Abstract 926: Experimental therapy of pancreatic cancer with KCN1, a novel anticancer agent targeting HIF-1α pathway

Abstract

Abstract Hypoxia is a major driving force in a majority of human cancers and correlates with a poor outcome of cancer treatment. Hypoxia Inducible Factor-1 (HIF1) has been identified as the key orchestrator of hypoxic response due to its transactivation of genes that are involved in many aspects of malignant tumor growth from cell survival and metabolism to angiogenesis and invasion. Thus, pharmacological targeting of HIF-1 represents a promising strategy to inhibit tumor growth and progression. The purpose of the present study was to determine anti-cancer activity and pharmacological properties of KCN1, a novel small molecule HIF-1α pathway inhibitor. We investigated the in vitro activity of KCN1 on the survival of several human pancreatic cancer cell lines, including HPAC, Panc-1 and BxPC3 cells. KCN1 exerted potent effects against the various cell lines, leading to a significant decrease in cell viability, and inhibited cell proliferation and cell cycle progression, leading to an arrest in the G1 phase. We also found that the expression of numerous proliferation-associated and cell cycle regulatory proteins were affected by KCN1. It reduced the expression of E2F1, Cyclin D1, Cyclin E, Cdc25c and CDK 2, 4, and 6 and, conversely, increased p21 expression. Moreover, KCN1 inhibited the growth of pancreatic cancer xenograft tumors in nude mice. There were no significant host toxicity and no gross organ abnormalities upon necropsy. We also developed an HPLC method for KCN1 quantitation and accomplished experiments to derive preclinical information for its further development. The HPLC method provided a linear detection of KCN1 in biological matrices in the range from 0.1 to 100 μM, and had a limit of quantitation of 0.085 μM in mouse plasma. KCN1 was relatively stable in plasma, being largely intact after an 8-hr incubation in mouse plasma at 37°C. The compound was extensively plasma bound, and was metabolized by S9 microsomal enzymes. Pharmacokinetic studies indicated that KCN1 could be detected in tumors and all of the normal tissues examined. In conclusion, our preclinical data indicate that KCN1 is a potential therapeutic agent for pancreatic cancer. The initial pharmacological data provide a basis for its future development as a preclinical and clinical lead HIF1 inhibitor. (This work was supported by NIH/NCI grant R01 CA116804.) 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 926. doi:1538-7445.AM2012-926