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.

Antibody-Drug Conjugates (ADCs) are fast growing classes of oncology therapeutics. They consist in a highly potent cytotoxic drug connected via a linker to an antibody that is specifically targeting certain tumor markers. By combining the cytotoxicity of the drug and the targeting properties of the antibody, ADCs kill cancer cells whilst leaving the healthy cells unaffected, a marked improvement compared to classical chemotherapies. However, limitations still exist which could fuel the development of new generations of ADCs with improved therapeutical properties. Targeted Anti-Cancer Therapies (TACT) is an innovative, international, multidisciplinary training and research programme which thus aims to train 11 Early- Stage Researchers (ESRs) on the development of state-of-the-art anti-cancer therapeutics and equip them with transferable, future career-enhancing skills to create the next generation of experts in Europe. More specifically, TACT’s research programme will focus on key priorities for the conception of new and more potent generations of Protein-Drug Conjugates (PDCs): site-specific bioconjugation methods, more potent payloads, environment-specific cleavable linkers, more efficient protein-based targeting systems and new analytical tools for acute characterization. This will be achieved by exposing the ESRs to the leading intersectoral research scientists and laboratories in Europe who are active in this field. In doing so, TACT combines state-of-the-art research with excellent training in PDCs, one of the hot topics in cancer and targeted therapies.

pHioniC brings together highly synergistic expertise, research and training facilities to investigate pancreatic ductal adenocarcinoma (PDAC), a frequent and aggressive cancer that is still incurable. The programme’s central hypothesis has a strong grounding in the physiology of the exocrine pancreas. Secretion of the alkaline pancreatic juice, normally associated with digestion, leads to acidifications of the pancreas stroma resulting in an acid adaptation of pancreatic cells. We are first to propose that this adaptation facilitates PDAC initiation and progression by selecting for more aggressive phenotypes in interplay with PDAC driver mutations. pHioniC will: (i) develop models (e.g. pancreas-/PDAC-specific pH-indicator mouse) to map the pH landscape in the normal and diseased pancreas, (ii) characterize the impact of the acidic microenvironment in PDAC development and (iii) design bespoke approaches to the treatment of PDAC that exploit the unique physiology of the pancreas and utilize a combination of nanocarrier and antibody technology for targeting. Thereby, pHioniC provides an innovative interdisciplinary and intersectoral training for ESRs at the forefront of oncological research. pHioniC comprises excellent complementary basic-research, clinical, and in silico laboratories that provided the seed discoveries for this novel concept, and industrial partners with a track record in therapeutic and diagnostic development in oncology. This highly synergistic team combines the state-of-the-art research tools and translational opportunities needed to meet the most ambitious doctoral programmes. pHioniC training for ESRs covers the fields of ion transport, oncology, imaging, bioinformatics and antibody technology, and is complemented by extensive transferable skills and personalised training elements. pHioniC will establish a lasting contribution towards European doctoral training beyond the lifetime of the project.

Deregulated nicotinamide adenine dinucleotide (NAD) biosynthesis and signaling underlies many aspects of carcinogenesis. NAD biosynthetic enzymes, such as nicotinamide phosphoribosyltransferase (NAMPT) and nicotinic acid phosphoribosyltransferase (NAPRT), are commonly upregulated in cancer cells, where they fuel increased metabolic demands and downstream enzymes involved in DNA repair and in the promotion of cell growth, cell motility, de-differentiation and immune escape. In addition, NAD-producing enzymes, such as NAMPT, moonlight in the extracellular space, exerting strongly pro-oncogenic, autocrine and paracrine effects. Many of these roles of NAD-producing and NAD-utilizing enzymes appear to be shared between solid and haematological cancers. Thus, agents targeting NAD production or signaling are expected to have broad applicability. INTEGRATA will: 1. develop new NAD biosynthesis and NAD/nucleotide signaling inhibitors; 2. assess pharmacology and toxicity of the new therapeutics in preclinical models; 3. achieve the proof-of-concept of activity of the newly generated agents in relevant in vivo cancer models. INTEGRATA will train 14 PhD students in an overarching, interdisciplinary training programme that will include training-by-research, joint courses of technical, scientific, and transferrable skills, active participation to public scientific events, and an intense intersectoral networking exchange plan. The INTEGRATA Consortium encompasses academic institutions, research centres, and SMEs/biotech pharma, all with proven experience in higher education and training, and geared with state-of-the-art scientific and technical expertise and infrastructures.

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.