Evaluating the Potential of PSMA Targeting in CNS Tumors: Insights from Large-Scale Transcriptome Profiling.
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BACKGROUND/OBJECTIVES: Prostate-specific membrane antigen (PSMA) is a well-established target in prostate cancer therapy that has shown potential as a theranostic target across non-central nervous system (CNS) and CNS tumor types. We aimed to investigate the pan-tissue expression pattern of the PSMA-encoding gene FOLH1 to assess whether transcriptome profiling can inform tumor diagnostic and theranostic probes. METHODS: We assessed FOLH1 expression from the Open Pediatric Cancer Project (OpenPedCan, n = 2132 specimens), the Cancer Genome Atlas (TCGA, n = 10,411 specimens), and the Genotype Tissue Expression Project (GTEx, n = 17,382 specimens) in relation to published reports of PSMA radionuclide uptake in various tumors. RESULTS: When comparing FOLH1 expression across tumor versus normal tissues, we found that non-CNS tumors exhibiting elevated expression of at least two-fold (FDR < 0.05) were reported to have significant PSMA radionuclide uptake in contrast to tumors with less than a two-fold elevation or with lower expression of FOLH1 relative to normal tissues. Notably, CNS tumors universally exhibited lower expression of FOLH1 relative to normal brain tissue, but we observed considerable variation in the expression of blood-tumor barrier (BTB) components associated with reports of BTB integrity and uptake of PSMA radiotracers. CONCLUSIONS: Large-scale transcriptomics data may help guide the application of PSMA-based radionuclide therapies in non-CNS tumors, but care should be taken to account for BTB effects in CNS tumors when assessing the potential for radionuclide success. This study demonstrates that FOLH1 showed a lack of tumor-specific expression for both adult and pediatric CNS tumors when compared to normal brain tissue, suggesting that PSMA is not a desirable target in brain tumors.