Ewing's Sarcoma: Development of RNA Interference-Based Therapy for Advanced Disease

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Abstract

Ewing's sarcoma tumors are associated with chromosomal translocation between the EWS gene and the ETS transcription factor gene. These unique target sequences provide opportunity for RNA interference(i)-based therapy. A summary of RNAi mechanism and therapeutically designed products including siRNA, shRNA and bi-shRNA are described. Comparison is made between each of these approaches. Systemic RNAi-based therapy, however, requires protected delivery to the Ewing's sarcoma tumor site for activity. Delivery systems which have been most effective in preclinical and clinical testing are reviewed, followed by preclinical assessment of various silencing strategies with demonstration of effectiveness to EWS/FLI-1 target sequences. It is concluded that RNAi-based therapeutics may have testable and achievable activity in management of Ewing's sarcoma.

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Most cited references 129

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Origins and Mechanisms of miRNAs and siRNAs.

Richard W. Carthew, Erik J. Sontheimer (2009)

Over the last decade, approximately 20-30 nucleotide RNA molecules have emerged as critical regulators in the expression and function of eukaryotic genomes. Two primary categories of these small RNAs--short interfering RNAs (siRNAs) and microRNAs (miRNAs)--act in both somatic and germline lineages in a broad range of eukaryotic species to regulate endogenous genes and to defend the genome from invasive nucleic acids. Recent advances have revealed unexpected diversity in their biogenesis pathways and the regulatory mechanisms that they access. Our understanding of siRNA- and miRNA-based regulation has direct implications for fundamental biology as well as disease etiology and treatment.

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Prediction of mammalian microRNA targets.

Benjamin Lewis, I-hung Shih, Matthew W Jones-Rhoades … (2003)

MicroRNAs (miRNAs) can play important gene regulatory roles in nematodes, insects, and plants by basepairing to mRNAs to specify posttranscriptional repression of these messages. However, the mRNAs regulated by vertebrate miRNAs are all unknown. Here we predict more than 400 regulatory target genes for the conserved vertebrate miRNAs by identifying mRNAs with conserved pairing to the 5' region of the miRNA and evaluating the number and quality of these complementary sites. Rigorous tests using shuffled miRNA controls supported a majority of these predictions, with the fraction of false positives estimated at 31% for targets identified in human, mouse, and rat and 22% for targets identified in pufferfish as well as mammals. Eleven predicted targets (out of 15 tested) were supported experimentally using a HeLa cell reporter system. The predicted regulatory targets of mammalian miRNAs were enriched for genes involved in transcriptional regulation but also encompassed an unexpectedly broad range of other functions.

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Nuclear export of microRNA precursors.

Elsebet Lund, Stephan Güttinger, Angelo Calado … (2004)

MicroRNAs (miRNAs), which function as regulators of gene expression in eukaryotes, are processed from larger transcripts by sequential action of nuclear and cytoplasmic ribonuclease III-like endonucleases. We show that Exportin-5 (Exp5) mediates efficient nuclear export of short miRNA precursors (pre-miRNAs) and that its depletion by RNA interference results in reduced miRNA levels. Exp5 binds correctly processed pre-miRNAs directly and specifically, in a Ran guanosine triphosphate-dependent manner, but interacts only weakly with extended pre-miRNAs that yield incorrect miRNAs when processed by Dicer in vitro. Thus, Exp5 is key to miRNA biogenesis and may help coordinate nuclear and cytoplasmic processing steps.

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Author and article information

Journal

Journal ID (nlm-ta): ISRN Oncol

Journal ID (iso-abbrev): ISRN Oncol

Journal ID (publisher-id): ISRN.ONCOLOGY

Title: ISRN Oncology

Publisher: International Scholarly Research Network

ISSN (Print): 2090-5661

ISSN (Electronic): 2090-567X

Publication date Collection: 2012

Publication date (Electronic): 11 March 2012

Volume: 2012

Electronic Location Identifier: 247657

Affiliations

¹Gradalis, Inc., Dallas, TX 75201, USA

²Mary Crowley Cancer Research Centers, Dallas, TX 75201, USA

³Texas Oncology, PA, Dallas, TX 75251, USA

⁴Medical City Dallas Hospital, Dallas, TX 75230, USA

Author notes

*John Nemunaitis: jnemunaitis@ 123456marycrowley.org

Academic Editors: B. Fang, F. Kuhnel, and M. Stracke

Article

DOI: 10.5402/2012/247657

PMC ID: 3317005

PubMed ID: 22523703

SO-VID: 4336ff1c-eae8-4f6e-b0a7-1d95b9309b4a

License:

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Ewing's Sarcoma: Development of RNA Interference-Based Therapy for Advanced Disease

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Abstract

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Karger: Oncology

Most cited references 129

Origins and Mechanisms of miRNAs and siRNAs.

Prediction of mammalian microRNA targets.

Nuclear export of microRNA precursors.

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