Abstract 3528: In vitro profiling of kinase inhibitors and targeted anticancer agents in panels of patient-derived xenografts using a clonogenic assay
Authors: Maier Armin , Metz Thomas , Krumbach Rebekka , Beckers Thomas , Fiebig Heinz-Herbert 
Published: June 2012

Novel cancer therapeutics target proteins with key functions in cell survival and migration, protein turnover, mitosis regulation, or angiogenesis. These targets include receptor tyrosine (Y) kinases (e.g. BCR/ABL, EGF-R, FLT-3, Her-2, PDGF-R, KDR, c-KIT, Src, VEGF-R), serine-threonine (S/T) specific kinases (e.g. Aurora A/B (ARK), B-raf), and the chaperone Hsp90. At Oncotest, a unique profiling screen for anticancer agents is routinely done, using a clonogenic assay in a panel of 48 proprietary solid tumor xenografts. The xenograft models were in general established directly from patient tumors, representing all major tumor histotypes (non-small cell lung cancer/NSCLC, pancreatic, prostate, colon, gastric, breast, ovarian and renal cancer, melanoma and sarcoma) as well as niche tumors (pleuramesothelioma, bladder and head and neck cancer). After an initial profiling screen in the 48 tumor panel, follow-up testing in defined tumor histotypes are of high value for hypothesis generation and selection of a clinical development strategy.

Here, activity profiles for inhibitors targeting multiple S/T and Y kinases (Dasatinib, Pazopanib, Sunitinib, Sorafenib), EGF-R (Erlotinib, Gefitinib), Her-2 (Lapatinib), Aurora A/B (VX-680), and Hsp90 (17-DMAG) are presented. Erlotinib and Gefitinib displayed a diverse pattern of activity with mean IC50 values of 36.5µM and 20.7µM, respectively. Selectivity was studied in an extended panel of NSCLC with tumors showing an activated EGF-R pathway being most sensitive. The Hsp90 inhibitor 17-DMAG was highly potent with a mean IC50 value of 19nM. As an example, tumor xenograft models selected based on clonogenic assay data responded very well in in vivo efficacy tests against 17-DMAG. The spectrum-kinase inhibitors Sunitinib and Sorafenib displayed a rather weak selectivity with mean IC50 values of 6.3µM and 10.5µM, respectively. In contrast the BCR/ABL and Src inhibitor Dasatinib was active with a mean IC50 of 5.4µM, and showed a highly differential activity against xenografts of solid tumors. Extended tests against 105 tumors of 16 different histotypes identified pancreatic, breast, small cell lung, and colon cancer to be the most sensitive ones. This implements that the use of this compound might not be limited to the treatment of chronic myelogenous leukaemia and gastrointestinal stromal tumors.

In conclusion, the presented panel screen using a clonogenic assay, by retaining important characteristics of the original patient tumor, is of high value for profiling of traditional cytotoxic as well as new targeted cancer agents. By revealing diverse activity and resistance patterns, molecular characterization data including gene and protein expression are guiding the selection of tumor entities and patients likely to respond to therapy.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3528. doi:10.1158/1538-7445.AM2011-3528