Abstract 3838: NKP-2235 exhibits a novel pattern of cytotoxicity with synergism across a broad range of antitumor agents demonstrated in multiple tumor types

Abstract Background: NKP-2235 is a first-in-class, orally bioavailable gallium based anti-cancer compound. The intracellular targets for NKP-2235 include the endoplasmic reticulum (ER). NKP-2235 treatment of tumor cells causes ER stress, intracellular Ca2+ release and induction of pro-apoptotic factors. In single agent in vitro cytotoxicity assays, NKP-2235 has shown activity against tumor lines resistant to many standard anti-cancer agents. The aims of this study were to evaluate the anti-tumor effects of NKP-2235 in combination with standard cytotoxics or targeted agents and assess its single agent cytotoxicity pattern in the NCI 60 tumor cell line anti-cancer drug screen and COMPARE analysis. Methods: NKP-2235 testing in the NCI 60 tumor cell line anticancer drug screen was performed by the NCI. COMPARE analysis was conducted using cytotoxicity data from 170 compounds in the NCI compound library. In vitro combination studies were performed in breast, colon, glioma, lung and prostate tumor cell lines. NKP-2235 was tested in combination with 5-FU, temozolomide, gemcitabine, paclitaxel, erlotinib, temsirolimus, or docetaxel either simultaneously or sequentially. For simultaneous combinations, cells were exposed to NKP-2235 and a combination agent, at their respective ED50, for 72hrs. For sequential NKP-2235 combinations cells were exposed to different dosing sequences, all agents at their respective ED50, for a total of 96 hrs. Cytotoxicity was determined using the MTT assay and combination index (CI) values were calculated using the Chou-Talalay method. Results: Screening against the NCI 60 tumor cell line panel and COMPARE analysis show that single agent NKP-2235 has a markedly different pattern of cytotoxicity from the 170 anti-cancer agents previously tested by the NCI. In addition, the screening confirmed that the NKP-2235 cytotoxicity is distinct from that of gallium salts such as gallium nitrate. The combination studies demonstrated that NKP-2235 has synergistic activity when combined simultaneously with: 5-FU (CI 0.6), temozolomide (CI 0.8), gemcitabine (CI 0.7), temsirolimus (CI 0.7), and docetaxel (CI 0.7) in the cell lines tested. Interestingly, while simultaneous combination is synergistic with docetaxel in prostate cancer cells, the NKP-2235-paclitaxel combinations required sequential dosing for synergistic activity (CI 0.09) in lung cancer cells. Similarly, the NKP-2235-temsirolimus combination is synergistic in simultaneous setting, while NKP-2235-erlotinib combination required sequential dosing for synergistic activity (CI 0.3) in lung cancer cells. Conclusions: This study demonstrates that NKP-2235 has a novel pattern of cytotoxicity and marked synergism in combination with a broad range of anti-tumor agents in many tumor types. These data support the study of this novel agent in single agent and combination clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3838. doi:1538-7445.AM2012-3838