PMPA for Nephroprotection in PSMA-Targeted Radionuclide Therapy of Prostate Cancer

Abstract

Radioactive ligands for the prostate-specific membrane antigen (PSMA) are under development for therapy of metastasized prostate cancer. Since PSMA expression is also found in the kidneys, renal tracer uptake can be dose-limiting. Because kidney kinetics differ from tumor kinetics, serial application of PSMA inhibitors such as 2-(phosphonomethyl)pentanedioic acid (PMPA) may improve the kidney-to-tumor ratio. In this study, we evaluated the effect of PMPA on the biodistribution of 2 promising PSMA ligands. Methods: Human prostate cancer xenografts (LNCaP) were transplanted subcutaneously into mice. After injection of 125 I-MIP1095, a 16-h latency period was allowed for tracer clearance from the blood and renal calices. After baseline scintigraphy, PMPA was injected in doses of 0.2-50 mg/kg (n 5 3 per dose, 5 controls), followed by scans at 2, 4, 6, and 24 h after PMPA injection. Kidney and tumor displacement was determined as a percentage of baseline. A shortened but similar design was used to evaluate the PSMA ligand MIP1404, which contains a chelate for 99m Tc/rhenium. Results: PMPA injection 16 h after MIP1095 translated into a rapid and quantitative relevant displacement of renal activity. Tumor uptake was reduced to a significantly lesser extent in a dose-dependent manner. PMPA doses of 0.2-1 mg/kg appear optimal for sustaining nearly complete tumor uptake while simultaneously achieving near-total blocking of specific renal PSMA binding. The effect was successfully validated with the PSMA ligand MIP1404. Conclusion: PSMA-targeted radionuclide therapy can benefit from serial PMPA comedication by reducing off-target radiation to the kidneys. These data will be used for a first approximation in clinical translation, although in patients an optimization of the dose and time schedule may be necessary.

177Lu-Labeled Prostate-Specific Membrane Antigen Radioligand Therapy of Metastatic Castration-Resistant Prostate Cancer: Safety and Efficacy

“…The high level of renal uptake may have been due to PSMA expression in renal tissue, which was better visualized on 177 Lu-PSMA images early after therapy (30). Blocking of specific PSMA binding in kidney tissues by the PSMA inhibitor 2-(phosphonomethyl)pentanedioic acid has been validated in preclinical studies; however, there is a lack of availability of this compound for clinical use, and its use may concurrently block uptake within tumors (31). The patients were hydrated with a combination of positively charged amino acids, as for peptide receptor radionuclide therapy with somatostatin analogs.…”

The 68Ga/177Lu theragnostic concept in PSMA targeting of castration-resistant prostate cancer: correlation of SUVmax values and absorbed dose estimates

“…36 GBq. In addition, co-medication of PSMA inhibitors such as 2-(phosphonomethyl) penanedioic acid (PMPA) could improve the kidney to tumour ratio [30], demonstrating future potential. Furthermore, the fractionation regime enables the administration of probably higher activities, in line with previous reports on peptide receptor radionuclide therapy with radiolabeled somatostatin analogues [31], as renal function maybeaffectedinmCRPCpatientsduetopriorchemotherapy and/or accompanying diseases diabetes and hypertension.…”

“…While Baum et al [13] reported that the median SUV max value decreased significantly in lesions with higher absorbed doses, we could not find a significant correlation of SUV max values and absorbed dose estimates in our patients. Kratochwil et al [30] also found 50% decreased SUV max values but no attempt to correlate them with absorbed dose calculation was made. In line with our data, in a very recent study, Okamoto et al [33] also report only moderate correlation of pre-therapeutic SUVs with absorbed dose estimates using a PSMA inhibitor for imaging and therapy (PSMA I&T).…”

Current status and future perspectives of PSMA-targeted therapy in Europe: opportunity knocks

“…Three cycles should generally suffice, although some patients might receive additional courses depending on individual responses and tolerance. A kidney protective effect of 2-phosphonomethyl-pentanedioic acid has been reported in mice, and this agent might ultimately be coadministered with the PSMA ligand [23].…”