Cancer is a leading cause of death in Europe. The process of cancer development is driven by the activation of specific cancer-causing genes, so-called oncogenes. This results in the reprogramming of normal cells and lets them acquire common functional hallmark of cancer. Most cancers are still treated by surgically removing the tumour, killing tumour cells by irradiation or chemotherapy. In many cases, tumour growth can initially be kept under control, but disseminated tumor cells may become insensitive to the treatments and seed metastasis, which are hard to control and commonly lead to the death of the patient. Over the past 20 years, so-called targeted anti-cancer drugs entered clinical practice. These targeted drugs act specifically on the gene products of the cancer-causing oncogenes – the oncoproteins. In a few cases these new treatments resulted in a therapeutic breakthrough. In contrast, the majority of targeted drugs suffer from short-lived responses due to drug resistance. In addition, the majority of oncoproteins remain untargeted. Therefore, novel approaches are needed to broaden the variety of targeted oncoproteins. This is expected to result in therapies with less side-effects and a better survival of cancer patients.
My lab has pioneered studies to target oncoproteins with monobody proteins. Monobodies are small engineered binding proteins that can be regarded as mini-antibodies. This makes them much easier to handle and to produce. Monobodies can be developed in the laboratory and do not require the immunization of animals. On the other hand, monobodies display most pharmacologic features of antibodies, which include a highly specific interaction and the tight binding to its targets. We demonstrated that monobodies can be developed to several oncoproteins for which no specific drugs exist. However, major questions regarding the possible use of monobodies as precision cancer therapeutics remain to be answered. In particular, it is unclear, if monobodies can be be engineered to enter cancer cells in sufficient quantities. In addition, the pharmacokinetics and immunogenicity of monobodies is completely unexplored.
In this ERC project, my lab developed monobodies to oncoproteins for which no chemical inhibitors or drugs exist. We developed new technologies to deliver monobody proteins into cancer cells. 'Mirror-image' monobodies were for the first time developed and we showed their improved stability and better pharmacological behaviour. Finally, we determined and improved the plasma stability and biodistribution of monobodies. The overall objectives of the project were achieved, and we made great progress towards our goal to establish monobodies as a novel class of intracellular protein-based therapeutics.
