Abstract A173: Profiling of targeted anticancer agents in a panel of 48 patient-derived xenografts using a clonogenic assay

Abstract

Abstract Novel experimental and approved cancer therapeutics target proteins with key functions in mitosis regulation, cell survival and migration, protein turnover or angiogenesis. These targets include receptor tyrosine (Y) kinases like EGF-R, PDGF-R, VEGF-R, c-KIT and FLT-3, serine-threonine (S/T) specific kinases like B-raf and Aurora A/B (ARK), mitotic kinesins like Eg5 (KSP), the chaperone Hsp90 and traditional targets, namely topoisomerase I / II and ß-tubulin. At Oncotest, a unique profiling screen for anticancer agents using a clonogenic assay using a panel of 48 proprietary solid tumor xenografts is routinely done. The xenograft models in general were established directly from patient tumor material, 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 including selection of a clinical development strategy. Here, activity profiles for inhibitors targeting EGF-R (Erlotinib), Aurora A/B (VX-680), multiple S/T and Y kinases (Sunitinib, Sorafenib), Eg5 (Ispinesib) and tububiln (Vincristine), Hsp90 (17-DMAG) and topoisomerase I (SN-38, active metabolite of Irinotecan) are discussed. Erlotinib displayed a diverse pattern of activity with a mean IC50 = 20.7µM. Selectivity was studied in an extended panel of NSCLC with tumors showing activated EGF-R being mainly most sensitive. The spectrum-kinase inhibitors Sunitinib and Sorafenib displayed weak selectivity with mean IC50 values of 7.9µM and 11.8µM, respectively. The Hsp90 inhibitor 17-DMAG, the topoisomerase I inhibitor SN-38 and Vincristine were highly potent with mean IC50 values of 28nM, 45nM, and 100nM, respectively. For 17-DMAG and SN-38 as examples, tumor xenograft models selected based on clonogenic assay data responded very well in in vivo efficacy tests. Further evaluation of Vincristine in an extended melanoma panel revealed a strong correlation of sensitivity with a B-raf wild type genotype and resistance with the B-raf V600E mutation. This result was described recently for melanoma patients with B-raf mutations, showing a diminished duration of response to treatment with Dacarbazine, Vincristine, Bleomycin, Lomustine, and human leukocyte interferon. In conclusion, the Oncotest 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 mutations and expression are guiding the selection of tumor entities and patients likely to respond to therapy. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A173.