Abstract 679: NDC-1308 nanoparticles inhibit tumor growth by novel mechanisms controlling cancer cell proliferation

Abstract

Abstract It has previously been demonstrated that treatment of tumor cells with an estrogen receptor beta (ER-β) agonist can lead to cessation of cell division and cell death. We recently reported the discovery of NDC-1308, a member of our estradiol-related family of ER-β agonists, which is cytotoxic to a broad range of human tumor cell lines (EC50 is 5-20 uM). Although NDC-1308 has similar binding affinity for ER-α and ER-β (70-100 nM), functional studies show that it activates ER-β about 5-fold more compared to ER-α. To understand the mechanism of cytotoxicity, A549 (lung), SKOV-3 (ovary), and Panc-1 (pancreatic) human tumor cell lines were treated with NDC-1308 and gene expression changes evaluated by microarray. In all cell lines, NDC-1308 caused a significant down-regulation of key genes critical for chromosome replication, along with the up-regulation of at least two nucleases, granzyme K (GzmK) and apoptosis enhancing nuclease (AEN). There was also a significant up-regulation of pro-apoptotic pathway genes including BBC3 and GDF15 and an up-regulation of a death receptor pathway gene TNFRSF10B (DR5). These results suggest that ER-β activation by NDC-1308 may be useful to trigger DNA damage, cell cycle arrest and ultimately the death of cancer cells. However, PK studies in rodents showed that NDC-1308 has a short half-life, thereby lowering its potential efficacy as a cancer therapeutic. In order to optimize the blood circulation time and to enhance the accumulation of NDC-1308 in tumors, the drug was formulated into several different types of nanoparticles (50-100 nm), including an amorphous drug particle, a lipid-containing particle and a micelle-based particle. Whole body imaging studies showed that NDC-1308 nanoparticles conjugated with AlexaFluor 750 could localize to human tumors such as colon adenocarcinomas, renal cell carcinomas and lung adenocarcinomas in nude mice (N=4 per tumor type). To determine the efficacy of NDC-1308 as an anti-cancer therapy, nude mice bearing A549 human tumors (N=12 per group) were dosed every other day with NDC-1308 nanoparticles (up to 24 mg/kg of the active drug) via tail vein injection. During treatment, this led to a significant, dose-dependent reduction in tumor size in drug treated animals versus untreated controls. We conclude that intravenous administration of NDC-1308 nanoparticles can inhibit the rate of human tumor growth in a mouse model of cancer. Our future development plans include large animal safety and toxicity studies, followed by IND submission and Phase 1 clinical trials. 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 679. doi:10.1158/1538-7445.AM2011-679