The amino acid asparagine is crucial for tumor cell growth, and removing it exposes a weakness in cancer cells. While interaction with this has already given rise to promising drug synergies when combining drugs like asparaginase (OncasparTM) with signaling kinase inhibitors, it is of interest to decipher whether other pathway inhibitors can also enhance the effect of asparaginase against GI cancers. The TP53 tumor suppressor gene, often mutated in cancers, plays a major role in cell response to therapy. P53 activation with MDM2 inhibitors is being tested in clinical studies, however, the results remain often limited.

While the group of Matthias Dobbelstein has pioneered ways to boost the anti-cancer effects of MDM2 or CDK inhibitors, the group of Laura Hinze has expertise in exploring the functional interaction of asparagine levels with intracellular signaling.

By joining our forces, we aim to explore the synergistic activities of amino acid depletion on the one hand and inhibitors of MDM2 and CDK4 on the other hand. Leveraging a wide field of molecular biology, e.g. tissue culture, gene editing, assays for cell survival and death, RNA and protein analyses, the PhD- and MD-candidates of the first cohort will associate with the Hinze lab and will focus on how asparaginase and inhibitors of MDM2/CDK4 affects the proliferation, viability, and death of colorectal cancer cells. The PhD- and MD-candidates of the second cohort (Dobbelstein group) will then go on to assess p53 and E2F activities upon inhibition of MDM2 or CDK4 in naive as well as asparaginase-adapted CRC and pancreatic ductal adenocarcinoma cells.

Through these conceptionally aligning thesis projects, we aim to understand how the metabolic environment determines the therapeutic efficacy of CDK4 inhibitors.