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

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

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.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aged
  • Alkaline Phosphatase / blood
  • Alkaline Phosphatase / genetics
  • Biomarkers, Tumor / genetics*
  • Biomarkers, Tumor / metabolism
  • Biopsy
  • Bone Neoplasms / genetics
  • Bone Neoplasms / mortality
  • Bone Neoplasms / radiotherapy*
  • Bone Neoplasms / secondary
  • Bone and Bones / metabolism
  • Bone and Bones / pathology
  • Bone and Bones / radiation effects
  • Cadherins / genetics
  • Cadherins / metabolism
  • Core Binding Factor Alpha 1 Subunit / genetics
  • Core Binding Factor Alpha 1 Subunit / metabolism
  • Disease Progression
  • Gene Expression
  • Humans
  • Male
  • Molecular Targeted Therapy / methods*
  • Neoplastic Cells, Circulating / metabolism
  • Neoplastic Cells, Circulating / pathology
  • Neoplastic Cells, Circulating / radiation effects
  • Osteonectin / genetics
  • Osteonectin / metabolism
  • Osteopontin / genetics
  • Osteopontin / metabolism
  • Prostate / metabolism
  • Prostate / pathology
  • Prostate / radiation effects
  • Prostatic Neoplasms, Castration-Resistant / genetics
  • Prostatic Neoplasms, Castration-Resistant / mortality
  • Prostatic Neoplasms, Castration-Resistant / pathology
  • Prostatic Neoplasms, Castration-Resistant / radiotherapy*
  • Radium / blood
  • Radium / pharmacokinetics
  • Radium / therapeutic use*
  • Survival Analysis
  • Tumor Microenvironment / genetics
  • Tumor Microenvironment / radiation effects

Substances

  • Biomarkers, Tumor
  • Cadherins
  • Core Binding Factor Alpha 1 Subunit
  • Osteonectin
  • RUNX2 protein, human
  • SPARC protein, human
  • SPP1 protein, human
  • Osteopontin
  • osteoblast cadherin
  • Radium-223
  • ALPL protein, human
  • Alkaline Phosphatase
  • Radium

Associated data

  • ClinicalTrials.gov/NCT02204943

Grants and funding

Funded as an investigator initiated study to Duke University by Bayer. For the PROPHECY study, we acknowledge funding from the Prostate Cancer Foundation and Movember and support from the Department of Defense Prostate Cancer Clinical Trials Consortium (DOD PCCTC).