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PLoS One. 2019 May 28;14(5):e0216934. doi: 10.1371/journal.pone.0216934. eCollection 2019.

Pharmacodynamic study of radium-223 in men with bone metastatic castration resistant prostate cancer.

Author information

1
Department of Medicine, Division of Medical Oncology, Duke Cancer Institute, Duke University, Durham, NC, United States of America.
2
Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, United States of America.
3
Duke Prostate and Urologic Cancer Center, Duke Cancer Institute, Durham, NC, United States of America.
4
Duke Molecular Physiology Institute, Duke University, Durham, NC, United States of America.
5
Department of Biostatistics, Duke University, Durham, NC, United States of America.
6
Department of Radiology, Duke University, Durham, NC, United States of America.
7
Weill Cornell Medical College, New York, NY, United States of America.
8
Duke Department of Pathology, Duke University, Durham, NC, United States of America.

Abstract

BACKGROUND:

Radium-223 is a targeted alpha-particle therapy that improves survival in men with metastatic castration resistant prostate cancer (mCRPC), particularly in men with elevated serum levels of bone alkaline phosphatase (B-ALP). We hypothesized that osteomimicry, a form of epithelial plasticity leading to an osteoblastic phenotype, may contribute to intralesional deposition of radium-223 and subsequent irradiation of the tumor microenvironment.

METHODS:

We conducted a pharmacodynamic study (NCT02204943) of radium-223 in men with bone mCRPC. Prior to and three and six months after radium-223 treatment initiation, we collected CTCs and metastatic biopsies for phenotypic characterization and CTC genomic analysis. The primary objective was to describe the impact of radium-223 on the prevalence of CTC B-ALP over time. We measured radium-223 decay products in tumor and surrounding normal bone during treatment. We validated genomic findings in a separate independent study of men with bone metastatic mCRPC (n = 45) and publicly accessible data of metastatic CRPC tissues.

RESULTS:

We enrolled 20 men with symptomatic bone predominant mCRPC and treated with radium-223. We observed greater radium-223 radioactivity levels in metastatic bone tumor containing biopsies compared with adjacent normal bone. We found evidence of persistent Cellsearch CTCs and B-ALP (+) CTCs in the majority of men over time during radium-223 therapy despite serum B-ALP normalization. We identified genomic gains in osteoblast mimicry genes including gains of ALPL, osteopontin, SPARC, OB-cadherin and loss of RUNX2, and validated genomic alterations or increased expression at the DNA and RNA level in an independent cohort of 45 men with bone-metastatic CRPC and in 150 metastatic biopsies from men with mCRPC.

CONCLUSIONS:

Osteomimicry may contribute in part to the uptake of radium-223 within bone metastases and may thereby enhance the therapeutic benefit of this bone targeting radiotherapy.

Conflict of interest statement

Drs. Armstrong and George receive consulting support and research support to Duke University from Bayer and serve as speakers for Bayer. Competing interest statement: Drs. George and Armstrong receive consulting and speaking income from Bayer as well as research funding (to Duke University) from Bayer. No other conflicts of interest to report. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.this does not alter our adherence to PLOS ONE policies on sharing data and materials.

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