A medication that specifically targets cancer cells and delivers its active agent without harming healthy cells – this was the pioneering vision of Nobel laureate Paul Ehrlich in the beginning of the 20th century. More than 100 years ago, the development of Ehrlich’s so-called “Zauberkugel” or “magic bullet” is still an enormous challenge. Long term disease control or cure remains the exception rather than the rule in the treatment of cancer. With more than 8 million deaths worldwide in 2012 based on the reports of the World Health Organization, cancer is still an enormous global health problem. Hence, efficient and well-tolerated cancer therapies are urgently needed. Current cancer therapies are usually accompanied by severe side effects. The reason for this is that active agents are used that are designed to poison and kill the cancer cells. Since these active agents are not able to distinguish between healthy and cancer cells, all cells in the human body are damaged.
In the frame of the EU-funded Horizon2020 Marie Skłodowska-Curie European Training Network MAGICBULLET, 15 Early Stage Researchers (ESRs) are working on gentle drug-conjugates to circumvent these severe side effects of chemotherapy. Their plan is to combine anticancer agents with a molecular “address label” that delivers toxic drugs to cancer cells only, while healthy cells are spared. For the development of such targeted cancer medication, the ESRs are attaching the toxic anticancer agent (payload) to a peptide (a small protein molecule-delivery vector). These delivery vectors recognize molecules that are typical for tumour cells, bind to them and deliver the payload, just as Paul Ehrlich’s “magic bullet”.
A few drugs of similar kind based on this principle are on the market as so-called Antibody-Drug Conjugates (ADCs). These conjugates contain antibodies, large protein molecules produced by means of biotechnology, as a delivery vector that specifically recognize molecular structures on cancer cells and deliver the anticancer drug to the tumour. However, ADCs have several limitations as in most cases they cannot penetrate the solid tumour efficiently. Besides that, the production process of such complex molecules is very challenging and leads to high manufacturing costs. In contrast, MAGICBULLET focuses on the development of much smaller protein molecules, peptides, for the transporter of the active agent as peptide-drug-conjugates (PepDC). Due to the hundredfold smaller size, PepDCs possess major advantages as the chemical production processes are much simpler than those for antibodies. In addition, peptides can take a higher load of active agent, easily penetrate tissue and can be produced in a highly purified form. Hence, the ETN MAGICBULLET pursues the following aims:
A. Application of peptides as homing devices addressing cell adhesion molecules or receptors that are highly abundant on cancer cells as a “delivery address”.
B. Attachment of different natural product-based toxins (paclitaxel, daunorubicin, cryptophycins, amanitins) to the homing peptide.
C. Combination of different moieties available in the Magicbullet network as a molecular toolbox to synthesize a large array of conjugates.
15 ESRs with strong backgrounds in chemistry, biology and biomedicine are hosted at Bielefeld University, University of Cologne, University of Milan, University of Insubria, University of Helsinki, Eötvös Loránd University, National Institute for Cancer Research Hungary and at the pharmaceutical companies Heidelberg Pharma and Exiris, supported by the industrial partners Italfarmaco, IRBM and Promidis, Bayer, Kineto Lab, as well as by the Optical Imaging Center Erlangen, Fraunhofer-Institute for Toxicology and Experimental Medicine and the Technical University of Darmstadt.
