Targeted Tumor-Penetrating siRNA Nanocomplexes for Credentialing the Ovarian Cancer Target ID4
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Author(s)
Ren, Yin
von Maltzhan, Geoffrey
Agrawal, Amit
Mesirov, Jill P.
Lo, Justin H.
Cheung, Hiu Wing
Cowley, Glenn S.
Weir, Barbara A.
Boehm, Jesse S.
Tamayo, Pablo
Alternative Title
Targeted Tumor-Penetrating siRNA Nanocomplexes for Credentialing the Ovarian Cancer Oncogene ID4
Date Issued
August 2012
Journal
Science Translational Medicine
Publisher
American Association for the Advancement of Science (AAAS)
Citation
Ren, Y., H. W. Cheung, G. von Maltzhan, A. Agrawal, G. S. Cowley, B. A. Weir, J. S. Boehm, et al. “Targeted Tumor-Penetrating siRNA Nanocomplexes for Credentialing the Ovarian Cancer Oncogene ID4.” Science Translational Medicine 4, no. 147 (August 15, 2012): 147ra112–147ra112.
Version
Author's final manuscript
Abstract
The comprehensive characterization of a large number of cancer genomes will eventually lead to a compendium of genetic alterations in specific cancers. Unfortunately, the number and complexity of identified alterations complicate endeavors to identify biologically relevant mutations critical for tumor maintenance because many of these targets are not amenable to manipulation by small molecules or antibodies. RNA interference provides a direct way to study putative cancer targets; however, specific delivery of therapeutics to the tumor parenchyma remains an intractable problem. We describe a platform for the discovery and initial validation of cancer targets, composed of a systematic effort to identify amplified and essential genes in human cancer cell lines and tumors partnered with a novel modular delivery technology. We developed a tumor-penetrating nanocomplex (TPN) that comprised small interfering RNA (siRNA) complexed with a tandem tumor-penetrating and membrane-translocating peptide, which enabled the specific delivery of siRNA deep into the tumor parenchyma. We used TPN in vivo to evaluate inhibitor of DNA binding 4 (ID4) as a novel oncogene. Treatment of ovarian tumor–bearing mice with ID4-specific TPN suppressed growth of established tumors and significantly improved survival. These observations not only credential ID4 as an oncogene in 32% of high-grade ovarian cancers but also provide a framework for the identification, validation, and understanding of potential therapeutic cancer targets.
MIT Department
Whitaker College of Health Sciences and Technology
Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science
Koch Institute for Integrative Cancer Research at MIT
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Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
https://doi.org/10.1126/scitranslmed.3003778
