RNA interference (RNAi) technology is a powerful tool and a non-biased approach for identifying genes whose suppression affects cell proliferation and viability. Although genome-wide RNAi screens have been widely used to identify new therapeutic targets in cancer, these screens are technically challenging and error-prone because of the high complexity of the short-hairpin RNA (shRNA) libraries. Using this conceptual approach, a series of relevant tumor suppressors have been identified which led to new therapeutic concepts for the treatment of various cancers, e.g. acute myeloid leukemia (AML), hepatocellular carcinomas (HCC), lung and pancreatic cancer.
The Medical Hospital in Tübingen harbors one of the very few facilities in the world with an established in vivo RNAi screening platform. Employing this technique, the molecular mechanism which leads to the development of resistance against Nexavar® (sorafenib) was discovered. Also, the activity of a protein kinase was identified as a molecular target and identified as being responsible for the resistance. Subsequently in collaboration with the Dept. of Pharmaceutical Chemistry, a drug substance which blocks kinase activity was discovered and, after testing in non-clinical safety studies, was successfully applied in patients with Sorafenib-resistant Hepatocellular Carcinoma. This example demonstrates our capacity for bench-to-bedside development of a new therapeutic concept, as illustrated in the scheme below.
Lars Zender Lab
