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    Chair of Biochemistry and Molecular Biology

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

    Prof. Dr. Martin Eilers
    Prof. Dr. Lars Zender
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    The research group comprises tumor researchers working at the universities of Tübingen and Würzburg. The aim of the group is to identify and test new molecular targets for the therapy of solid tumors.

    Almost all current strategies to find new molecular targets rely on sequencing of tumor genomes and on finding proteins that are mutated in human cancer genomes. However, to drive unrestrained cell growth tumor cells also depend on a multitude of physiological adaptions, for example in tumor metabolism, in cell cycle control and in protein synthesis and degradation. These differences between normal and tumor cells offer molecular targets and open “therapeutic windows” that enable the selective eradication of solid tumors.

    This research group will therefore systematically survey basic cellular processes such as intermediary metabolism, protein translation or DNA replication to systematically identify genes and proteins, for which tumor cells show an altered dependence relative to normal cells and test whether they can be exploited to tumor therapy. To achieve this aim, researchers will use approaches that combine advanced in vitro and in vivo shRNA screening technologies in animal tumor models with state-of-the art imaging and multiple biochemical technologies.

    Projects

    TP01 - Professor Dr. Lars Zender

    Prof. Dr. Lars Zender

    Characterization and development of Rpl15 as a therapeutic target in liver cancer

    Hepatocellular carcinoma (HCC) represents a particularly aggressive and therapy resistant tumor type, for which new treatment approaches are urgently needed. Previous research has shown that inhibition of translation triggers cellular senescence, designated ribosomal checkpoint induced senescence (RCIS), in aggressive liver cancer cells but only a reversible cell cycle arrest in normal cells. The aim of the project is to dissect the mechanisms underlying RCIS induction in HCC. Furthermore, we will use direct in vivo RNAi screening technology to systematically probe factors involved in ribosome biogenesis and translation in order to unveil further vulnerabilities of cancer cells which might be exploited for cancer therapy.

    TP02 - Professor Dr. Nisar Malek

    APCcdh mediated turnover of the ER stress regulator gadd34 as target for tumor therapy

    Within this research proposal we are aiming to use ER stress responses as a target for cancer treatment. Liver cancers show an increased activity of the unfolded protein response (UPR) as a sign of increased ER stress compared to normal liver tissues. We have previously shown that degradation of the GADD34 protein by APCcdh1 is of central importance for the survival of stressed cells. Within this proposal we will study the roles of APCcdh1 and GADD34 in mediating the death of the stressed tumor cell. We plan to systematically map the stress response of liver cancer cells both in vitro and in orthotopic transplantation models and employ shRNA screening technology to find additional modulators of ER stress responses in liver cancer.

    TP03 - Professor Dr. Martin Eilers

    Prof. Dr. Martin Eilers

    Myc-dependent gene expression as a therapeutic target for solid tumors

    Myc oncoproteins contribute to the genesis of a majority of all human tumors. Myc proteins are transcription factors. Whereas normal cells express low levels of Myc proteins, many tumors depend on high-level expression of Myc for survival. Many strategies are currently being explored to target these proteins for tumor therapy. We have found that the high levels of Myc found in many tumors regulate a unique set of target genes that are not regulated by physiological Myc levels. The project uses models of colon and pancreatic cancer to explore whether these target genes and the cell biological processes they are involved in offer a new understanding of tumor development and new strategies to target both tumor types.

    TP04 - Professor Dr. Almut Schulze

    Prof. Dr. Almut Schulze

    Targeting lipid synthesis and NADPH regeneration in cancer

    In the proposed project, we will address the essentiality of lipid metabolism and NADPH regeneration in preclinical mouse models of cancer. We will use advanced functional genomics to systematically identify new targets required for tumour growth in vivo. Moreover, we will establish the consequences of target inhibition and define cellular stress responses that are indicative of desired therapeutic endpoints. The aim of the study is to identify targetable entities within essential metabolic processes that could be promising for drug development.

    TP05 - Dr. Svenja Meierjohann

    Exploiting ROS defense mechanisms as therapeutic target

    The maintenance of a functional redox balance is an essential cellular process. In most solid cancer types, oncogenic effectors and tumor-induced altered metabolic conditions constitute endogenous sources of reactive oxygen species (ROS). Consequently, tumors require strong anti-oxidant measures to counteract the elevated ROS production and ensure survival. Project 05 focuses on ROS defense mechanisms as therapeutic tumor targets by using various murine models of melanoma.

    TP06 - Professor Dr. Caroline Kisker

    Ubiquitin-mediated oncoprotein degradation as an essential druggable process

    The ubiquitin proteasome system controls the degradation of many cellular proteins including tumor suppressors and oncoproteins. Ubiquitin-dependent pathways have been exploited for cancer therapy, but current approaches are nonspecific and suffer from high toxicity. Deubiquitinating enzymes are attractive drug targets as they selectively modulate substrate degradation. The Usp28 deubiquitinase stabilises several key oncoproteins and promotes tumor development. In this project, we will investigate the potential of Usp28 inhibition in cancer therapy using mouse models of cancer, shRNA screening and crystallography.

    TP06 - Dr. Nikita Popov

    Ubiquitin-mediated oncoprotein degradation as an essential druggable process

    The ubiquitin proteasome system controls the degradation of many cellular proteins including tumor suppressors and oncoproteins. Ubiquitin-dependent pathways have been exploited for cancer therapy, but current approaches are nonspecific and suffer from high toxicity. Deubiquitinating enzymes are attractive drug targets as they selectively modulate substrate degradation. The Usp28 deubiquitinase stabilises several key oncoproteins and promotes tumor development. In this project, we will investigate the potential of Usp28 inhibition in cancer therapy using mouse models of cancer, shRNA screening and crystallography.

    TP07 - Dr. Mathias Rosenfeldt

    Identification of mechanisms that regulate tumor addiction to autophagy

    Our previous work has demonstrated that the tumor suppressor p53 determines the impact of autophagy, a cellular self-digestion process, during the development of pancreatic ductal adenocarcinoma (PDAC). Using a mouse model of the disease, we have shown that autophagy ablation prevents tumor development in wild-type p53 mice but accelerates tumor onset when p53 is absent. The aim of the current project is to identify mechanisms that allow p53-deficient PDAC cells to overcome autophagy inhibition and to analyse the role of autophagy in established and metastasized PDAC. We will use advanced RNA-interference screening technology to identify metabolic vulnerabilities of autophagy-deficient cancer cells in vitro and in vivo to devise novel strategies that could improve PDAC therapy.

    TP08 - Professor Dr. Martin Röcken

    Induction of p16Ink4a-dependent senescence arrest through exogenous signals

    Tumor cells have an enhanced propensity to undergo a permanent form of cell cycle arrest termed senescence and therapeutic induction of senescence may open a significant window of opportunity. Previous data from our laboratory have shown that simultaneous activation of interferon (IFN) and TNF-signaling causes p16INK4a-dependent senescence in cancer cells. In this project, we will study the molecular interactions between these pathways in cancer. We will use functional genetic screening to identify metabolic liabilities of cancer cells during IFN/TNF mediated senescence and investigate how the immune system clears senescent cancer cells. Targets identified through this approach provide the rationale for designing IFN-based combination therapies to induce a permanent growth arrest in tumors.

    TP09 - Dr. Daniel Dauch

    Targeting Rpa3 for cancer treatment

    The Replication protein A (Rpa) protects the ssDNA in the replication forks and prohibits replication catastrophe upon replicative stress. By applying shRNA-mediated knockdown of Rpa3 (a subunit of the Rpa heterotrimer) we observed that liver cancer- and pancreatic cancer growth can be efficiently decreased by Rpa3 suppression. Using a shRpa3 transgenic mouse strain, we could show that short-term knockdown of Rpa3 is tolerated by mice. TP09 aims to characterize the cellular stress response of tumor cells upon Rpa3 inhibition either alone or in a combinatorial therapy and to determine the potential of targeting Rpa3 in cancer therapy.

    TP09 - Professor Dr. Stefan Laufer

    Targeting Rpa3 for cancer treatment

    Structure-based design and synthesis of Small molecule inhibitors of Rpa-function

    Replication protein A (Rpa) constitutes the major single-stranded DNA binding protein in eukaryotic cells. It plays an important role in mainly all metabolic pathways of DNA, making it an outstanding target for cancer treatment. Rpa forms a heterotrimeric complex composed of three subunits: Rpa1,2 and 3. Targeting protein-protein interaction by small molecule inhibitors is considered very difficult. Rpa3 may host small molecules, preventing the formation of the complex and his functionality.

    Z01 - Prof. Dr. Martin Eilers, Prof. Dr. Lars Zender, Prof. Dr. Andreas Rosenwald

    ShRNA Screening and Histopathology

    Z02 - Prof. Dr. Bernd Pichler, Dr. Andreas Beilhack

    Multiparametric and Metabolic imaging

    Z03 - Prof. Dr. Martin Eilers, Prof. Dr. Lars Zender

    Coordination

    Contact

    Lehrstuhl für Biochemie und Molekularbiologie
    Am Hubland
    97074 Würzburg

    Phone: +49 931 31-84112
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