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

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.

• Authors: Andrew J Armstrong, Santosh Gupta, Patrick Healy, Gabor Kemeny, Beth Leith, Michael R Zalutsky, Charles Spritzer, Catrin Davies, Colin Rothwell, Kathryn Ware, Jason A Somarelli, Kris Wood, Thomas Ribar, Paraskevi Giannakakou, Jiaren Zhang, Drew Gerber, Monika Anand, Wen-Chi Foo, Susan Halabi, Simon G Gregory, Daniel J George
• Journal: PloS one (PLoS One) Vol. 14 Issue 5 Pg. e0216934 ( 2019) ISSN: 1932-6203 [Electronic] United States
• PMID: 31136607 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• 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

Topics

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