Abstract 3123: Fracturing the tumor-bone alliance in metastatic prostate cancer with Ra-223

Abstract Radium-223 dichloride (Ra-223) is a calcium-mimetic alpha-emitting radiopharmaceutical homing to bone, approved for the treatment of bone metastases in castration-resistant prostate cancer (CRPC), significantly prolonging overall survival in patients with advanced disease. This study integrates preclinical and clinical studies to investigate the effects of Ra-223 on tumor volume, bone structure, transcriptomics alterations, and to identify biomarkers of therapeutic response to Ra-223. Using patient-derived xenografts (MDA PCa PDX), which mimic the hallmark characteristics of clinical bone-forming metastases, mice with tumor-bearing and non-tumor-bearing bones were treated with Ra-223 or vehicle. Tumor burden was monitored via magnetic resonance imaging (MRI), bone parameters were assessed through microCT and bone histomorphometry, and transcriptomics changes were evaluated using RNA sequencing in both, tumor and stroma. Ra-223 treatment significantly reduced tumor volume and altered bone architecture, promoting bone remodeling and increasing bone density. Histomorphometric analysis revealed suppressed osteoclast activity in both tumor-bearing and non-tumor-bearing bones treated with Ra-223, with a more pronounced effect in non-tumor-bearing sites. Transcriptomic profiling identified differential expression of immune, metabolic, and cell-cycle pathways, with TP53 and MYC as central regulators. Additionally, we analyzed human serum samples from patients with CRPC bone metastases. We profiled novel candidate protein markers of Ra-223 response on serial serum samples collected at baseline (prior to initiation of Ra-223 treatment), on-treatment (OT), and at end of treatment (EoT) from 25 patients enrolled in a single-center, open-label clinical study (NCT02135484). Subjects received six intravenous doses of Ra-223 (50 kBq/kg) every four weeks, unless they experienced disease progression or toxicity, or until withdrawal. Our analysis highlighted IL18, SPARC, MET, TFF3 and TNFSF11 as survival-associated proteins significantly deregulated in patients receiving Ra-223 therapy. In particular, multivariable analyses showcased that elevated levels of TFF3 were independently linked to lower overall survival and possible resistance to Ra-223, suggesting its potential as a predictive biomarker of treatment efficacy. In summary, our findings suggest that Ra-223 has a more extensive impact on the tumor-bone microenvironment than previously understood. The increases in bone density and associated transcriptomics alterations pave the way for future investigations into combination therapies that enhance Ra-223’s benefits while addressing potential risks. Considering the clinical importance of TFF3, further validation in larger patient cohorts is essential to refine treatment strategies to improve outcomes for patients with CRPC bone metastases. Citation Format: Pablo Sanchis, Agustina Sabater, Juan Bizzotto, Gaston Pascual, Nicolas Anselmino, Jiabin Dong, Jun Yang, Ganiraju Manyam, Bradley Broom, Zhongcheng Shi, Shixia Huang, Rocio Seniuk, Eleonora Dondossola, Teocharis Panaretakis, John Araujo, Peter Shepherd, Patricia Troncoso, Nora Navone, Christopher J. Logothetis, Daniel E. Frigo, Elba Vazquez, Paul Corn, Geraldine Gueron, Estefania Labanca. Fracturing the tumor-bone alliance in metastatic prostate cancer with Ra-223 [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 3123.