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Targeted tumor-penetrating siRNA nanocomplexes for credentialing the ovarian cancer oncogene ID4
Yin Ren1, Hiu Wing Cheung, Geoffrey von Maltzhan
1Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
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.
Insights
Researchers developed a novel tumor-penetrating nanocomplex (TPN) for targeted delivery of cancer therapies. This platform successfully identified and validated inhibitor of DNA binding 4 (ID4) as an oncogene, suppressing ovarian tumor growth and improving survival.
Area of Science:
- Oncology
- Molecular Biology
- Nanotechnology
Background:
- Comprehensive cancer genome characterization yields numerous genetic alterations, complicating the identification of critical tumor maintenance mutations.
- Many identified cancer targets are difficult to manipulate with traditional small molecules or antibodies.
- Effective and specific delivery of RNA interference therapeutics to tumor cells remains a significant challenge.
Purpose of the Study:
- To develop a platform for discovering and validating cancer targets.
- To create a novel modular delivery technology for therapeutic agents.
- To investigate inhibitor of DNA binding 4 (ID4) as a potential oncogene in ovarian cancer.
Main Methods:
- Systematic identification of amplified and essential genes in human cancer cell lines and tumors.
- Development of a tumor-penetrating nanocomplex (TPN) using small interfering RNA (siRNA) and a tandem tumor-penetrating and membrane-translocating peptide.
- In vivo evaluation of ID4-specific TPN in ovarian tumor-bearing mice.
Main Results:
- The TPN enabled specific delivery of siRNA deep into the tumor parenchyma.
- Treatment with ID4-specific TPN suppressed the growth of established ovarian tumors.
- Significant improvement in survival was observed in treated mice.
- ID4 was credentialed as an oncogene in 32% of high-grade ovarian cancers.
Conclusions:
- The developed platform facilitates the discovery and validation of novel cancer targets.
- The TPN technology offers a promising approach for targeted delivery of RNA interference therapeutics.
- ID4 represents a potential therapeutic target for high-grade ovarian cancers.
