Perspectives of Targeted Radionuclide Imaging and Therapy of Fibroblast Activation Protein (FAP) in Cancer

Group Gourni   Tumors develop within a complex microenvironment consisted of diverse cell types surrounded by a matrix rich of proteins, termed tumor stroma. Stroma includes immune cells, fibroblasts and vascular enothelial cells. Cancer cells rely on extensive support from the stroma to survive, proliferate and invade, thus making stroma an important potential target for anti-cancer therapy. Targeting elements of stroma, may be a useful therapeutic strategy to prevent tumor growth and progression. One of those elements is the fibroblast activation protein (FAP) which is overexpressed on activated fibroblasts on several tumors types.
The current project aims at designing and evaluating novel FAP-specific inhibitors for the generation of radiotracers with the potential to be used for the diagnosis and treatment of FAP-positive tumors. The novel radiotracers are thoroughly investigated in vitro and in vivo using cell lines and xenografted tumor models to understand their binding properties and their in vivo performance.

Targeting cellular metabolism to augment cancer therapy

Group Marti   The aim of this project is to investigate how the nucleotide/lactate metabolism and the DNA damage response machinery are associated with the tumor initiating capacity, the chemotherapy response, and the metastatic capacity of lung and mesothelioma cancer stem cells. In addition, we are exploiting treatment induced cellular adaptations as novel targets for cancer therapy.

Towards understanding the role of the minor spliceosome in cancer

Group Rubin   Genes are composed of coding units (exons), interspersed with non-coding regions called introns. The process of protein production involves splicing together exons while removing introns from the mRNA molecule. Evolution has given rise to a cellular apparatus called the spliceosome, responsible for carrying out this splicing process. Alternative splicing enables the generation of diverse protein isoforms from a single gene. Splicing is tightly regulated under normal physiological conditions. Our recent findings indicate that cancer cells use a specialized spliceosome, the so-called minor spliceosome, to increase cancer relevant mRNAs. As such cancer hijacks the minor intron-splicing machinery to enhance the expression of transcripts containing minor introns. Proteins encoded by those genes have been shown to activate critical cell survival pathways such as cell cycle regulation and DNA repair. Exploiting the reliance of cancer cells on minor intron-containing genes presents a novel therapeutic opportunity for targeting cancer. By inhibiting the minor spliceosome, we can selectively induce cell death in cancer cells while sparing healthy neighboring cells.

Cancer cell motility supported by oncogene induced autophagy

Group Tschan   We discovered an oncogenic splice variant of the tumor suppressor and transcription factor DMTF1 active in the p53 pathway. We found that this splice variant, DMTF1β, promotes breast cancer cell motility by activating autophagy. We are currently unravelling mechanisms how DMTF1β is regulated and how it promotes cancer cell motility by activating autophagy. Our aim is to identify tumor types and cellular conditions where common cancer therapies in combination with autophagy inhibition is beneficial to block migration.