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.

Despite the continuing development of new and more efficient treatments, cancer remains the second cause of premature death worldwide. Multi-faceted interdisciplinary research efforts in industry and academia on different aspects of cancer have provided a knowledge basis for the development of novel therapeutic approaches. Paul Ehrlich, Nobel laureate in Physiology of 1908, had the early vision that a compound could be made to selectively target a disease-causing organism or tumor. A toxin for the particular tissue could be delivered by an agent of selectivity. Such an ideal therapeutic agent would be a "magic bullet" that only kills the target cells. This ETN initiative with the title Magicbullet::reloaded refers to Ehrlich’s bold idea and builds on the previous experience of the highly successful ETN MAGICBULLET (2015-2018, grant agreement No. 642004). As a consequence of the outstanding results, the ETN Magicbullet::reloaded will expand the field of investigation from peptide-drug conjugates (PDCs) to small molecule-drug conjugates (SMDCs) with a special focus on drugs capable to stimulate tumor immune responses and overcome resistance to immuno-therapy. The consortium has been substantially expanded to perfectly address the needs of the new research direction. The planned ETN will design and synthesize an array of SMDCs (including PDCs), also targeting less investigated tumor antigens, investigate their pharmacokinetic behaviour, their implication on the immune system, as well as their tumor selectivity and antitumor activity. The consortium brings together interdisciplinary expert knowledge in Organic Chemistry, Peptide Chemistry, Medicinal Chemistry, Drug Discovery, Biochemistry, Pharmacology and Cell Biology. This high complementarity is required for the different scientific tasks in the development pipeline. Vice versa, the recruited ESRs will be exposed to a challenging research environment leading to a broad range of scientific competences to be acquired.

Cancer is the second leading cause of death in Europe with an expected increase of about 25% by 2035. A wide and unacceptable variability in terms of access to research, innovation and quality care exists between and within countries. Possible solutions are an increase in knowledge by funding research, and a more equitable transfer of what we already know to everyone. Comprehensive Cancer Centers and Comprehensive Cancer Care Networks may be the core of CCIs that deliver quality care and provide resources to improve and integrate care, research and education. Data already available confirm that the level of "CCI maturity" in Member States is widely different, from some countries lacking CCIs completely. A European initiative, implemented in all Member States, based on a capacity building programme (CBP), will help reduce inequalities, in the context of other actions ongoing, such as CRANE, JANE and UNCAN. CBP is a complex intervention that requires multiple and integrated actions delivered to all the relevant stakeholders. CBP will be designed with an inclusive approach, tailored to the baseline status, capable of creating a change and improvement in research and care, with greater integration between them, supported by an education programme. It will operate at various levels: Individuals, Institutions and Systems. The CSA will implement the following steps: define CCI Maturity Model including quality indicators; profile the CCIs in each MS and a few ACs in terms of CCI presence and levels of maturity; design tailored CBP interventions, giving priority to MSs without any CCI; deliver online training courses open to teams in all MSs and ACs, implement targeted onsite interventions; scale up and sustain development; disseminate, exploit and report results. The CSA will maximize impact by bridging with the work of ongoing EU cancer research projects. National focal points will be key informants in making the links between the CSA, the EC and MSs.