Abstract 2573: Combinations of QBI-139, a clinical stage ribonuclease drug

Abstract

Abstract RNA has been recognized as a drug target for cancer therapy, as evidenced by the ongoing clinical trials of RNAi and antisense therapies. An alternative approach that circumvents the delivery and stability issues of RNAi and antisense is to harness the activity of naturally occurring enzymes that degrade RNA. The ribonuclease approach is partially validated by objective clinical responses seen in clinical trials of ribonuclease (RNase) discovered in frog eggs. Our research has focused on creating variants of human RNases with the ability of frog RNase to evade the human RNase inhibitor. Diminished binding of mammalian RNases to the inhibitor have been shown to endow the RNase with the ability to kill cancer cells. One of the RNase variants, called QBI-139, demonstrated particularly strong anti-cancer activity against a variety of tumor types in in vivo models. QBI-139 is differentiated from the frog RNase because QBI-139 is 95 % identical to a native human RNase, while the frog RNase is only 20% similar. This difference may be what has led to a significantly improved tolerability profile for QBI-139 across species. QBI-139 was selected for clinical development and is now in a Phase I trial of solid tumors. In charting the clinical development path for QBI-139, the ability of the RNase to work in combination with a variety of standard of care agents had to be evaluated. Based in the single agent activity of QBI-139 in colon, non-small cell lung, ovarian and pancreatic cancers, the potency of QBI-139 in combination with the standard of care agents for these indications was explored. In in vitro screening, QBI-139 has demonstrated additive and synergistic activity in combination with cisplatin, 5-FU and docetaxel. The treatments were evaluated using fixed ratios of QBI-139 and the combination drug based on their EC50 values. The Combination Index (CI) was determined using median effect analysis. A CI of 1 indicates additive effects, whereas a CI < 1 indicates synergy. Synergy was demonstrated with QBI-139 in combination with cisplatin against solid tumors of non-small cell lung cancer (A549 and H1975) and an additive effect in ovarian (Ovcar-3) cancer. 5-FU and docetaxel also were synergistic with QBI-139 against solid tumors of colon (HCT-116) and ovarian (SK-OV-3) cancer, respectively.The goal of this project is development of an innovative, differentiated therapy, QBI-139, to provide clinical benefit to patients with colon, non-small cell lung and ovarian cancer, which are among the seven deadliest forms of cancer in the United States. In addition to being serious diseases, effective treatment of these cancers also represent unmet medical needs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2573. doi:10.1158/1538-7445.AM2011-2573