Periodic Reporting for period 2 - MAGICBULLET (Peptide-Drug Conjugates for Targeted Delivery in Tumor Therapy)
Reporting period: 2017-01-01 to 2018-12-31
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.
Receptors present on the cell surface are a second promising target for directed cancer therapy under investigation. Especially breast and prostate tumours are frequently hormone-dependent. In most cases, these tumours produce unnaturally high amounts of hormone receptors on the cell surface, which makes them highly prone to hormone-induced growth upon binding even at low hormone concentrations. Receptors of the gonadotropin releasing hormone (GnRH) are one example of cell surface receptors that are in the focus of MAGICBULLET. These receptors are highly abundant in many kinds of tumours in contrast to healthy cells and they can be addressed selectively via its natural binding hormone GnRH. Conjugates of GnRH analogues with the cytotoxic drug daunorubicin showed a remarkable selectivity towards colon cancer cells, combined with fewer side effects compared to free daunorubicin. In the same way, other hormone receptors for somatostatin, vascular endothelial growth factor, prostate specific membrane antigen and the aminopeptidase N receptor are addressed for targeted cancer therapy. As a result, MAGICBULLET developed and validated a large array of completely new peptide-drug conjugates based on a highly combinatorial synthesis of different cytotoxic drugs, linkers and well-known or even novel peptide-homing devices. Preclinical assays are still ongoing and several highly promising conjugates could be identified for further development.