Background
toxicity, cancer, tumor, human malignancies
CANCER, TUMOR, ADVANCED CANCER
Non-coding RNAs (ncRNAs) have emerged as key regulators of crucial biological pathways driving cancer onset and progression. As such, ncRNAs have garnered major interest as targets for innovative therapeutic approaches to treat a range of human malignancies.Of the different classes of ncRNAs, microRNAs (miRNAs) are the most well studied [Among deregulated miRNAs, miR-221 has been widely investigated for its oncogenic role and as a promising therapeutic target [The targeting of oncogenic miRNAs has been widely investigated using antisense oligonucleotides (ASOs). ASOs act as inhibitors by forming a duplex with the guide strand of the target miRNA via Watson–Crick base pairing, therefore preventing interaction between the miRNA and its target mRNAs. This leads to restoration of downstream tumor suppressor protein expression and function. However, translation of these agents to the clinic has been hampered by inefficient and unspecific target binding, which results in low biological activity and off-target effects that lead to toxicity. To overcome these limitations several approaches for chemical modification of ASO backbones have been introduced [To this end, we have developed a 13-mer locked nucleic acid (LNA) inhibitor of miR-221 with a fully phosphorothioate (PS)-modified backbone. This miRNA-221 inhibitor, named LNA-i-miR-221, demonstrated efficient downregulation of miR-221, upregulation of canonical miR-221 targets, and anti-tumor activity in several preclinical tumor models [On these bases, we aimed to evaluate this first-in-class miR-221 inhibitor in advanced cancer patients in a phase I dose-escalation study. The primary objective of this study was the safety of LNA-i-miR-221, the identification of the maximum tolerated dose (MTD), and of the recommended dose for phase II trials (RP2D). Exploratory analysis of pharmacokinetics, pharmacodynamics, and of anti-tumor activity was also planned.