AZD9150, a next-generation antisense oligonucleotide inhibitor of STAT3 with early evidence of clinical activity in lymphoma and lung cancer
Après des travaux sur divers modèles précliniques de lymphome et de cancer du poumon non à petites cellules, cet essai de phase I (25 patients) évalue la dose maximale tolérée et l'activité antitumorale d'un inhibiteur du facteur de transcription STAT3
STAT3 is a transcription factor that plays an oncogenic role in many cancers, which has proven very difficult to target with chemical inhibitors. Now, Hong et al. have demonstrated that antisense technology is a feasible alternative to small-molecule inhibitors for targeting STAT3. The authors used high-affinity next-generation antisense oligonucleotides, which have higher potency than previous generations and can be systemically administered without a lipid vehicle. One of these new antisense oligonucleotides, AZD9150, demonstrated activity in a variety of preclinical cancer models, as well as in cancer patients who have failed one or more previous treatments, paving the way for additional clinical testing of this therapy.Next-generation sequencing technologies have greatly expanded our understanding of cancer genetics. Antisense technology is an attractive platform with the potential to translate these advances into improved cancer therapeutics, because antisense oligonucleotide (ASO) inhibitors can be designed on the basis of gene sequence information alone. Recent human clinical data have demonstrated the potent activity of systemically administered ASOs targeted to genes expressed in the liver. We describe the preclinical activity and initial clinical evaluation of a class of ASOs containing constrained ethyl modifications for targeting the gene encoding the transcription factor STAT3, a notoriously difficult protein to inhibit therapeutically. Systemic delivery of the unformulated ASO, AZD9150, decreased STAT3 expression in a broad range of preclinical cancer models and showed antitumor activity in lymphoma and lung cancer models. AZD9150 preclinical activity translated into single-agent antitumor activity in patients with highly treatment-refractory lymphoma and non–small cell lung cancer in a phase 1 dose-escalation study.