Small Activating RNA Modulation of the G Protein‐Coupled Receptor for Cancer Treatment

Abstract

G protein-coupled receptors (GPCRs) are the most common and important drug targets. However, >70% of GPCRs are undruggable or difficult to target using conventional chemical agonists/antagonists. Small nucleic acid molecules, which can sequence-specifically modulate any gene, offer a unique opportunity to effectively expand drug targets, especially those that are undruggable or difficult to address, such as GPCRs. Here, the authors report for the first time that small activating RNAs (saRNAs) effectively modulate a GPCR for cancer treatment. Specifically, saRNAs promoting the expression of Mas receptor (MAS1), a GPCR that counteracts the classical angiotensin II pathway in cancer cell proliferation and migration, are identified. These saRNAs, delivered by an amphiphilic dendrimer vector, enhance MAS1 expression, counteracting the angiotensin II/angiotensin II Receptor Type 1 axis, and leading to significant suppression of tumorigenesis and the inhibition of tumor progression of multiple cancers in tumor-xenografted mouse models and patient-derived tumor models. This study provides not only a new strategy for cancer therapy by targeting the renin-angiotensin system, but also a new avenue to modulate GPCR signaling by RNA activation.

A PD‐L1 Antibody‐Conjugated PAMAM Dendrimer Nanosystem for Simultaneously Inhibiting Glycolysis and Promoting Immune Response in Fighting Breast Cancer

“…effective vector for siRNA delivery and gene knockdown in various cells, including cancer cells, stems cells, and primary immune cells, as well as in animal models of different diseases. [25][26][27][28] AD can complex siRNA molecules into small and uniform nanoparticles that protect them from degradation and promote cell uptake. In the present work, we employed AD for siPDK1 delivery.…”

“…Recently, we developed amphiphilic dendrimers as precision vectors for siRNA delivery by virtue of their well-defined dendritic structure and cooperative multivalence. [23][24][25][26][27][28] These amphiphilic dendrimers also boast combined delivery advantages of both lipid and polymer vectors, the two most advanced vectors for siRNA delivery. Notably, cationic amphiphilic dendrimers strongly bind to negatively charged siRNAs, forming stable nanoparticles that protect the RNA molecules from degradation and prolong its half-life, leading to enhanced siRNA accumulation in tumor lesions via the enhanced permeation and retention (EPR) effect, also known as passive tumor targeting.…”

Small RNA activation of CDH13 expression overcome BCR-ABL1-independent imatinib-resistance and their signaling pathway studies in chronic myeloid leukemia

“…Currently, in clinical trials, the rst saRNA treatment (MTL-CEBPA) targets and up-regulates the myeloid transcription factor CCAAT enhancer binding protein (CEBPA) in advanced hepatocellular cancer 17,18 . RNAa, a novel member of the RNA family, not only provides a new platform for the study of gene function, but also shows exceptional clinical therapeutic potential 19 .…”

Modulating the expression of tumor suppressor genes using activating oligonucleotide technologies as a therapeutic approach in cancer

“…(Ref. 37 ) CCND1, cyclin D1; CDH1, cadherin-1; CDKN1A, cyclin dependent kinase inhibitor 1A; HCC, hepatocellular carcinoma; PDAC, Pancreatic ductal adenocarcinoma; PIP 2, phosphatidylinositol 4,5-bisphosphate; PIP 3 , phosphatidylinositol 3,4,5-trisphosphate. …”