Abstract 5275: Mechanistic insights into the anti-tumor activity of 212Pb-PSMA radioligand therapy

Abstract Introduction: Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) with lutetium-177 (177Lu) has demonstrated clinical benefit in prostate cancer (PC). Although alpha-emitters offer superior cytotoxic efficacy, the complex toxicity profile of actinium-225 (225Ac)-PSMA limits its therapeutic application. Lead-212 (212Pb) possesses favorable physical properties, including high linear energy transfer, a 10.6-hour half-life, and a simple decay scheme with a single alpha-emitting daughter nuclide, enabling precise, potent radiation delivery at the cellular level. In this study, we combine in vitro and in vivo models with multiomics and functional assays to elucidate the mechanisms underlying the anti-tumor efficacy of PSMA-targeted RLT. Materials and Methods: 212Pb-ADVC001, a novel 212Pb-based PSMA-targeting RLT in Phase I/II clinical development (NCT05720130) for the treatment of metastatic PC, was used as the 212Pb-PSMA-RLT agent. 177Lu-PSMA-I&T was used as the 177Lu-PSMA-RLT agent. The kinetic mechanisms associated with 212Pb-ADVC001 mediated cell-death were investigated in vitro and ex vivo using transcriptomics and proteomics analyses. To validate the omics findings, functional assays were conducted to assess the effects of 212Pb-PSMA on PC’s cell cycle progression, reactive oxygen species (ROS) generation, and lipid peroxidation in PC cells. Results: 212Pb-ADVC001 displayed potent cytotoxic activity with a mean EC50 of 2.7, 7.2 and 3.3 kBq/mL in PC cell lines PC-3-PIP (PSMAhigh), C4-2 (PSMAint) and LNCaP (PSMAint), respectively. Transcriptomic and proteomic analysis of in vitro treated PC cells and in vivo tumors harvested longitudinally revealed multiple mechanisms of action involving DNA damage, cell cycle arrest and cell death, and immune response modulation. In vitro functional assays confirmed the involvement of ROS production, lipid peroxidation, and cell cycle arrest upon treatment with 212Pb-ADVC001. Particularly, 212Pb-ADVC001 caused significant DNA damage, and reduced DNA content in the S-phase of the cell cycle with a concomitant increase in the G1- and G2/M-phase arrest compared to 177Lu-PSMA-I&T (p < 0.05). Conclusion: Multiomics analyses highlighted the involvement of multiple mechanisms of action in the efficacy of 212Pb-ADVC001 which collectively resulted in effective cancer cell death. Mechanistic studies furthered the understanding of PC radiobiology and cellular responses to beta- and alpha-based RLT with the identification of a cell cycle arrest in PC specifically induced by 212Pb-PSMA. Citation Format: Feifei Liu, Melissa Monterosso, Didier Boucher, Anna Amiss, Stelle Shakti, Kwong Ching Li, Chanwoo Kim, Aimee Horsfall, Kevin Kuan, William Tieu, Stephen Rose, Simon Puttick, Joana Brilhante, Gary Li, Anna Karmann, Thomas Kryza. Mechanistic insights into the anti-tumor activity of 212Pb-PSMA radioligand therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5275.