Main Session
Sep
28
PQA 03 - Digital Health Innovation and Informatics, Patient Safety & Quality, and Radiation and Cancer Biology
2653 - Efficacy Enhancement of PSMA-Targeted a- and ß --TRT by DNA-PK Inhibition Enables Dose De-Escalation
Presenter(s)
Ruth Winter, PhD - German Cancer Research Center (DKFZ), Heidelberg, Baden-Wurt
R. C. Winter1,2, U. Bauder-Wüst1, M. Schäfer3, Y. Remde3, M. Roscher3, R. L. Perez4, and M. Benešová-Schäfer1; 1Translational Radiotheranostics, German Cancer Research Center, Heidelberg, Germany, 2Heidelberg University, Faculty of Physics and Astronomy, Heidelberg, Germany, 3Service Unit Radiopharmaceuticals und Preclinical Studies, German Cancer Research Center, Heidelberg, Germany, 4Clinical Cooperation Unit Molecular and Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
Purpose/Objective(s):
Treatment resistance remains a major limitation of targeted radionuclide therapy (TRT). Although [Lu-177]Lu- and [Ac-225]Ac-PSMA-617 demonstrate promising results in metastatic castration-resistant prostate cancer, 20-30% of patients exhibit primary or acquired TRT-resistance despite adequate target expression. While combining TRT with other treatment modalities may improve outcomes, systematic preclinical evaluation is limited. Analyses of biopsies from resistant patients revealed alterations in DNA damage repair pathways, leading us to hypothesize that combining PSMA-TRT with DNA repair inhibition could enhance efficacy and overcome radioresistance.Materials/Methods:
PSMA-positive C4-2 and PSMA-negative PC-3 prostate cancer cells were exposed to [Lu-177]Lu- or [Ac-225]Ac-PSMA ligands for 4 h. Using optimized in vitro methods, alpha- and beta-minus-emitting PSMA-TRT were directly compared within a unified experimental platform, alongside standard external photon irradiation. Therapeutic efficacy was evaluated using a resazurin-based metabolic cell proliferation assay. For proof-of-concept combination study, PSMA-TRT was paired with Nedisertib®, a second-generation DNA-PK inhibitor targeting the non-homologous end-joining DNA repair pathway. Non-toxic inhibitor concentrations were derived from monotherapy dose-response curves and applied in a 24 h Nedisertib® pre-treatment prior to PSMA-TRT.Results:
Nedisertib® monotherapy yielded IC50 values of 6.35 µM (C4-2) and 9.13 µM (PC-3). Non-cytotoxic inhibitor concentrations selected for PSMA-TRT combination studies were 0.1 µM [100/102%] and 1 µM [111/103%] cell proliferation, normalized to C4-2/PC-3 controls. Combination therapy outperformed monotherapy across all irradiation modalities (Ac-225, Lu-177, and external photon irradiation), with the strongest effects observed for alpha-emitter-based TRT. For Ac-225, low-dose combination (0.1 µM + 0.156 kBq/mL) achieved antiproliferative effects [20/49%] comparable to or exceeding the highest TRT monotherapy (10 kBq/mL) [21/64%] in both cell lines. For the beta-minus emitter Lu-177, similar effects were observed for monotherapy (5000 kBq/mL) [54/93%] and combination (1 µM + 1250 kBq/mL) [54/82%].Conclusion:
DNA-PK inhibition significantly enhances the therapeutic response to PSMA-TRT and enables dose de-escalation. The response even in PSMA-negative PC-3 cells highlights the potential of Ac-225-based combination strategies for overcoming radioresistance. These findings support further mechanistic studies and in vivo validation of PSMA-TRT/DNA-PK inhibitor combinations.