FOR 2314:  Targeting therapeutic windows in essential cellular processes for tumor therapy

• Subject Area: Medicine ; Biology
• Term: from 2015 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 267467939

The research unit aims to identify and validate novel targets for the therapy of solid tumors using a combination of genetic and small molecule-based strategies. The research unit is based on the recognition that cancer cells, in addition to mutated oncogenic driver genes, depend on a broad range of cellular processes due to the selective pressure to proliferate and survive under suboptimal growth conditions. As consequence, tumor cells share characteristic changes in physiology and rely on specific stress support pathways independently of the specific aggregate of mutations that are present in an individual tumor. The research unit aims to exploit such tumor-specific vulnerabilities for therapy. To achieve this, we have built up an experimental pipeline that includes a series of advanced mouse models of human solid tumors, in vitro and in vivo shRNA screening of focused shRNA libraries, standardized assessment of cellular stress responses in cultured cells as well as the visualization of metabolic alterations and stress responses in vivo. Exploiting this pipeline, we have identified tumor cell-specific and therapeutically exploitable dependencies on proteins involved in the MYC transcriptional pathway, in protein translation, intermediary metabolism, ubiquitination and protein turnover, DNA replication. We have also followed observations that the interaction of tumor cells with immune cells elicits tumor cell-specific stress responses that can be triggered for therapy. In several instances, tool compounds have become available or have been generated as part of our work that enable us to explore whether targets defined by genetic tools (e.g. by shRNAs) can be targeted by small molecules. In the next funding period, we propose to continue work on some of the previously identified molecular targets and to explore new targets that were identified by members of the research unit during the last funding period.

• DFG Programme: Research Units

Projects

• Coordination Funds (Applicant Zender, Lars )
• Exploiting ROS defense mechanisms as therapeutic target (Applicant Meierjohann, Svenja )
• Induction of p16Ink4a-dependent senescence through exogenous signals (Applicant Röcken, Martin )
• Inhibierung von HECT-Ligasen zur Krebstherapie (Applicants Laufer, Stefan ;  Lorenz, Sonja Gisela ;  Popov, Nikita )
• Multiparametric Imaging and Molecular Probe Design Platform (Applicants Pichler, Bernd ;  Poso, Antti )
• ShRNA Screening and Histopathology (Applicants Eilers, Martin ;  Rosenwald, Andreas ;  Zender, Lars )
• Targeting lipid synthesis and NADPH regeneration in cancer (Applicants Dauch, Ph.D., Daniel ;  Schulze, Almut )
• Targeting metabolism and autophagy to treat pancreatic cancer (Applicant Rosenfeldt, Mathias )
• Targeting MYC-driven hepatocellular carcinoma via Aurora-A ligands (Applicants Eilers, Martin ;  Laufer, Stefan ;  Zender, Lars )
• Targeting MYC in pancreatic cancer (Applicant Eilers, Martin )
• Targeting oncogene-driven translation and integrated stress response signaling in Cancer (Applicants Malek, Nisar Peter ;  Wiegering, Armin )
• Targeting oncoprotein stability for cancer therapy (Applicants Kisker, Caroline ;  Popov, Nikita )
• Targeting Rpa3 for cancer treatment (Applicants Dauch, Ph.D., Daniel ;  Laufer, Stefan )
• Therapeutic Induction and Image Guided Exploitation of Cellular senescence for Cancer Therapy (Applicants Pichler, Bernd ;  Zender, Lars )

• Spokesperson: Professor Dr. Lars Zender