Theranostics of Primary Prostate Cancer: Beyond PSMA and GRP-R

Abstract

The imaging of Prostate-Specific Membrane Antigen (PSMA) is now widely used at the initial staging of prostate cancers in patients with a high metastatic risk. However, its ability to detect low-grade tumor lesions is not optimal. Methods: First, we prospectively performed neurotensin receptor-1 (NTS1) IHC in a series of patients receiving both [68Ga]Ga-PSMA-617 and [68Ga]Ga-RM2 before prostatectomy. In this series, PSMA and GRP-R IHC were also available (n = 16). Next, we aimed at confirming the PSMA/GRP-R/NTS1 expression profile by retrospective autoradiography (n = 46) using a specific radiopharmaceuticals study and also aimed to decipher the expression of less-investigated targets such as NTS2, SST2 and CXCR4. Results: In the IHC study, all samples with negative PSMA staining (two patients with ISUP 2 and one with ISUP 3) were strongly positive for NTS1 staining. No samples were negative for all three stains—for PSMA, GRP-R or NTS1. In the autoradiography study, binding of [111In]In-PSMA-617 was high in all ISUP groups. However, some samples did not bind or bound weakly to [111In]In-PSMA-617 (9%). In these cases, binding of [111n]In-JMV 6659 and [111In]In-JMV 7488 towards NTS1 and NTS2 was high. Conclusions: Targeting PSMA and NTS1/NTS2 could allow for the detection of all intraprostatic lesions.

Two Novel [68Ga]Ga-Labeled Radiotracers Based on Metabolically Stable [Sar11]RM26 Antagonistic Peptide for Diagnostic Positron Emission Tomography Imaging of GRPR-Positive Prostate Cancer

“…All three clinically tested compounds demonstrated tumor/kidney ratios about 3 as early as 1 h pi in murine models and a low to moderate activity accumulation was confirmed clinically. 17,31,33 Based on the comparison above, it is expected for [ 68 Ga]Ga-NOTA-PEG2-[Sar 11 ]RM26 and [ 68 Ga]Ga-NODAGA-PEG2-[Sar 11 ]RM26 to have very promising clinical performances, presumably even better than the radioligands mentioned above.…”

“…Despite the huge success, the fact that PSMA expression level is strongly associated with later stages of PCa, hinders their efficacy in detection of lesions, both primary and metastatic, in the onset of the disease. More and more attention is drawn on development of GRPR-targeting radiopharmaceuticals, since GRPR is shown to be overexpressed in the majority of cases of PCa, especially in early stages, with retained expression both in primary and metastatic sites. − …”

“…On this point, a comparison with other [ 68 Ga]Ga-labeled radioligands would be of interest. Especially in comparison with GRPR-targeting radioconjugates tested in clinical trials, like: [ 68 Ga]Ga-SB3 (DOTA- p -aminomethylaniline-diglycolic acid-DPhe-Gln-Trp-Ala-Val-Gly-His-Leu-NHEt), , [ 68 Ga]Ga-RM2 (DOTA-Pip-DPhe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH 2 ), ,, and [ 68 Ga]Ga-NOTA-PEG3-RM26 (NOTA-PEG3-d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH 2 ). ,, One should be careful with those comparisons, though. In these studies, different strains of mice, different batches of PC-3 cells, and even different injected activities and masses were used; thus, a head-on comparison is not that straightforward and it needs to be made with caution.…”

“…24,29 On this point, a comparison with other [ 68 Ga]Ga-labeled radioligands would be of interest. Especially in comparison with GRPR-targeting radioconjugates tested in clinical trials, like: [ 68 Ga]Ga-SB3 (DOTA-p-aminomethylaniline-diglycolic acid-DPhe-Gln-Trp-Ala-Val-Gly-His-Leu-NHEt), 30,31 [ 68 Ga]Ga-RM2 (DOTA-Pip-DPhe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH 2 ), 17,32,33 and [ 68 Ga]Ga-NOTA-PEG3-RM26 (NOTA-PEG3-d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH 2 ). 19,24,34 One should be careful with those comparisons, though.…”

“…On the other hand, GRPR is proven to have higher expression in the early stages of PCa, which is even retained on metastatic sites. − The inverse correlation between the two biomolecules indicates that not only both are valid as targets for PCa therapy and/or diagnosis (theranostics) but also they are complementary to each other. , …”