Targeted tumor-penetrating siRNA nanocomplexes for credentialing the ovarian cancer oncogene ID4.
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.
Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Yin
Y
Ren
Hiu Wing
HW
Cheung
Geoffrey
G
von Maltzhan
Amit
A
Agrawal
Glenn S
GS
Cowley
Barbara A
BA
Weir
Jesse S
JS
Boehm
Pablo
P
Tamayo
Alison M
AM
Karst
Joyce F
JF
Liu
Michelle S
MS
Hirsch
Jill P
JP
Mesirov
Ronny
R
Drapkin
David E
DE
Root
Justin
J
Lo
Valentina
V
Fogal
Erkki
E
Ruoslahti
William C
WC
Hahn
Sangeeta N
SN
Bhatia
D000818:Animals; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics*; D051379:Mice; D053758:Nanoparticles / Q000009:adverse effects / Q000737:chemistry*; D009857:Oncogenes / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology*; D034741:RNA, Small Interfering / Q000378:metabolism*; D040521:Subcutaneous Tissue / Q000473:pathology; D014158:Transcription, Genetic
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018398:Homeodomain Proteins; C490128:ID4 protein, human; D051796:Inhibitor of Differentiation Proteins; D034741:RNA, Small Interfering; C097899:homeobox protein HOXA9