Research Report 2010 - MDC

Structure of the GroupIduna FichtnerGroup LeaderDr. Iduna FichtnerScientistsDr. Michael BeckerDr. Klaus EckertDr. Reiner ZeisigDr. Diana BehrensExperimental PharmacologyPersonalized medicine will be the future goal of treatment options in cancer therapy. To achievethis, the routine use of biomarkers for the prediction of response or inherited resistance of anindividual tumor is necessary. Patient-derived tumor grafts gain increasing interest for the definition,characterization and validation of relevant biomarkers and are especially suitable models toinvestigate the dynamic regulation of genes or proteins in a clinically related way. The group“Experimental Pharmacology” has established a variety of patient-derived models from breast, colon,lung, ovarian carcinomas and from leukemias and sarcomas. Recent research was mainly focused onnon-small cell lung carcinomas and their biomarker profiling in relation to the response to classical ortargeted therapies. Further interest of the group concentrated on the generation of nanoparticulateformulations with a potential influence on vascular metastasis or for the treatment of brainmalignancies. The continued stem cell research focused on comparisons between adult haematopoieticand embryonic stem cells. Both in vitro and in vivo methods were used to evaluate thetransdifferentiation potential of these both cell types. It could be shown that embryonic stem cellshave a higher potential for differentiation into hepatic lineage cells than adult stem cells.Potential of patient derived xenografts for theidentification of biomarkersAs recently reported, our group in cooperation with theEvangelische Lungenklinik Berlin-Buch (Dr. Merk) wasable to establish a panel of non-small cell lung cancer(NSCLC) xenografts by transplanting patient derivedsurgical specimens directly to immunodeficient miceand keeping them in low passages. These tumor graftswere characterized using the expression of epidermalgrowth factor receptor (EGFR) related markers on thegenetic (Affymetrix profiling, mutational analysis) andprotein levels. It could be shown that there was a highcongruence between the original and the xenotransplantedtumor concerning histology, immunohistochemistryand gene expression pattern. Thechemotherapeutic responsiveness of the tumor graftsto classical cytotoxic drugs (paclitaxel, gemcitabine,carboplatin, etoposide, vinorelbine) as well as towardstargeted therapeutics (cetuximab, erlotinib) resembledthe clinical situation. No correlation could be foundbetween mutations in the EGFR, p53, c-met or PI3K andresponse to therapy. However, a correlation between K-ras mutations and response to erlotinib was registered.After treatment with Cetuximab, a down-regulation ofEGFR was observed in some sensitive but never in theresistant tumor models. The lack of therapeuticresponse of the NSCLC xenografts was not related tothe expression of resistance markers like BCRP, LRP,MDR1 and MRP1 at RNA or protein level.The comparison of the genome-wide gene expressionprofiling revealed a close clustering between the originalpatient tumor and the derived xenografts with correlationcoefficients between 0.945 and 0.782 (Figure 1).193 probe sets were differentially expressed. From136 Cancer Research