Evaluating the Potential of PSMA Targeting in CNS Tumors: Insights from Large-Scale Transcriptome Profiling

Area of Science:

• Oncology
• Molecular Biology
• Genomics

Background:

• Prostate-specific membrane antigen (PSMA) is a key target in prostate cancer therapy.
• PSMA has shown potential as a theranostic target in both non-central nervous system (CNS) and CNS tumors.

Purpose of the Study:

• To investigate the pan-tissue expression pattern of the FOLH1 gene, which encodes PSMA.
• To determine if transcriptome profiling can inform the development of diagnostic and theranostic probes for PSMA.

Main Methods:

• Assessed FOLH1 expression across 2132 specimens from the Open Pediatric Cancer Project (OpenPedCan).
• Analyzed FOLH1 expression in 10,411 specimens from The Cancer Genome Atlas (TCGA) and 17,382 specimens from the Genotype Tissue Expression Project (GTEx).
• Correlated FOLH1 expression with published data on PSMA radionuclide uptake in various tumors.

Main Results:

• Non-CNS tumors with at least a two-fold increase in FOLH1 expression (FDR < 0.05) showed significant PSMA radionuclide uptake.
• CNS tumors exhibited universally lower FOLH1 expression compared to normal brain tissue.
• Variations in blood-tumor barrier (BTB) component expression influenced PSMA radiotracer uptake in CNS tumors.

Conclusions:

• Large-scale transcriptomics can guide PSMA-based radionuclide therapy for non-CNS tumors.
• BTB effects must be considered for CNS tumor theranostic applications.
• PSMA is not a suitable target for brain tumors due to a lack of tumor-specific FOLH1 expression.