Abstract 4405: RNases: Approaching RNA as a target for cancer therapy.

Abstract

Abstract Ribonucleases (RNases) are a unique class of anti-cancer drugs that target the RNA in cancer cells without the complications of delivering RNA. Efficacious RNases have diminished binding to the naturally occurring RNase inhibitor protein in the cytosol of cells. Since human RNase I binds tightly to the inhibitor, changes to the amino acid residues in the contact region were made and resulted in the lead candidate referred to as QBI-139. This variant maintains 95% sequence identity with the wild type human RNase 1. Broad efficacy and a strong therapeutic window were seen across multiple tumor types in xenograft models and QBI-139 was advanced to an ongoing Phase I clinical trial. For the Investigational New Drug application package, rat and dog toxicology studies were used to aid in selection of the starting dose for humans. Exposure levels (pharmacokinetics, PK) are an important factor in evaluating whether toxicity and efficacy will be comparable across the species. A complicating issue in the evaluation of the results is the range of routes of administration across species, specifically intraperitoneal injection (mice), intravenous injection (rat and dog) and intravenous infusion (human). One parameter that is consistent is rapid clearance, which is likely due to the small size of QBI-139 (15 kiloDaltons). With preliminary results from the early stage clinical trial, the exposure levels across the experiments will be compared. The results demonstrate that the exposure profiles in the clinic where the route of administration is intravenous infusion, is most similar to that in the mouse efficacy models, which is intraperitoneal injection. A human RNase variant, called QBI-139 provides an innovative drug development approach to targeting RNA. In model systems, QBI-139 has shown broad in vivo anti-tumor activity alone and in combination with standard of care therapies and a strong tolerability profile. The knowledge gained about the impact of PK on therapeutic effect will be valuable as the method of administration is selected and confirmed in the next stage of clinical trials. Citation Format: Laura E. Strong, John Kink, Baigen Mei, Mark Shahan, Ronald T. Raines. RNases: Approaching RNA as a target for cancer therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4405. doi:10.1158/1538-7445.AM2013-4405