2. Academic Validation
  3. DNA-Dependent Protein Kinase Inhibitor Peposertib Enhances Efficacy of 177Lu-Based Radioimmunotherapy in Preclinical Models of Prostate and Renal Cell Carcinoma

DNA-Dependent Protein Kinase Inhibitor Peposertib Enhances Efficacy of 177Lu-Based Radioimmunotherapy in Preclinical Models of Prostate and Renal Cell Carcinoma

  • J Nucl Med. 2025 Jan 30:jnumed.124.268695. doi: 10.2967/jnumed.124.268695.
Cameron N Johnstone 1 2 3,  Laura D Osellame 1 2,  Zhipeng Cao 1 2 4,  Alexander F McDonald 1 2 4,  Angela Rigopoulos 1 2,  Ingrid J G Burvenich 1 2,  Christian W Wichmann 1 2 4,  Nancy Guo 1,  Alesia N Ivashkevich 5,  Michael P Wheatcroft 5,  Edwin B Yan 5,  Astrid Zimmermann 6,  Frank T Zenke 7,  Christian Sirrenberg 6,  Fiona E Scott 1 2,  Andrew M Scott 8 2 4 9
Affiliations

Affiliations

  • 1 Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia.
  • 2 School of Cancer Medicine, La Trobe University, Bundoora, Victoria, Australia.
  • 3 Department of Clinical Pathology, University of Melbourne, Parkville, Victoria, Australia.
  • 4 Department of Molecular Imaging and Therapy, Austin Health, Heidelberg, Victoria, Australia.
  • 5 Telix Pharmaceuticals, North Melbourne, Victoria, Australia.
  • 6 Merck KGaA, Darmstadt, Germany.
  • 7 EMD Serono, Billerica, Massachusetts; and.
  • 8 Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia; andrew.scott@onjcri.org.au.
  • 9 Department of Medicine, University of Melbourne, Parkville, Victoria, Australia.
PMID: 39884775 DOI: 10.2967/jnumed.124.268695
Abstract

Novel radiation sensitizers, including inhibitors targeting DNA damage response, have been developed to enhance the efficacy of Anticancer treatments that induce DNA damage in Cancer cells. Peposertib, a potent, selective, and orally administered inhibitor of DNA-dependent protein kinase, impedes the nonhomologous end-joining mechanism for DNA double-strand break (DSB) repair. We investigated radioimmunotherapy alone or with peposertib in preclinical models of renal cell carcinoma (RCC) or prostate Cancer. Methods: 177Lu-DOTA-girentuximab (targeting Carbonic Anhydrase IX) or 177Lu-DOTA-rosopatamab (targeting prostate-specific membrane antigen) was used to deliver β-radiation to tumors via a single intravenous dose (3 or 6 MBq) in mice bearing SK-RC-52 RCC or LNCaP prostate Cancer xenografts, respectively. Peposertib (50 mg/kg daily for 14 d) was administered via oral gavage. Biodistribution and in vivo imaging of 177Lu-based radioimmunotherapy were performed for both preclinical models. Tumor growth and body weight were monitored until the endpoint. Assessment of DNA damage was performed by measuring DSBs through analysis of γH2AX foci formation in tumor sections. Results: Ex vivo biodistribution and in vivo SPECT/MRI revealed excellent tumor uptake of each radiopharmaceutical. Mouse body weight was stable in all treatment arms. Peposertib alone did not show a significant antitumor effect. The addition of peposertib to 177Lu-DOTA-girentuximab showed enhanced antitumor efficacy compared with 177Lu-DOTA-girentuximab alone in the SK-RC-52 animal model, with a 4 of 4 complete response rate in the 177Lu-DOTA-girentuximab (6 MBq) plus peposertib arm. Peposertib combined with low-dose 177Lu-DOTA-girentuximab (3 MBq) demonstrated antitumor activity comparable to 177Lu-DOTA-girentuximab (6 MBq) monotherapy. In the LNCaP prostate Cancer model, the combination of 177Lu-DOTA-rosopatamab (6 MBq) and peposertib achieved a 3 of 4 complete response rate. Increased DSBs were observed with the addition of peposertib to 177Lu-based radioimmunotherapy. Conclusion: The combination of peposertib with 177Lu-based radioimmunotherapy was well tolerated in preclinical models of RCC and prostate Cancer. Our findings suggest a synergistic effect between peposertib and 177Lu-based radioimmunotherapy, wherein peposertib enhanced the efficacy of radioimmunotherapy. This synergy indicates the potential to reduce the necessary dose of radioimmunotherapy for effective Cancer treatment.

Keywords

177Lu; DNA damage response; girentuximab; peposertib; rosopatamab.

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