Stimulating the immune system to eradicate cancer is an attractive strategy that has been met with limited clinical success due to drug resistance issues. This indicates the need for novel approaches to reactivate anti-tumor immune surveillance as most tumors are poorly immunogenic. To address this problem, scientists of the EU-funded Magicbullet::Reloaded project are exploring new tumor antigens as drug targets. The idea is to develop small molecules that not only induce specific anti-tumor immune responses but may also complement existing immunotherapy strategies. Undoubtedly, therapeutics that selectively kill cancer cells is the way forward in cancer therapy

The ETN MAGICBULLET consortium is composed of scientific teams from various European universities, research institutions and companies. In the first funding period, so-called small molecule drug conjugates (SMDCs) were successfully produced. Here, instead of antibodies as in ADCs, small molecules were used for tumor targeting and coupled with different payloads. The potential advantage of such SMDCs is better penetration of solid tumors. Heidelberg Pharma successfully produced Amanitin-based SMDCs and demonstrated their efficacy in vivo (Gallo, et al. J. Med. Chem. 64, 4117-4129).

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. New tumor antigens will be identified, and their pharmacokinetics, selectivity and antitumor activity will be investigated.

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.

The INTEGRATA Consortium encompasses academic institutions, research centers, 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.

pHioniC is an innovative training network on the role of pH and ion transport proteins in pancreatic cancer. 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 program’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 programs. pHioniC training for ESRs covers the fields of ion transport, oncology, imaging, bioinformatics and antibody technology, and is complemented by extensive transferable skills and personalized training elements. pHioniC will establish a lasting contribution towards European doctoral training beyond the lifetime of the project.

Antibody-drug conjugates (ADCs) represent the fast-growing class of cancer therapeutics. They consist of a highly potent cytotoxic drug linked 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 selectively kill cancer cells.

The EU-funded TACT project is an innovative, international, multidisciplinary training and research program designed to train 11 early-stage researchers in the field of anti-cancer therapeutics, creating a new generation of experts. Specifically, the TACT research program will focus on key principles of the development of a new and more potent generation of protein-drug conjugates employing site-specific bioconjugation methods, environment-specific cleavable linkers, more efficient protein-based targeting systems and new analytical tools for protein characterization.