Abstract
Abstract The leukemia inhibitory factor (LIF), an IL-6 family member, is a pleotropic cytokine has been demonstrated as an oncogene and involved in multiple cellular mechanisms during the initiation and progression of various human malignancies. Overexpression of LIF was significantly correlated with advanced tumor stage, larger tumor size and worse relapse free survival rate. In the present study EC330, a novel steroidal LIF inhibitor showed cytotoxicity in various cancer cell lines and NCI-60 cell line panel at low nano-molar range. EC330 blocked formation of colonies in soft agar and inhibited angiogenesis (tube formation) in human umbilical vein endothelial cells. EC330 binds to LIF/LIFR complex by insilico docking studies and reduced the STAT3 phosphorylation in a dose dependent manner through blocking LIF-JAK-STAT signaling. EC330 showed marked specificity in MCF-7 cells overexpressing LIF verses MCF-7 cells. The compound further showed cytoskeletal disruption and targeting cancer associated fibroblasts (CAFs). EC330 treatment (0.5 and 2.5mg/kg) dose dependently reduced tumor burden in ovarian (IGROV-1) and triple negative breast cancer (MDA-MB-231) cell xenografted mouse models. These findings establish EC330 as a novel LIF inhibitor having targeted therapeutic perspectives for patients with aggressive primary tumors. LIF targeting may result in the blockade of cancer fibroblast associated pro invasive tumor microenvironment in regular as well as therapy resistant tumors. Citation Format: Hareesh B. Nair, Bindu Santhamma, Surya Viswanadhapa, Klaus J. Nickisch. First-in-class steroidal leukemia inhibitory factor (LIF) inhibitor in targeted cancer therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-208.
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