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Article

Preclinical Assessment of the Combination of PSMA-Targeting Radionuclide Therapy with PARP Inhibitors for Prostate Cancer Treatment

1
Department of Radiology and Nuclear Medicine, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands
2
Department of Experimental Urology, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands
3
Department of Molecular Genetics, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands
*
Author to whom correspondence should be addressed.
In memoriam.
Academic Editors: Francesca Sanguedolce and Luigi Cormio
Int. J. Mol. Sci. 2022, 23(14), 8037; https://doi.org/10.3390/ijms23148037
Received: 17 June 2022 / Revised: 12 July 2022 / Accepted: 18 July 2022 / Published: 21 July 2022
(This article belongs to the Special Issue Urogenital Tumors: From Molecular Basis to Therapy)
Prostate specific membrane antigen targeted radionuclide therapy (PSMA-TRT) is a promising novel treatment for prostate cancer (PCa) patients. However, PSMA-TRT cannot be used for curative intent yet, thus additional research on how to improve the therapeutic efficacy is warranted. A potential way of achieving this, is combining TRT with poly ADP-ribosylation inhibitors (PARPi), which has shown promising results for TRT of neuroendocrine tumor cells. Currently, several clinical trials have been initiated for this combination for PCa, however so far, no evidence of synergism is available for PCa. Therefore, we evaluated the combination of PSMA-TRT with three classes of PARPi in preclinical PCa models. In vitro viability and survival assays were performed using PSMA-expressing PCa cell lines PC3-PIP and LNCaP to assess the effect of increasing concentrations of PARPi veliparib, olaparib or talazoparib in combination with PSMA-TRT compared to single PARPi treatment. Next, DNA damage analyses were performed by quantifying the number of DNA breaks by immunofluorescent stainings. Lastly, the potential of the combination treatments was studied in vivo in mice bearing PC3-PIP xenografts. Our results show that combining PSMA-TRT with PARPi did not synergistically affect the in vitro clonogenic survival or cell viability. DNA-damage analysis revealed only a significant increase in DNA breaks when combining PSMA-TRT with veliparib and not in the other combination treatments. Moreover, PSMA-TRT with PARPi treatment did not improve tumor control compared to PSMA-TRT monotherapy. Overall, the data presented do not support the assumption that combining PSMA-TRT with PARPi leads to a synergistic antitumor effect in PCa. These results underline that extensive preclinical research using various PCa models is imperative to validate the applicability of the combination strategy for PCa, as it is for other cancer types. View Full-Text
Keywords: prostate specific membrane antigen; targeted radionuclide therapy; radiosensitization; PARP inhibitors prostate specific membrane antigen; targeted radionuclide therapy; radiosensitization; PARP inhibitors
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MDPI and ACS Style

Ruigrok, E.A.M.; Verkaik, N.S.; de Blois, E.; de Ridder, C.; Stuurman, D.; Roobol, S.J.; Van Gent, D.C.; de Jong, M.; Van Weerden, W.M.; Nonnekens, J. Preclinical Assessment of the Combination of PSMA-Targeting Radionuclide Therapy with PARP Inhibitors for Prostate Cancer Treatment. Int. J. Mol. Sci. 2022, 23, 8037. https://doi.org/10.3390/ijms23148037

AMA Style

Ruigrok EAM, Verkaik NS, de Blois E, de Ridder C, Stuurman D, Roobol SJ, Van Gent DC, de Jong M, Van Weerden WM, Nonnekens J. Preclinical Assessment of the Combination of PSMA-Targeting Radionuclide Therapy with PARP Inhibitors for Prostate Cancer Treatment. International Journal of Molecular Sciences. 2022; 23(14):8037. https://doi.org/10.3390/ijms23148037

Chicago/Turabian Style

Ruigrok, Eline A. M., Nicole S. Verkaik, Erik de Blois, Corrina de Ridder, Debra Stuurman, Stefan J. Roobol, Dik C. Van Gent, Marion de Jong, Wytske M. Van Weerden, and Julie Nonnekens. 2022. "Preclinical Assessment of the Combination of PSMA-Targeting Radionuclide Therapy with PARP Inhibitors for Prostate Cancer Treatment" International Journal of Molecular Sciences 23, no. 14: 8037. https://doi.org/10.3390/ijms23148037

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