Abstract B39: Inhibition of the oncoprotein FUBP1 by SN-38 represents a novel therapeutic option for the treatment of hepatocellular carcinoma

Autor: Maria A. Gonzalez-Carmona, Jörg O. Schulze, Stephan Zangos, Stefan Zeuzem, Jörg Trojan, Sabrina Khageh Hosseini, Martin Zörnig, Dieter Steinhilber, Stefanie Hauck, A Vogt, Josephine Wesely, Thomas J. Vogl, Eugen Proschak, Christian P. Strassburg, Ricardo M. Biondi
Rok vydání: 2016
Předmět:
Zdroj: Cancer Research. 76:B39-B39
ISSN: 1538-7445
0008-5472
Popis: Hepatocellular carcinoma (HCC) is the most common form of liver cancer. It is accounting for one million deaths per year, mostly due to the late time point of diagnosis and especially to the lack of a specified therapy. In more than 90% of HCCs the oncoprotein FUSE Binding Protein 1 (FUBP1) is overexpressed, with neglectable levels in healthy liver tissue. FUBP1 is a single-stranded DNA-binding protein, which was originally discovered as a major upstream regulator of C-MYC gene expression. Additionally, FUBP1 is known to regulate cell cycle inhibitors like p21 and apoptosis regulating proteins like BIK. In a previous study we could show, that the knockdown of FUBP1 sensitizes HCC cell lines for apoptotic stimuli, e.g. mitomycin c treatment, and reduces tumor engraftment and growth in a Hep3B xenograft model. Consequently, FUBP1 inhibition is a very promising starting point of a targeted HCC therapy. In a screening of FDA-approved drugs, using ALPHA-Screen technology, 1,200 substances were tested for their potential to inhibit or prevent the binding of FUBP1 to its target DNA sequence FUSE. We could demonstrate for the first time the effective inhibition of FUBP1 with small molecules: the known Topoisomerase 1 (TOP1) inhibitor camptothecin (CPT) and its clinically used analog 7-ethyl-10-hydroxycamptothecin (SN-38). Both molecules inhibited the interaction between FUBP1 and FUSE in ALPHA-Screen, Surface Plasmone Resonance (SPR) and Microscale Thermopheresis (MST) assays. Furthermore, SN-38 and CPT caused significant increase of the expression levels of FUBP1 target genes (p21, BIK) in hepatocellular carcinoma cell lines as well as in the TOP1-mutated cell line HCT116 G7. Treatment of mice injected subcutaneously with human HCC cell lines (Hep3B or HepG2) or orthotopically with murine Hepa129 cells showed high efficacy of a double treatment including irinotecan, the pro-drug of SN-38, and the apoptosis-inducing agent mitomycin c. Mice treated with either single or double treatment showed significantly prolonged tumor free survival period compared to control groups, with lower rates of tumor remission concerning irinotecan / mitomycin c drug exposure. Most importantly, treatment of 5 patients suffering from intermediate unresectable HCCs with a combinational therapy of irinotecan and mitomycin c delivered via transarterial chemoembolization (TACE) revealed 100% response rate. Two of these patients showed complete tumor remission, with one of them being tumor free for over 1 year untill today, whereas the remaining 3 patients are in stable disease with no major side effects. Along with the in vitro and in vivo experiments, these early clinical results point to a significant breakthrough in HCC-therapy not seen before. Citation Format: Stefanie Hauck, Sabrina Khageh Hosseini, Josephine Wesely, Dieter Steinhilber, Jörg Schulze, Annabelle Vogt, Maria Gonzalez-Carmona, Christian Strassburg, Stefan Zeuzem, Thomas Vogl, Jörg Trojan, Stephan Zangos, Ricardo Biondi, Eugen Proschak, Martin Zörnig. Inhibition of the oncoprotein FUBP1 by SN-38 represents a novel therapeutic option for the treatment of hepatocellular carcinoma. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr B39.
Databáze: OpenAIRE
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