You have a completed Master's degree (or equivalent) in:

• Pharmaceutical Sciences
• Biochemistry
• Chemical Biology
• (Molecular) Biology

The language of the doctoral school is English; therefore English is required, German is an advantage.

Further expectations are:

• Experience in molecular biology, biochemistry and/or chemical biology and a passion for drug discovery.
• A deep interest and an enthusiasm for scientific work.
• A critical and analytical mind Ability to work responsibly, reliably and independently perform experiments.
• Ability to work in a multidisciplinary team within the group and with external collaborators.
• A passion for training colleagues and students in the laboratory.
• Experience in the most commonly employed techniques in the laboratory (see Approach / Methods section).
• Programming skills in python and R with experience in statistical data analysis are an advantage.

Lung cancer is the most prevalently occurring and deadly cancer, whereby 85% of cases are NSCLC. A common drug target in NSCLC is the EGFR, since it frequently hosts activating mutations in patients. Mutated EGFR can be targeted over the wild-type version with covalent drugs, such as afatinib and osimertinib, which are anchored to the protein through a Michael reaction between the reactive element (‘chemotype’ or ‘warhead’) acrylamide and C797. These sophisticated drugs, however, fall prey to the high adaptability and evasiveness of NSCLC. Two key resistance mechanisms exist: 1) genetic alterations, such as ON- or OFF-target mutations; and 2) phenotypic plasticity which is based on non-mutational epigenetic reprogramming and leads to cell state transitions. A key example for the latter is the epithelial-to-mesenchymal transition (EMT), which is connected to enhanced H₂O₂ signaling and sets the foundation for metastases and drug resistance.

Hydrogen peroxide (H2O2) is a second messenger that mediates e.g. phenotypic plasticity, cell proliferation and drug resistance by relaying signals onto proteins through the installation of oxidative posttranslational modifications (oxPTMs) on cysteines, such as sulfenic acid. To modulate cell proliferation, H2O2 signaling is highly interconnected with kinase signaling. The activation of the EGFR, for instance, leads to NOX2-mediated H2O2 production which sulfenylates the EGFR at C797 thereby enhancing its kinase activity in a positive feedback loop. However, since the C797 thiol serves as an anchor for the inhibitors afatinib and osimertinib, the installation of an oxPTM hinders the covalent labelling of the protein and establishes a resistance against the drugs.

The projects harnesses state-of-the-art chemical biology, biochemistry and molecular biology methods. The most commonly used techniques in the laboratory are cell culture, molecular cloning, flow cytometry, (chemo)proteomics, biochemical assays and western blots. We consider programming skills in python and R with experience in statistical data analysis as a bonus. We encourage students to apply who have experience with most of these methods and are excited to expand their skillset with the approaches that they are not yet familiar with. Programming skills in python and R with experience in statistical data analysis, especially with large omics datasets, are a strong bonus.

We are a young and enthusiastic team that is focused on developing new treatments against drug resistant and metastatic states of lung cancers by working at the interface of, cancer chemical biology, (chemo)proteomics medicinal chemistry and chemical methodology development. The project is strongly connected to the key goal of the group to study phenotypic plasticity with regard to cancer progression, hydrogen peroxide signaling and ferroptosis. The group is currently transitioning from the Ludwig Maximilian University (LMU) Munich to the University of Vienna. For more information, visit: https://konrad.cup.uni-muenchen.de/.

"Epithelial-mesenchymal transition and H₂O₂ signaling – a driver of disease progression and a vulnerability in cancers", Anna V. Milton, D. B. Konrad*, Biol. Chem. 2022, 403, 377-390. DOI: 10.1515/hsz-2021-0341