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Sci Transl Med DOI:10.1126/scitranslmed.3003778

Targeted tumor-penetrating siRNA nanocomplexes for credentialing the ovarian cancer oncogene ID4.

Publication TypeJournal Article
Year of Publication2012
AuthorsRen, Y, Cheung, HWing, von Maltzhan, G, Agrawal, A, Cowley, GS, Weir, BA, Boehm, JS, Tamayo, P, Karst, AM, Liu, JF, Hirsch, MS, Mesirov, JP, Drapkin, R, Root, DE, Lo, J, Fogal, V, Ruoslahti, E, Hahn, WC, Bhatia, SN
JournalSci Transl Med
Volume4
Issue147
Pages147ra112
Date Published2012 Aug 15
ISSN1946-6242
KeywordsAnimals, Cell Proliferation, Cell Transformation, Neoplastic, Cyclin-Dependent Kinase Inhibitor p21, Female, Gene Expression Regulation, Neoplastic, Homeodomain Proteins, Humans, Inhibitor of Differentiation Proteins, Mice, Nanoparticles, Oncogenes, Ovarian Neoplasms, RNA, Small Interfering, Subcutaneous Tissue, Transcription, Genetic
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.

URLhttp://stm.sciencemag.org/cgi/pmidlookup?view=short&pmid=22896676
DOI10.1126/scitranslmed.3003778
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/22896676?dopt=Abstract

Alternate JournalSci Transl Med
PubMed ID22896676
PubMed Central IDPMC3633234
Grant ListU54 CA119335 / CA / NCI NIH HHS / United States
U54 CA151884 / CA / NCI NIH HHS / United States
R33 CA128625 / CA / NCI NIH HHS / United States
P30 CA014051 / CA / NCI NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
P50 CA105009 / CA / NCI NIH HHS / United States
P30 CA14051 / CA / NCI NIH HHS / United States
U01 CA152990 / CA / NCI NIH HHS / United States
/ / Canadian Institutes of Health Research / Canada
/ / Howard Hughes Medical Institute / United States
U54 CA119349 / CA / NCI NIH HHS / United States
U54 CA112962 / CA / NCI NIH HHS / United States
RC2 CA148268 / CA / NCI NIH HHS / United States
R01 CA152327 / CA / NCI NIH HHS / United States
R01 CA124427 / CA / NCI NIH HHS / United States