Abstract 3747: Radium 223 inhibits prostate cancer in bone via zonal cytotoxicity

Abstract

Abstract Bone metastases are the initial site of progression and account for many complications experienced by men with metastatic prostate cancer (PCa), with limited therapeutic options. Targeting the bone environment has recently resulted in the approval of Radium-223 (Rad-223), a new life-prolonging therapy for patients with metastatic castrate-resistant prostate cancer. Rad-223 is a rare earth metal radioisotope that displays chemical properties similar to calcium, becomes enriched in bone after in vivo administration and emits alpha particles with locally high energy but limited penetrance in tissues (<100 µm). Confoundingly, the clinical response to Radium-223 is often followed by detrimental relapse and progression, and whether Radium-223 causes tumor-cell directed cytotoxicity in vivo remains unclear. We hypothesized that limited radiation penetrance in situ defines outcome and addressed the principles discriminating Radium-223 efficacy from failure by combining 3D intravital microscopy, in silico modeling and end-point analysis in preclinical PCa models in bone. Radium-223 induced profound but zonally confined cancer cell lethality along the bone interface (200-300 µm), while the more distant tumor core remained unperturbed. As consequence, macro-lesions persisted and grew, whereas micro-tumors in the bone niche showed severe growth delay or eradication. The relative inefficacy in controlling large tumors points to application of Radium-223 in secondary prevention of early bone-metastatic disease and regimens co-targeting the tumor core or broadening the zonal toxicity. Citation Format: Eleonora Dondossola, Stefano Casarin, Claudia Paindelli, Elena De-Juan-Pardo, Dietmar Hutmacher, Christopher Logothetis, Peter Friedl. Radium 223 inhibits prostate cancer in bone via zonal cytotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3747.