Molecular signaling pathways control tumor cell behavior and shape the cellular response to anti-cancer therapies. Our research focuses on how pro-oncogenic signals in medulloblastoma cells are initiated, processed and translated into a biological response. We specifically focus on kinase signaling pathways activated by receptor tyrosine kinases and adhesion receptors, which control actin dynamics, receptor turnover and cell motility. Our objective is to modulate pro-oncogenic signaling such that the capability of the tumor cells to migrate and invade is repressed.
FGFR signaling promotes growth and tissue invasion in medulloblastoma. We rationally designed and develop a small molecule targeting strategy to block pro-invasive FGFR signaling. We furthermore explore whether novel combinations of existing drugs could enable efficient blockade of pro-metastatic cell functions.
The coordinate remodeling of the actin cytoskeleton mediates motility and invasiveness of cancer cells. It is the interplay of a plethora of signaling pathway components that orchestrates the underlying control of actin cytoskeleton remodeling. We identify relevant signaling pathways that promote cell migration and tissue invasion in medulloblastoma and determine key molecular regulators in these pathways that act as therapy targets for existing drugs or novel compounds.
We develop a tissue model for pediatric brain tumor research that allows monitoring of cell behavior, tissue integrity and drug response in real time. Our established organotypic cerebellar slice culture system allows the end-point investigation of molecular mechanisms of tumor growth and tissue invasion and to test novel therapeutic approaches in a physiological environment ex vivo. Our objective is to develop this model further for real-time monitoring of biological responses in a physiologically relevant tissue environment.
Drug discovery: RaSMID
SNF Sinergia Project:
Rational Small Molecule Inhibition of Dissemination (RaSMID) for pediatric brain tumors
The lack of effective therapeutics that allow precise targeting of biological mechanisms promoting tumor progression still hampers the development of anti-metastatic therapies. The targeted disruption of protein-protein interaction (PPI) is an emerging concept in drug discovery, which might help to overcome this bottleneck. If successfully implemented, it offers a highly creative approach towards specific repression or subversion of protein functions under pathological conditions. Elementary prerequisites for the discovery of effective and safe small molecule PPI inhibitors are efficient computational (‘in silico’) screening, functional validation technologies and physiologically relevant model systems for monitoring biological consequences of compound effects and protein-protein interaction inhibition.
We apply this discovery approach to finding small molecular entities against medulloblastoma, the most common malignant pediatric brain tumor. With the expected lead structures targeting dissemination and the establishment of novel methodologies for bioactive compound validation, we hope to markedly contribute to ongoing efforts to provide patients with efficacious and save treatments in the future.
Our collaborators:
Prof. Gisbert Schneider, Computer-assisted Drug Design
Prof. Stephan Neuhauss, Neuhauss Group
Our funding sources: SNF, Swiss Cancer League/Krebsforschung Schweiz, Innosuisse, Kinderkrebsforschung Schweiz
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