A Novel RNA Aptamer-Based Targeted Therapy for Ovarian Cancer with PRKCI Gene Amplification

Abstract

Ranked fifth in cancer death among women, ovarian cancer cure rates have remained low over the past two decades due to unsuccessful detection of early-stage disease, stagnant methodologies of treatment, and high relapse rates. Stage IV invasive epithelial ovarian cancer patients have a meager 17% relative 5-year survival rate and around 70% of patients relapse within the first two years of diagnosis. Accounting for more deaths than any other cancer of the female reproductive system, it is paramount to strategically offer ovarian cancer patients targeted therapies to improve outcome. Ovarian cancer contains a host of copy number aberrations (CNA) that can lead to the silencing or amplification of tumor suppressor genes, oncogenes, or non-coding RNAs that modify the expression of genes. Clinically, gene amplifications have prognostic and diagnostic usefulness as they can be a mechanism to promote tumorigenesis and/or attainment of drug resistance. Protein kinase C iota (PKCiota), a cytoplasmic serine-threonine protein kinase, is highly amplified and overexpressed within the 3q26 amplicon in ovarian cancer and is identified as an oncogene in multiple cancers. However, selectively targeting the iota isoform with small molecule inhibitors is challenging since it shares a 72% overall homology with another atypical PKC isoform, zeta. We found that small-molecule inhibitors currently being investigated do not offer selective inhibition nor specificity in ovarian cancer cell lines. We hypothesize that PRKCI amplification offers a unique opportunity to stratify patients into different risk categories and that specifically targeting PRKCI using a siRNA-aptamer can offer therapeutic benefits by impairing ovarian cancer cell tumorigenesis. We expect this approach to provide potent and selective anti-tumor activity compared to targeting using other pharmaceutical approaches. To test this hypothesis, we identified ovarian cancer cell lines with PRKCI gene amplification, identified a pattern of onco-addiction specificity in cell lines with amplification, and created an RNA-based aptamer that efficiently becomes internalized in ovarian cancer cells and mediates PRKCI mRNA silencing. In conclusion, we have identified a rationale to target, specifically, the PKCiota gene amplification in ovarian cancer and our RNA-based aptamer prevents ovarian tumorigenesis both in vitro and in vivo, opening a door for future therapies.