title: 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 into groups (n= 12-17) based on lesion grade and/or serum PSA level and administered 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 after treatment, providing further evidence of the antitumor effects.Conclusions:Taken together, radium-223 therapy exhibits a dual targeting mode-of-action that induces tumor cell death and suppresses tumor-induced pathologic bone formation in tumor microenvironment of osseous CRPC growth in mice.Clin Cancer Res; 23(15); 4335-46. ©2017 AACR.
authors.affiliation: Pharmatest Services Ltd., Turku, Finland.
authors.forename: Mari I
authors.initials: MI
authors.lastname: Suominen
authors.affiliation: Pharmatest Services Ltd., Turku, Finland.
authors.forename: Katja M
authors.initials: KM
authors.lastname: Fagerlund
authors.affiliation: Pharmatest Services Ltd., Turku, Finland.
authors.forename: Jukka P
authors.initials: JP
authors.lastname: Rissanen
authors.affiliation: Pharmatest Services Ltd., Turku, Finland.
authors.forename: Yvonne M
authors.initials: YM
authors.lastname: Konkol
authors.affiliation: Pharmatest Services Ltd., Turku, Finland.
authors.forename: Jukka P
authors.initials: JP
authors.lastname: Morko
authors.affiliation: Pharmatest Services Ltd., Turku, Finland.
authors.forename: ZhiQi
authors.initials: Z
authors.lastname: Peng
authors.affiliation: Avoltus Oy, Turku, Finland.
authors.forename: Esa J
authors.initials: EJ
authors.lastname: Alhoniemi
authors.affiliation: Aurexel Life Sciences Ltd., Askainen, Finland.
authors.forename: Salla K
authors.initials: SK
authors.lastname: Laine
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington.
authors.forename: Eva
authors.initials: E
authors.lastname: Corey
authors.affiliation: Bayer AG, Pharmaceuticals Division, Drug Discovery, Therapeutic Research Groups Oncology, Berlin, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Mumberg
authors.affiliation: Bayer AG, Pharmaceuticals Division, Drug Discovery, Therapeutic Research Groups Oncology, Berlin, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Ziegelbauer
authors.affiliation: Aurexel Life Sciences Ltd., Askainen, Finland.|Department of Cell Biology and Anatomy, University of Turku, Turku, Finland.
authors.forename: Sanna-Maria
authors.initials: SM
authors.lastname: Käkönen
authors.affiliation: Pharmatest Services Ltd., Turku, Finland.
authors.forename: Jussi M
authors.initials: JM
authors.lastname: Halleen
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Vessella
authors.affiliation: Bayer AG, Pharmaceuticals Division, Drug Discovery, Therapeutic Research Groups Oncology, Berlin, Germany. arne.scholz@bayer.com.
authors.forename: Arne
authors.initials: A
authors.lastname: Scholz
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001859:Bone Neoplasms / Q000473:pathology / Q000532:radiotherapy* / Q000556:secondary; D001842:Bone and Bones / Q000473:pathology / Q000528:radiation effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000528:radiation effects; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D051379:Mice; D010010:Osteoclasts / Q000528:radiation effects; D064129:Prostatic Neoplasms, Castration-Resistant / Q000473:pathology / Q000532:radiotherapy*; D011868:Radioisotopes / Q000008:administration & dosage; D011883:Radium / Q000008:administration & dosage*; D059016:Tumor Microenvironment / Q000528:radiation effects
chemical_list: D000970:Antineoplastic Agents; D011868:Radioisotopes; C000615150:Radium-223; D011883:Radium