Document Detail


Noninvasive measurement of androgen receptor signaling with a positron-emitting radiopharmaceutical that targets prostate-specific membrane antigen.
MedLine Citation:
PMID:  21606347     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Despite encouraging clinical results with next generation drugs (MDV3100 and abiraterone) that inhibit androgen receptor (AR) signaling in patients with castration-resistant prostate cancer (CRPC), responses are variable and short-lived. There is an urgent need to understand the basis of resistance to optimize their future use. We reasoned that a radiopharmaceutical that measures intratumoral changes in AR signaling could substantially improve our understanding of AR pathway directed therapies. Expanding on previous observations, we first show that prostate-specific membrane antigen (PSMA) is repressed by androgen treatment in multiple models of AR-positive prostate cancer in an AR-dependent manner. Conversely, antiandrogens up-regulate PSMA expression. These expression changes, including increased PSMA expression in response to treatment with the antiandrogen MDV3100, can be quantitatively measured in vivo in human prostate cancer xenograft models through PET imaging with a fully humanized, radiolabeled antibody to PSMA, (64)Cu-J591. Collectively, these results establish that relative changes in PSMA expression levels can be quantitatively measured using a human-ready imaging reagent and could serve as a biomarker of AR signaling to noninvasively evaluate AR activity in patients with CRPC.
Authors:
Michael J Evans; Peter M Smith-Jones; John Wongvipat; Vincent Navarro; Sae Kim; Neil H Bander; Steven M Larson; Charles L Sawyers
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-05-23
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  108     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2011 Jun 
Date Detail:
Created Date:  2011-06-09     Completed Date:  2011-08-26     Revised Date:  2013-06-28    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  9578-82     Citation Subset:  IM    
Affiliation:
Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
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MeSH Terms
Descriptor/Qualifier:
Androgen Antagonists / pharmacology
Androgens / pharmacology
Animals
Antibodies, Monoclonal / chemistry,  immunology,  pharmacokinetics
Antigens, Surface / genetics*,  immunology,  metabolism
Cell Line, Tumor
Copper Radioisotopes / pharmacokinetics
Dihydrotestosterone / pharmacology
Gene Expression Regulation, Neoplastic / drug effects
Glutamate Carboxypeptidase II / genetics*,  immunology,  metabolism
Heterocyclic Compounds, 1-Ring / chemistry
Humans
Immunoblotting
Male
Mice
Mice, SCID
Neoplasms, Experimental / genetics,  metabolism,  pathology
Orchiectomy
Phenylthiohydantoin / analogs & derivatives,  pharmacology
Positron-Emission Tomography / methods*
Prostate-Specific Antigen / genetics,  metabolism
Prostatic Neoplasms / genetics*,  metabolism,  pathology
Radiopharmaceuticals / immunology,  pharmacokinetics
Receptors, Androgen / genetics*,  metabolism
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction / drug effects,  genetics*
Transplantation, Heterologous
Grant Support
ID/Acronym/Agency:
P30 CA08748/CA/NCI NIH HHS; P50-CA86483/CA/NCI NIH HHS; R24 CA83084/CA/NCI NIH HHS; R24 CA86307/CA/NCI NIH HHS; R25-CA096945/CA/NCI NIH HHS; //Howard Hughes Medical Institute
Chemical
Reg. No./Substance:
0/Androgen Antagonists; 0/Androgens; 0/Antibodies, Monoclonal; 0/Antigens, Surface; 0/Copper Radioisotopes; 0/Heterocyclic Compounds, 1-Ring; 0/J591 monoclonal antibody; 0/MDV 3100; 0/Radiopharmaceuticals; 0/Receptors, Androgen; 2010-15-3/Phenylthiohydantoin; 521-18-6/Dihydrotestosterone; 60239-18-1/1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; EC 3.4.17.21/Glutamate Carboxypeptidase II; EC 3.4.17.21/glutamate carboxypeptidase II, human; EC 3.4.21.77/Prostate-Specific Antigen
Comments/Corrections

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