Radium-223 Inhibits Osseous Prostate Cancer Growth by Dual Targeting of Cancer Cells and Bone Microenvironment in Mouse Models

Abstract

Purpose Radium-223 dichloride (radium-223, Xofigo®), a targeted alpha therapy, is currently used for the treatment of patients with castration-resistant prostate cancer (CRPC) with bone metastases. This study examines the mode-of-action and antitumor efficacy of radium-223 in two prostate cancer xenograft models. Experimental Design Mice bearing intratibial LNCaP or LuCaP 58 tumors were randomized to groups (n = 12–17) based on lesion grade and/or serum PSA level and administered with radium-223 (300 kBq/kg) or vehicle, twice at 4-week intervals. X-rays and serum samples were obtained biweekly. Soft tissue tumors were observed macroscopically at sacrifice. Tibiae were analyzed by gamma counter, micro-CT, autoradiography and histology. Results Radium-223 inhibited tumor-induced osteoblastic bone growth and protected normal bone architecture leading to reduced bone volume in LNCaP and abiraterone-resistant LuCaP 58 models. Furthermore, radium-223 resulted in lower PSA values and reduced total tissue and tumor areas, indicating that treatment constrains prostate cancer growth in bone. In addition, radium-223 suppressed abnormal bone metabolic activity as evidenced by decreased number of osteoblasts and osteoclasts and reduced level of the bone formation marker PINP. Mode-of-action studies revealed that radium-223 was deposited in the intratumoral bone matrix. DNA double-strand breaks were induced in cancer cells within 24 hours after radium-223 treatment and PSA levels were significantly lower 72 hours post treatment providing further evidence of the anti-tumor effects. Conclusion Taken together, radium-223 therapy exhibits a dual targeting mode-of-action that induces tumor cell death and suppresses tumor-induced pathological bone formation in tumor microenvironment in osseous CRPC growth in mice.

Preclinical Efficacy of a PSMA-Targeted Thorium-227 Conjugate (PSMA-TTC), a Targeted Alpha Therapy for Prostate Cancer

“…Prostate cancer most commonly metastasizes to bone, with up to 90% of mCRPC patients demonstrating bone metastases (22)(23)(24). To evaluate the activity of PSMA-TTC in a model mimicking the clinical situation of prostate cancer metastasized to bone, a bone growth model was established by injecting luciferase-labeled LNCaP cells into the mouse tibiae (25). Potent antitumor activity of PSMA-TTC was observed in this model: mice treated with a single dose of PSMA-TTC (100 or 200 kBq/kg) had less LNCaP-luc tumor burden in bone compared with vehicle-treated animals as determined by BLI ( Fig.…”

223Ra Therapy in Patients With Advanced Castration-Resistant Prostate Cancer With Bone Metastases

“…There it emits high-energy alpha particles of short range (<100 μm; 2-10 cell layers), causing double-strand DNA breaks leading to a cytotoxic effect on tumor cells and cells in the tumor microenvironment. 1,2 In the phase 3 ALSYMPCA trial, CRPC patients were treated with 223 Ra or placebo, either before or after docetaxel chemotherapy. 3 The outcome was a significant median overall survival (OS) benefit of 3.6 months in favor of 223 Ra over placebo.…”

The Contemporary Use of Radium-223 in Metastatic Castration-resistant Prostate Cancer

“…[20][21][22] Radium-223 decays to emit predominantly high energy alpha particles over a short range (< 1 mm), leading to cytotoxicity through the production of predominantly unrepairable DNA double strand breaks in nearby tumor and cells forming the cancer microenvironment. [20][21][22][23] By contrast, beta particle-emitting radionuclides have a comparatively lower energy than radium-223, resulting in less effective DNA damage, and a longer range and higher penetration, leading to higher exposure and toxicity to more distant normal myeloproliferative cells. [23][24][25] Unlike radium-223, which has demonstrated a survival benefit in mCRPC, beta particle emitting radionuclides have shown activity exclusively in relation to bone pain palliation; furthermore, their recent use has diminished.…”

“…54,55 The mode of action of radium-223 impacts both on tumor growth and tumor-induced pathologic osteoblastic bone growth, and would suggest a primary effect on serum ALP levels. 22 In early studies, changes in ALP levels appeared to be a marker of radium-223 effects. 33,56 In the pivotal phase III study, radium-223 treatment significantly prolonged time to increase in total ALP (tALP) levels, and a higher proportion of patients showed a tALP response (!…”