Abstract 4856: Suppression of PRKCI gene-amplified ovarian cancer using aptamer-delivered siRNA

Abstract

Abstract Ranked fifth in cancer death among women, ovarian cancer cure rates have remained at 30% over the past two decades. Treatment options have steadily followed the same methodology, surgery and then first-line chemotherapy. With a 70% relapse rate within the first two years of diagnosis and limited secondary options, acquiring more targeted treatments is imperative. Copy number aberrations, more than mutations, are commonly found in high grade serous ovarian cancer. Copy number gains of the Protein Kinase C iota (PRKCI) gene are found in over 33% of ovarian cancer patients. According to the TCGA database, patients with PRKCI gene amplification have a significantly poor overall survival than those that do not. With this information and the fact that it is a previously identified oncogene in ovarian cancer, Protein Kinase C iota (PKCi) serves as an excellent target. Unfortunately, the Protein Kinase C iota isoform shares an overall homology of 72% with the Protein Kinase C zeta isoform which makes selective targeting of the iota form a challenge. Previous publications have used gold-based compounds to block atypical PKC family members from interactions that are crucial for apical-basal polarity. We found, however, that these compounds exhibit no specific selectivity for PRKCI gene amplified ovarian cancer cell lines.To specifically target PKCi, we have created an RNA-based aptamer that contains a siRNA sequence against the PRKCI mRNA and EpCAM moieties on either end. The aptamer efficiently becomes internalized after binding to the cell surface EpCAM via clathrin-dependent endocytosis. Once inside, the aptamer is processed by Dicer to release the two unique siRNA duplex intermediates. The guide strand of the siRNA loads into the RNA-induced silencing complex (RISC) complex and Argonaute (Ago) protein family members mediate PRKCI mRNA silencing.We hypothesize that PRKCI gene amplification status offers a unique opportunity to stratify patients into different risk categories and RNA-aptamer targeting of PRKCI can provide therapeutic benefits, by impairing ovarian cancer cell proliferation and tumorigenesis. We expect this approach to provide potent and selective anti-tumor and anti-metastasis activity compared to targeting using other pharmaceutical options. Citation Format: Hina Rehmani. Suppression of PRKCI gene-amplified ovarian cancer using aptamer-delivered siRNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4856.