Targeted inhibition of prostate cancer metastases with an RNA aptamer to prostate-specific membrane antigen

Justin P Dassie; Luiza I Hernandez; Gregory S Thomas; Matthew E Long; William M Rockey; Craig A Howell; Yani Chen; Frank J Hernandez; Xiu Ying Liu; Mary E Wilson; Lee-Ann Allen; Daniel A Vaena; David K Meyerholz; Paloma H Giangrande

doi:10.1038/mt.2014.117

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Targeted inhibition of prostate cancer metastases with an RNA aptamer to prostate-specific membrane antigen

Journal article

Open access

Peer reviewed

Targeted inhibition of prostate cancer metastases with an RNA aptamer to prostate-specific membrane antigen

Justin P Dassie, Luiza I Hernandez, Gregory S Thomas, Matthew E Long, William M Rockey, Craig A Howell, Yani Chen, Frank J Hernandez, Xiu Ying Liu, Mary E Wilson, …

Molecular therapy, Vol.22(11), pp.1910-1922

11/2014

DOI: 10.1038/mt.2014.117

PMCID: PMC4429728

PMID: 24954476

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Abstract

Cell-targeted therapies (smart drugs), which selectively control cancer cell progression with limited toxicity to normal cells, have been developed to effectively treat some cancers. However, many cancers such as metastatic prostate cancer (PC) have yet to be treated with current smart drug technology. Here, we describe the thorough preclinical characterization of an RNA aptamer (A9g) that functions as a smart drug for PC by inhibiting the enzymatic activity of prostate-specific membrane antigen (PSMA). Treatment of PC cells with A9g results in reduced cell migration/invasion in culture and metastatic disease in vivo. Importantly, A9g is safe in vivo and is not immunogenic in human cells. Pharmacokinetic and biodistribution studies in mice confirm target specificity and absence of non-specific on/off-target effects. In conclusion, these studies provide new and important insights into the role of PSMA in driving carcinogenesis and demonstrate critical endpoints for the translation of a novel RNA smart drug for advanced stage PC.

Prostatic Neoplasms - metabolism

Humans

Male

Aptamers, Nucleotide - administration & dosage

Prostatic Neoplasms - therapy

Xenograft Model Antitumor Assays

Cell Movement - drug effects

Neoplasm Metastasis

Animals

Glutamate Carboxypeptidase II - metabolism

Antigens, Surface - metabolism

Cell Line, Tumor

Aptamers, Nucleotide - pharmacokinetics

Cell Proliferation - drug effects

Mice

Molecular Targeted Therapy - methods

Details

Title: Subtitle: Targeted inhibition of prostate cancer metastases with an RNA aptamer to prostate-specific membrane antigen
Creators: Justin P Dassie - Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
Luiza I Hernandez - Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
Gregory S Thomas - Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
Matthew E Long - 1] Molecular and Cellular Biology Program, University of Iowa, Iowa City, Iowa, USA Inflammation Program, University of Iowa, Iowa City, Iowa, USA
William M Rockey - Department of Radiation Oncology, University of Iowa, Iowa City, Iowa, USA
Craig A Howell - Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
Yani Chen - Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
Frank J Hernandez - Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
Xiu Ying Liu - Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
Mary E Wilson - 1] Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA Department of Microbiology, University of Iowa, Iowa City, Iowa, USA Veteran's Affairs Medical Center, University of Iowa, Iowa City, Iowa, USA
Lee-Ann Allen - 1] Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA Molecular and Cellular Biology Program, University of Iowa, Iowa City, Iowa, USA Inflammation Program, University of Iowa, Iowa City, Iowa, USA Department of Microbiology, University of Iowa, Iowa City, Iowa, USA Veteran's Affairs Medical Center, University of Iowa, Iowa City, Iowa, USA
Daniel A Vaena - Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
David K Meyerholz - Department of Pathology, University of Iowa, Iowa City, Iowa, USA
Paloma H Giangrande - 1] Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA Molecular and Cellular Biology Program, University of Iowa, Iowa City, Iowa, USA Department of Radiation Oncology, University of Iowa, Iowa City, Iowa, USA
Resource Type: Journal article
Publication Details: Molecular therapy, Vol.22(11), pp.1910-1922
DOI: 10.1038/mt.2014.117
PMID: 24954476
PMCID: PMC4429728
NLM abbreviation: Mol Ther
ISSN: 1525-0016
eISSN: 1525-0024
Publisher: United States
Grant note: T32HL07344 / NHLBI NIH HHS T32 HL007344 / NHLBI NIH HHS R21DE019953 / NIDCR NIH HHS R21 DE019953 / NIDCR NIH HHS R01 CA138503 / NCI NIH HHS I01 BX001983 / BLRD VA R01CA138503 / NCI NIH HHS P01 AI044642 / NIAID NIH HHS P30CA086862 / NCI NIH HHS P30 CA086862 / NCI NIH HHS U54 AI057160 / NIAID NIH HHS
Language: English
Date published: 11/2014
Academic Unit: Microbiology and Immunology; International Programs; Epidemiology; Pathology; Radiation Oncology; Medicine Administration; Internal Medicine
Record Identifier: 9984001144202771

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