Circular RNAs With Efficacy in PreclinicalIn VitroandIn VivoModels of Esophageal Squamous Cell Carcinoma

Abstract

Esophageal cancer is associated with a dismal prognosis. The armamentarium of approved drugs is focused on chemotherapy with modest therapeutic benefit. Recently, checkpoint inhibitory monoclonal antibody Pembrolizumab was approved. In order to identify new targets and modalities for the treatment of esophagus squamous cell carcinoma (ESCC) we searched the literature for circRNAs involved in the pathogenesis of ESCC. We identified two down-regulated and 17 up-regulated circRNAs as well as a synthetic circRNA with efficacy in preclinical in vivo systems. Down-regulated circRNAs sponge microRNAs directed against tumor suppressor genes. Up-regulated circRNAs sponge microRNAs directed against mRNAs, which encode proteins with pro-tumoral functions. We discuss issues such as reconstitution of down-regulated circRNAs and inhibition of up-regulated circRNAs with short interfering RNA (siRNA)-related entities. Also, we address druggability issues of the identified targets.Esophageal carcinoma is the seventh most common cancer worldwide with 570,000 cases annually (1). Two major histological sub-types are esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). ESCCs arise in squamous cells that line the esophagus, whereas EACs derive from glandular cells of the esophagus (2). The ratio of incidence between ESCC and EAC depends on the geographic location with ESCC emerging as the most frequent subtype worldwide (3). Therapies such as endoscopic resection, surgery, chemo-and radio-therapy and treatment with immune-checkpoint inhibitory monoclonal antibodies (mAbs) only confer minimal survival advantages (4-7). Among the agents under development are epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), vascular endothelial growth factor receptor (VEGFR), hepatocyte growth factor (HGF)-tyrosine protein kinase c-MET and fibroblast growth factor receptor 2 (FGFR2) signaling inhibitors in the format of mAbs or small molecule tyrosine kinase inhibitors (4) as well as small molecule inhibitors of mechanistic target of rapamycin (mTOR), poly(ADP)ribose-polymerase 1 (PARP1) and cyclindependent kinases (CDKs) (8-10), most of them affecting rat sarcoma (RAS), rapidly accelerated firbrosarcoma (RAF), extracellular signal-regulated kinase (ERK), mitogen-activated protein kinase(MAPK), phosphoinosite-3-kinase (PI3K), serine-threonine kinase AKT and mTOR pathways.Despite these ongoing efforts, identification of new targets and treatment modalities for ESCC is an issue of high priority. In this review, we focus on circRNAs with documented efficacy in preclinical efficacy in in vivo models for treatment of ESCC. Circular RNASeveral types of non-coding RNAs such as t-RNA, r-RNA, siRNA, lncRNA and circRNA have been described (11). CircRNAs are covalently closed circles of RNA and are products of backsplicing events in which one exon is spliced to a preceding exon (12). A unique junction is generated which allows their specific detection by molecular probes (12). At least 30000 circRNA...

Hepatocellular Carcinoma: Up-regulated Circular RNAs Which Mediate Efficacy in PreclinicalIn VivoModels

“…Bioinformatic-based techniques have speeded up the identification of HCC-related circ RNAs (205)(206)(207), such as circMRD27 which mediates resistance to levantinib (208). Previously we have reviewed the role of circular RNAs in breast cancer (209,210), esophageal squamous cell carcinoma (211) and colorectal cancer (212). We have extended this work to HCC and identified circRNAs which promote growth of HCC in preclinical in vivo models by sponging miRs.…”

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

“…These issues are not discussed in further details in this review. Among the issues are pharmacokinetic CANCER GENOMICS & PROTEOMICS 21: 213-237 (2024) and pharmacodynamic aspects of the corresponding agents, immunogenicity, specificity, and delivery (15)(16)(17). The optimization process depends on the specific approach and the clinical scenario to be pursued.…”

“…Physiologically, circRNAs are involved in a plethora of cellular functions (13). In cancer, circRNAs can exert oncogenic as well as tumor-suppressive functions modulating proliferation, angiogenesis, migration, and metastasis (14)(15)(16)(17). In addition, circRNAs can act as scaffolds or sponges for proteins, regulate transcription, interact with RNAs, modulate translation and, in some cases, they can encode proteins (18).…”

Up-regulated Circular RNAs in Colorectal Cancer: New Entities for Therapy and Tools for Identification of Therapeutic Targets

“…CircRNAs are covalently closed RNAs which have a length between hundred to thousands of nucleotides and are generated by backsplicing (9). They are exceptionably stable and have potential as diagnostic and prognostic biomarkers as well as therapeutic targets in cancer patients (10,11). In addition, they exhibit a regulatory function in tissue development, neurogenesis and myogenesis (12).…”