An integrated platform to discover and validate new oncogenes in animal models of cancer. (A) Genomes of tumors (n=489) obtained from patients are analyzed in a high-throughput fashion to identify genes that are amplified in cancer. (B) Subsequently, short-hairpin RNAs (shRNAs) targeting the entire genome are introduced into cancer cell lines, and genes that are essential for the survival of cancer cells are then identified (n=1825). Combining with data from A, this yielded over 200 (n=206) genes that are both amplified in tumors and essential for cancer cells. Unfortunately, the complexity and sheer volume of data has made dissecting the underlying biology and developing new drugs difficult. (C) RNA interference (RNAi) provides a means to act on candidate oncogenes. However, progress has been stymied by the "delivery" challenge. Here, novel tumor-penetrating nanoparticles carrying siRNA can penetrate into the tumor parenchyma, deliver siRNA therapeutics to tumor cells in a receptor-specific manner, and enables the rapid discovery and validation of gene targets in mouse models of cancer. (D) Follow-up studies can identify the mechanism by which the newly discovered oncogene, ID4, act to render normal epithelial ovarian cells into malignant cancer cells. This image relates to a paper that appeared in the Aug. 15, 2012 issue of Science Translational Medicine, published by AAAS. The paper, by Dr. Y. Ren at Massachusetts Institute of Technology in Cambridge, Mass., and colleagues, was titled, "Targeted Tumor-Penetrating siRNA Nanocomplexes for Credentialing the Ovarian Cancer Oncogene ID4."