SP 5

Identification, validation and exploitation of modulators

Lung cancer is the third most common cancer in Germany, but still the most common cause of cancer death. Each year, approximately 34,000 men and 15,600 women are diagnosted with lung cancer. The development of personalized approaches to treat lung cancer in recent years has already led to a hitherto thought possible prolong survival for some patients. This development is based on advances in (cancer) genome analysis.
One of the first examples of the use of a personalized targeted therapy is the treatment of lung cancer patients with EGFR mutations (Endothelial Growth Factor Receptor) with EGFR-targeted tyrosine kinase inhibitors (TKI). In a recent study, we observed about 24 months longer survival for this group of patients with the personalized therapy compared with chemotherapy (CLCGP and NGM, Sci Transl Med, 2013). But despite successful treatment patients often develop a secondary resistance during therapy.

In subproject TP5 of the SMOOSE consortium we strive sequencing rebiopsies of patients after targeted personalized therapies in order to obtain a better understanding of the molecular changes in the reacurrence. In addition, we will establis cellular models of potential modulators that are present in therapy-naive tumors. These are validated to confirm the predicted phenotype and analyzed in cell-based screens with various compounds. After validation in cellular models single modulator are selected for validation in genetically engineered mouse models. Finally, all results from these experiments will be used for the development of a clinical diagnostic cancer genome assay. In summary, the work proposed in this project is crucial for the discovery and validation of novel modulators in cancer. 

Keywords: resistance mechanism, lung cancer, genome sequencing