Abstract 49: Targeting the TNF network in human ovarian cancer - A systems biology approach

Abstract

Abstract In a recent publication (Kulbe et al Cancer Res 2011 epub ahead of print), we have shown how key pathways in cancer-related inflammation and Notch signaling are part of an autocrine malignant cell network in high-grade serous ovarian cancer, HGSOC. This network, that we have named the TNF network, has paracrine actions on angiogenesis, the stromal signature and the immune cell infiltrate in HGSOC. We have now used a systems biology approach, combining data from phospho-proteomic mass spectrometry and gene expression array analysis, to define the best therapeutic targets within the network and to identify drugs that may synergise with cytokine and chemokine inhibitors. First, we established a hierarchy of kinases involved in the TNF network and analyzed the constitutively active kinases in one of the high TNF network cell lines. Of 45 constitutively active kinases, 33 of these kinases showed direct interactions with each other. Next, we mapped gene expression microarray data onto the Connectivity Map of drugs in order to identify compounds having an effect on transcription similar to that of the TNF network. Among the identified candidate drugs were luteolin, apigenin and resveratrol. One of the known targets of this class of drugs is the protein kinase Casein kinase II (CSNK2A1), a kinase activated in association with the TNF network. In conclusion, we have identified kinases, particularly CK2, associated with the TNF network that may play a central role in sustaining the cytokine network and/or mediating its effects in ovarian cancer. We believe our findings have implications for our understanding of ovarian cancer biology and the development of new and more effective treatments for this disease. 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 49. doi:1538-7445.AM2012-49