How our Switch lab plans to catch tumors in a spider’s web

17 February 2017
​Boiled eggs, beer foam and spider silk might seem unrelated at first glance. However, their proteins all share a similar structural element: amyloid. Although these ‘clumps’ of proteins are usually associated with disease development, their properties could be used to fight a wide array of conditions. Enter Pept-inTM: a brand-new technology platform that exploits the power of protein aggregation to develop novel medicines. Credits go to our Switch Laboratory (VIB-KU Leuven) and inventors Frederic Rousseau and Joost Schymkowitz (VIB-KU Leuven).

The first validated result of this new technology is called vascin, a designer amyloid that targets a well-known cancer protein. In short, vascin penetrates a cell and induces the formation of protein aggregates of its target protein, VEGFR2. These ‘clumps’ are the result of VEGFR2 proteins sticking together, making them nonfunctional. Because VEGFR2 is crucial to the survival of certain cancer types, its inactivation kills the cancer cells and reduces the tumor’s growth.

Fighting human and plant diseases
The principle of using amyloids to destroy the function of cancer drivers? “Like catching oncogenic proteins in a spider’s web,” Frederic sums up. “But Pept-inTM is valuable beyond cancer applications as well. Because these principles apply to virtually any protein, our approach may also be useful in treating drug-resistant infections. Although we don’t yet know if functional amyloids could be used in humans for therapeutic applications, the potential for novel drugs is huge. Our team will now spend the coming years trying to turn this into direct benefits for patients.”

Apart from fighting tumor growth, the Switch Lab collaborated with several research groups, both inside and outside VIB, to demonstrate that this technology could also be suitable for a variety of other applications. These include treating drug resistant bacterial infections (in collaboration with Johan Van Eldere, KU Leuven), combatting fungal infections (in collaboration with the Patrick Van Dijck lab, VIB-KU Leuven) and even engineering improved crops (in collaboration with the lab of Jenny Russinova, VIB-UGent).

The journey towards Pept-inTM
Of course, developing an entirely new technology platform did not happen overnight. The idea was first formulated shortly after the publication of the TANGO algorithm in 2004, used to predict protein aggregation. It is based on the short stretch hypothesis of protein aggregation, which states that short aggregation prone regions in a protein drive its aggregation in a sequence-specific manner.

“In an era where the entire field was working to prevent aggregation, our lab turned things upside down,” remembers Joost. “After all, we were trying to induce the controlled aggregation of specific target proteins. Although we wanted to understand the difference between functional and pathological aggregation, the potential implications of such a protein knock-down technology were immediately apparent. Turning the idea into practice, however, turned out to be much more challenging than initially anticipated and required many steps of technical innovation and fine-tuning.”

After a decade of intensive research, the Switch team was able to disclose information, eventually leading to a publication in the peer-reviewed journal Science. Meanwhile, the technology was subject to broad patent protection.

New business strategies
In close collaboration with the Switch Lab, VIB’s tech transfer team is actively pursuing the translation of this top science achievement into societal value. According to Els Beirnaert, Senior Manager New Ventures VIB, Pept-inTM differentiates itself in many aspects from competing platforms. Els: “Its novel mode of action and designability and potential to knock down challenging intracellular disease targets make this technology an attractive basis for the development of groundbreaking medicines for a variety
of diseases.”


Publications
Science Paper
Gallardo et al., Science in press 2016

Paper with Van Eldere Lab
Bednarska et al., Mol Microbiol 2015

Plant paper with Jenny Russinova Lab
Betti et al., Plant Physiology 2016


From left to right: Filip Claes, Frederic Rousseau, Ladan Khodaparast, Joost Schymkowitz, Rodrigo Gallardo, Laleh Khodaparast, Frederik De Smet and Matyas Desager