Abstract 2180: Development of novel targeted therapies for non-small cell carcinoma by novel Midkine inhibitors.

Abstract

Abstract In the past few years a subset of driver mutations has been identified in non-small cell lung carcinoma (NSCLC), the most common type of lung adenocarcinoma. These driver mutations have differential sensitivities to various targeted therapies. The number of identified mutations in lung adenocarcinomas is limited, therefore identification of more molecular targets is needed in order to develop new treatments for NSCLCs. Efforts to find target mutations in lung adenocarcinoma with KRAS mutations are especially important because such adenocarcinomas account for 20% of lung adenocarcinoma, the most frequent type of lung adenocarcinomas. Midkine is a heparin-binding cytokine that is induced by retinoic acid in embryonal carcinoma cells. It is involved in the development of cancer because of its mitogenic effect, promotion of angiogenesis, anti-apoptotic activity and transforming activity. Midkine expression is increased in various malignant tumors, including lung, esophageal, stomach, colon, hepatocellular, breast and pancreatic carcinomas, when compared with the level of expression in normal tissues. In a proof-of-principle effort to identify novel compounds that inhibit Midkine expression, we recently conducted cell-based high-throughput screening (HTS) of 44,000 compounds in the compound library using the Midkine promoter. We identified sixteen small molecules that inhibit Midkine promoter activity. Significantly, many of these inhibitors, which reduced Midkine protein, also inhibited proliferation in non-small cell lung cancer cells which express high levels of endogenous Midkine. We assigned the name iMDK1 to one of these compounds and assessed its ability to target non-small cell lung cancer cells. 48 hours after treatment, iMDK1 dose-dependently inhibited cell growth of Midkine expressing H441 pulmonary adenocarcinoma cells but did not impair the viability of normal proliferating human lung fibroblast cells. Hoechst 33342 staining and cell cycle analysis performed by flow cytometry demonstrated that the iMDK1 compound induced apoptosis in H441 cells. Furthermore, immunoblot analysis showed that iMDK1 inhibits the PI3 kinase pathway in H441 cells. These results indicate that iMDK1 might be a promising new therapeutic tool for the treatment of Midkine -expressing lung adenocarcinoma with KRAS mutations. Here we show a novel strategy to treat non-small cell lung cancer with Midkine inhibitors. Citation Format: Takuya Fukazawa, Yutaka Maeda, Huifang Hao, Tomoki Yamatsuji, Munenori Takaoka, Nagio Takigawa, Yoshio Naomoto. Development of novel targeted therapies for non-small cell carcinoma by novel Midkine inhibitors. [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 2180. doi:10.1158/1538-7445.AM2013-2180