Chemotherapy has been and remains to be the most powerful tool to treat cancer, and, despite all progress of recent years, research continues to find new chemotherapy drugs as well as new uses for existing ones. The concept of targeted therapy aims at identifying mechanisms which are highly critical for the survival and growth of cancer cells while being less relevant for normal cells.
RNA interference (RNAi) technology is a powerful tool and nonbiased approach for identifying genes whose suppression affects cell proliferation and viability. Although genome-wide RNAi screens have been widely used for the identification of new therapeutic targets in cancer, these screens are technically challenging, tedious, and error-prone because of the high complexity of the short-hairpin RNA (shRNA) libraries.[1] 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 (Prof. Lars Zender’s laboratory) 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), the only available targeted therapy of HCC, was elucidated and the activity of a protein kinase has been identified as molecular target and being responsible for the developed resistance.[2] Subsequently, in collaboration with the Dept. of Pharmaceutical Chemistry (chair: Prof. Stefan Laufer), a drug substance, which blocks the activity of this kinase was discovered and after testing in non-clinical safety studies, successfully applied in patients with HCC and a developed resistance against sorafenib treatment. This example demonstrates Tübingen’s capacity for bench-to-bedside development of a new therapeutic concept, as illustrated in the scheme below.
