Abstract B27: Identification of novel anti-metastatic drugs targeting oncogenic E2F1:coregulator complexes by applying a systems pharmacology approach

Abstract

Abstract Tumour metastasis is considered to be one of the most important problems in cancer research and the identification of mechanisms that drive this multistep process provides urgently needed opportunities for therapeutic interventions. Many cancer types are driven by the dysfunction of transcriptional coregulators which interact with transcription factors such as E2F1 that has been associated with cancer aggressiveness and poor patient survival prognosis. Although the role of E2F1 in malignant progression is not fully understood, its physical interaction with oncogenic coregulators is clearly linked to the activation of prometastatic gene expression programs. In order to identify metastatic E2F1:coregulator complexes that determine occurrence of metastases and clinical outcome, we employed co-immunoprecipitation assays in advanced-stage metastatic cancer cells combined with high throughput mass spectrometry. We identified a hitherto unknown regulatory network of E2F1 interaction partners, which were validated by Western blotting, confocal laser scanning microscopy, ChIP and promoter reporter assays. Knockdown and overexpression studies in a large panel of metastatic cell lines originating from various tumor entities showed a clear impact of these proteins on cancer motility and invasiveness. Genome-wide transcriptome analyses were applied to uncover the metastasis gene signature regulated by the E2F1-coregulator complexes that predicts aggressive behavior. Finally, we developed a pharmacophore model of E2F1 interacting proteins and predicted potential drug molecules which can be used as inhibitors of E2F1:coregulator complexes based on a computer-assisted virtual screening of FDA-approved compounds. Taken together, our straight forward approach on finding new prometastatic E2F1 coregulators and potential inhibitors to disrupt these complexes may shed new light into future cancer therapy. This research was funded by grants from the German Cancer Aid, Dr. Mildred Scheel Stiftung (109801 to B.M.P. and D.E.) and German Federal Ministry of Education and Research (BMBF) as part of the eBio:SysMet project (0316171 to B.M.P.). Note: This abstract was not presented at the conference. Citation Format: Deborah Goody, David Engelmann, Stefan Mikkat, Shailendra K. Gupta, Brigitte M. Pützer. Identification of novel anti-metastatic drugs targeting oncogenic E2F1:coregulator complexes by applying a systems pharmacology approach. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B27.