Deregulated circRNAs in Epithelial Ovarian Cancer With Activity in PreclinicalIn VivoModels: Identification of Targets and New Modalities for Therapeutic Intervention

Abstract

Epithelial ovarian cancer (EOC) is associatedwith a dismal prognosis due to development of resistance to chemotherapy and metastasis in the peritoneal cavity and distant organs. In order to identify new targets and treatment modalities we searched the literature for up-and and downregulated circRNAs with efficacy in preclinical EOC-related in vivo systems. Our search yielded circRNAs falling into the following categories: cisplatin and paclitaxel resistance, transmembrane receptors, secreted factors, transcription factors, RNA splicing and processing factors, RAS pathwayrelated components, proteolysis and cell-cycle regulation, signaling-related proteins, and circRNAs regulating proteins in additional categories. These findings can be potentially translated by validation and manipulation of the corresponding targets, inhibition of circRNAs with antisense oligonucleotides (ASO), small interfering RNAs (siRNA) or small hairpin RNA (shRNA) or by reconstituting their activity.The incidence of ovarian cancer (OC) in the USA is 22,000 cases per year and 14,000 deaths, and 29,000 deaths in Europe (1). The vast majority are epithelial ovarian cancers (EOC). This type of tumor is typically treated with a combination of surgery and chemotherapy, which often includes cisplatin (DDP) and paclitaxel (PTX). An exciting development was the treatment of homologous recombination-deficient ovarian tumors with breast cancer antigen (BRCA) mutations or deletions with poly-ADP-ribose polymerase (PARP) inhibitors (2). Three PARP inhibitors (olaparib, rucaparib and niraparib) have been approved for the treatment of OCs in different clinical settings. In addition, anti-angiogenic therapy with Bevacizumab was approved (3). Nevertheless, recurrence due to resistance mechanisms is commonly observed and significantly impairs the therapeutic benefit of treatment (4). Epithelial ovarian cancer (EOC) gains a growth advantage due to interactions with fat cells, mesothelial cells, and cancerassociated fibroblasts. These interactions enhance the activation of pathways that support its growth (5-7). Also, its dissemination in ascites fluid and formation of nodules in the peritoneum are a unique mechanism of metastasis hampering therapeutic intervention (8, 9). Immunotherapy with checkpoint inhibitors such as Pembrolizumab has shown limited success (10). Diverse mechanisms of immune escape in a tumorlocation specific manner have been observed (11). Taken together, there is a tremendous medical need for identification of new targets and modalities for treatment of OC. Therefore, we searched the literature for circular RNAs (circRNAs) that are up-or down-regulated in EOC and upon their modulation exhibit efficacy in preclinical in vivo models of EOC. Circular RNA in CancercircRNA can be generated during mRNA processing by intramolecular mRNA pairing followed by circularization, RNA-213