylase level was not checked for the diagnosis. Previous studies have shown high uptake of the [ 177 Lu]Lu-PSMA-based radiopharmaceuticals by the salivary glands [ 8 , 22 ]. A recent study showed that mild xerostomia occurred in 2 out of 56 patients after 3 to 4 cycles of treatment but spontaneously resolved before 3 months [ 23 ] and was recoverable [ 24 ], and applying external cooling with ice packs may reduce the salivary gland uptakes [ 25 ].…”

“…A compound chemically modified to prevent degradation of NAAG, the in vivo substrate of PSMA, could become a substance that can specifically target PSMA [ 7 ]. Compounds based on glutamate-urea-lysine (GUL) structure are being studied for diagnosis and treatment of prostate cancer [ 8 ], and in particular compounds bound with radioisotopes are showing great promise.…”