PSMA expression in the Hi‐Myc model; extended utility of a representative model of prostate adenocarcinoma for biological insight and as a drug discovery tool

Abstract

Prostate‐specific membrane antigen (PSMA), also known as glutamate carboxypeptidase II (GCPII), is highly overexpressed in primary and metastatic prostate cancer (PCa). This has led to the development of radiopharmaceuticals for targeted imaging and therapy under current clinical evaluation. Despite this progress, the exact biological role of the protein in prostate cancer development and progression has not been fully elucidated. This is in part because the human PSMA and mouse PSMA (mPSMA) have different patterns of anatomical expression which confound study in the most widely utilized model organisms. Most notably, mPSMA is not expressed in the healthy murine prostate. Here, we reveal that mPSMA is highly upregulated in the prostate adenocarcinoma of the spontaneous Hi‐Myc mouse model, a highly accurate and well characterized mouse model of prostate cancer development. Antibody detection and molecular imaging tools are used to confirm that mPSMA is expressed from early prostatic intraepithelial neoplasia (PIN) through adenocarcinoma.

The Future of PSMA-Targeted Radionuclide Therapy: An Overview of Recent Preclinical Research

“…This difference in PSMA expression might be explained by the difference in PSMA amino acid sequence between humans and mice (91% similarity). Furthermore, the PSMA structures in murine kidneys and salivary glands have been reported to differ [117,118]. Finally, the high PSMA binding in the salivary gland in humans may not only be due to PSMA expression, but might also be the result of non-specific binding [119,120].…”

The prostate-specific membrane antigen holds potential as a vascular target for endogenous radiotherapy with [177Lu]Lu-PSMA-I&T for triple-negative breast cancer

“…Besides of kidneys, no apoptosis was detected in any of the analyzed organs underlining the safety of [ 177 Lu]Lu-PSMA-I&T in this setting. The minor apoptotic effect in kidneys is probably due to the murine-specific expression of PSMA in renal tubules and Bowman's capsule [ 23 ]. Similarly, in PCa patients, both [ 177 Lu]Lu-PSMA-I&T and [ 177 Lu]Lu-PSMA-617 are reported to be safe and well tolerated with only minor and easily manageable side effects [ 24 , 25 ].…”

Preclinical and Clinical Status of PSMA-Targeted Alpha Therapy for Metastatic Castration-Resistant Prostate Cancer

“…Only the most optimal and safest PSMA-targeted radioligands from preclinical studies are tested in humans. However, radiotoxicity in rodents is not the most accurate predictor of toxicity in humans because the human, rat, and mouse PSMA have different patterns of anatomical expression in normal tissues [ 195 , 196 , 197 ]. For example, PSMA levels in human submandibular gland are approximately four-fold higher compared with mouse and fifty-four-fold higher compared with rat submandibular gland [ 197 ].…”