Abstract 1827: Investigating the efficacy of 177-Lu therapeutics in a series of castrate resistant prostate cancer PDX models

Abstract Recent advancements in alpha and beta particle-emitting radiopharmaceuticals underscore the therapeutic potential of targeted radionuclide therapy, presenting a promising alternative for patients with advanced or metastatic disease where conventional treatments fall short. This field is pushing the boundaries of personalized medicine, allowing clinicians to tailor treatments to individual patients' genetic and molecular profiles, thereby improving outcomes. As translational research in radiopharmaceutical development progresses, it holds significant promise for redefining therapeutic options and setting new standards in patient care. Targeting and maintaining high specificity to chosen targets, such as PSMA, is crucial for the clinical success of novel radiopharmaceuticals. The development and translation of these therapies require a series of steps through the drug discovery pipeline, including selecting the right radionuclide, chemistry, model, and biomarkers for patient selection. Historically, radiopharmaceutical development has relied on cell lines. While cell-derived xenografts are cost-effective and essential for initial characterization, screening, biodistribution, and efficacy, clinically relevant pre-clinical models predictive of patient outcomes are indispensable for de-risking radiopharmaceutical development. Unfortunately, these models have been underutilized due to the limited availability of combined PDX and radiopharmaceutical capabilities. Here, we present an end-to-end approach for testing 177-Lu therapeutics, from dosimetry and biodistribution in cell lines to efficacy in metastatic castration-resistant PDX models. When treated with 177-Lu based prostate therapeutics, PDX models exhibited a diverse range of responses. RNA-seq and proteomics analyses confirmed that Champions Oncology metastatic castration-resistant prostate cancer PDX models expressed varying levels of PSMA, reflecting the patient population in clinical settings. Our results highlight the importance of integrating robust radiochemistry and biodistribution workflows with clinically relevant patient-derived models to derive translational insights and accelerate the development of radiopharmaceuticals. This comprehensive approach not only enhances the predictive power of pre-clinical models but also ensures that the therapeutic strategies developed are closely aligned with the clinical realities faced by patients. Citation Format: Stefano Cairo, Benedetta Arno, Mara Gilardi, Hsiu-Wen Tsai, Juliana Maynard, Marianna Zipeto, Michael Ritchie. Investigating the efficacy of 177-Lu therapeutics in a series of castrate resistant prostate cancer PDX models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1827.