Cancer is one of the most devastating diseases of modern time. Because it is caused by cells from the patient’s own body, targeted therapy represents one of the grand challenges in cancer medicine. How can therapeutic strategies discriminate between “good” and “bad” and eliminate only the cancer cells without harming others?
In this project, we aim to combat cancer by targeting specific changes in the cancer cells’ outer membrane and microenvironment using pore-forming toxins (PFTs), proteins with unique structural plasticity. Expressed as soluble proteins, PFTs assemble into transmembrane pores upon binding to a target cell, disrupting their membranes and killing them in the process. PFTs are part of the bacterial arsenal of virulence factors that allow them to infect other organisms, but they are also expressed by higher organisms for defense against these intruders, giving rise to a structurally and evolutionarily diverse group of proteins that share the same functionality: Selectively kill target cells without causing self-harm. For this, PFTs have evolved regulatory mechanisms, such as binding of specific cell surface receptors, proteolytic activation or restriction of activity to specific environmental conditions. We will exploit these regulatory mechanisms in order to engineer designer PFTs highly selective towards cancer cell surface markers and the tumor microenvironment.
In addition, we are establishling a cancer-on-chip screening platform for characterizing drug candidates on complex cancer cell cultures. Over 90% of potential drugs fail in clinical trials, which shows that our pre-clinical tools for drug screening desperately require improvement. Microfluidics can miniaturize large-scale screening efforts for improved efficiency, and with recent advances in organ-on-chip technology, we will design a platform that provides an ideal framework for high throughput screening of drugs in a “close-to-life” context. This will allow more robust drug characterization in the pre-clinical phase compared to conventional cell models and will reduce the need for animal experiments, which are costly, slow and ethically complicated.
Taken together, this unique approach towards tackling cancer will provide new, innovative treatment approaches and new pre-clinical drug screening strategies, which will advance the state-of-the-art in both cancer therapy and drug development.
