Abstract 5422: Drug combination studies in a panel of 30 cell lines established from patient-derived tumor xenograft
Authors: Gerhard Kelter, Victoria Smith, Thomas Metz, Heinz-Herbert Fiebig, Thomas Beckers
Journal: Cancer Research (2010)

Abstract In recent years, the focus of anticancer drug development has changed from conventional cytotoxic drugs to targeted agents interfering with cell proliferation, migration or survival. In most cases, signaling pathways, key regulatory complexes or biological processes of pathophysiological relevance are selected and proteins with key functions targeted. These include signaling cascades originating from receptor tyrosine kinases (e.g. c-Met, EGFR or HER2), the mitotic machinery (eg5, Aurora / ARK or polo-like kinases / Plk), protein turnover (Hsp70/90, 26S proteasome) and the nucleosome (e.g. HDACs, HATs). However, as a single agent new targeted drugs often demonstrate weak antitumor activity in preclinical testing and clinical trials. Combinations of new targeted agents or with standard cytotoxic drugs are a suitable strategy resulting in potent anti-cancer therapies. As the number of possible drug combinations is essentially limitless and a scientific rationale is only available in few cases, a screening strategy to identify the most promising drug combinations in vitro is crucial for success in further development. At Oncotest a panel of 30 proprietary solid tumor cell lines established from patient-derived xenografts is routinely used. All major histologies are represented such as NSCLC, colon and breast cancer, as well as niche tumors like pleuramesothelioma, bladder and liver cancer. Chemosensitivity information for most standard-of-care drugs and experimental compounds as well as genomic and proteomic characterization data are available. By using this cell line panel, systematic combination studies were performed with the propidium iodide standard cytotoxicity / proliferation assay. Synergistic or antagonistic activity was assessed according to the method of Chou-Talalay by calculating “Combination Index” (CI) values using the CalcuSyn software. Activity profiles were established for well described experimental an approved agents targeting for example c-Met (PF-04217903), EGFR / HER2 (Lapatinib, Erlotinib), Hsp90 (17-DMAG), Eg5 (Ispinesib, Monastrolin), Plk1 (BI2536), ARK A/B (Tozasertib), HDAC (Vorinostat, Etinostat) in combination with each other as well as with standard chemotherapeutic agents like Cisplatin, Paclitaxel or 5-Fluorouracil. The most promising combinations will be presented, for example the combination of HDAC or c-met inhibitors with EGFR receptor tyrosine kinase inhibitors displaying additive or synergistic activity. In conclusion, the Oncotest solid tumor cell line panel is suitable for a broad, systematic evaluation of drug combinations including cytotoxic and new targeted anti-cancer agents to identify potential beneficial combinations for further preclinical and clinical studies. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5422.