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.