Nucleic Acid Aptamers in Cancer Therapy

Background and aim: nucleic acid therapeutics, including sirnas and mirnas/antimirs, are emerging highly promising molecules for the precise treatment of refractory aggressive gbm. as matter of fact, transcription factors and micro-rnas essential to maintain the tumor initiating capacity of gscs and the ability to invade the normal brain have been described as potential therapeutic targets (including signal transducer and activator of transcription-3, stat3, and mir-10b). however, the need for precise and safe targeted cell delivery and the lack of effective drugs to eradicate gscs has revealed this as a challenging objective. in the last decade due to their high affinity for specific ligands, high intra-tumor penetration and chemical flexibility, short single-stranded nucleic acid aptamers are emerging as very attractive carriers for various therapeutic oligonucleotides.method: in order to develop a combined strategy enabling to target both the stem-like and the adherent bulk tumor cells, as targeting moieties to drive rna drugs here we used two aptamers ligands for two receptor tyrosine kinase (rtks) in combination. the first, named gint4.t that binds to and antagonizes the rtk, pdgfrβ, overexpressed in gscs; the second, named gl21.t that binds to and antagonizes the rtk, axl, overexpressed and involved in several tumor types including gbm. stat3 has been reported as key regulator of the highly aggressive mesenchymal gbm subtype and of survival and propagation of gscs. using the gint4.t aptamer, we recently designed a novel aptamer-sirna chimera (asic, gint4.t-stat3).results: because of the pivotal role of stat3 in maintaining the tumor initiating capacity of gsc population and tumor relapse, here we explored the potential of gint4.t-stat3 to inhibit the stat3-dependent gene expression impairing the stem-like gscs phenotype. further, we show that gint4.t-stat3 synergizes with a chimera containing the anti-axl aptamer gl21.t linked to the single chain antagonist of mir-10b (gl21.t-10b) to effectively and specifically prevent patient-derived gsc function and expansion.conclusions: results highlight the potential of the combined treatment with two complementary chimeras as a highly effective and selective inhibitor of gbm tumor growth and dissemination.