This project has received funding from the European Union′s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 642004.
Many tumor cells are characterized by the overexpression of certain antigens. Molecules that specifically recognize these structures are suitable as homing devices in tumor therapy. Conjugates of anticancer drugs with such a delivery vector targeting tumors would be a "magic bullet" according to the Nobel laureate Paul Ehrlich. Three antibody-drug conjugates (ADC) have already been approved for anticancer therapy. However, ADC have e.g. limitations with respect to tumor penetration, high manufacturing costs, and require challenging conjugation chemistry. Peptide-drug conjugates can have a high drug loading, easily penetrate tissue, and can be easily prepared in a homogenous form with straightforward and well-defined conjugation chemistry.
The ETN MAGICBULLET will focus on chemistry-driven approaches toward conjugates between peptides (delivery vectors) that recognize tumors and anticancer drugs (payloads or warheads) in order to selectively fight cancer, a topic with a high demand of research activities. The ETN will develop and validate an array of new peptide-drug conjugates combining either known tumor-specific peptides or newly discovered tumor-homing peptides with potent cytotoxic drugs. The tumor-selective peptides are designed for cellular uptake mediated either by endocytosis or by cell-penetrating peptides. The consortium of the ETN MAGICBULLET covers tumor biology, biochemistry, pharmacology, synthetic chemistry, medicinal chemistry, spectroscopy, conformational analysis, and computational chemistry. The training program focuses on multidisciplinary research to explore and validate molecular targets for innovative treatment or investigations on the molecular mechanisms in organ-specific metastatic growth processes. It aims at scientific multilingualism and relies e.g. on concerted learning, a combination of introductory training, hands-on learning "on the bench", teaching by peers, and training in additional skills.
The ETN MAGICBULLET will
identify, modify, and validate tumor-selective peptides for known and new cell surface receptor targets (e.g. integrins, VEGFR, cadherins);
study different linker systems for release of the anticancer payloads at the appropriate site;
conjugate known and new anticancer agents or drugs to tumor-selective peptides;
investigate the biological activity in vitro and in vivo to demonstrate their efficacy.
The combination of an array of tumor-selective peptides targeting different receptors and different uptake mechanisms with diverse antitumor drugs acting on different cellular targets is a powerful strategy to minimize potential risks and increase the efficacy. Because the number of receptors on tumor cells is limited, the combination of different target peptide–drug conjugates may enhance the bioactivity. The influence of the treatment schedule of such combination therapy on the antitumor activity will also be evaluated.