Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - MAGICBULLET (Peptide-Drug Conjugates for Targeted Delivery in Tumor Therapy)

Teaser

A medication that specifically targets cancer cells and delivers its active agent without harming healthy cells – this was the pioneering vision of Nobel laureate Paul Ehrlich in the beginning of the 20th century. More than 100 years ago, the development of Ehrlich’s...

Summary

A medication that specifically targets cancer cells and delivers its active agent without harming healthy cells – this was the pioneering vision of Nobel laureate Paul Ehrlich in the beginning of the 20th century. More than 100 years ago, the development of Ehrlich’s so-called “Zauberkugel” or “magic bullet” is still an enormous challenge. Long term disease control or cure remains the exception rather than the rule in the treatment of cancer. With more than 8 million deaths worldwide in 2012 based on the reports of the World Health Organization, cancer is still an enormous global health problem. Hence, efficient and well-tolerated cancer therapies are urgently needed. Current cancer therapies are usually accompanied by severe side effects. The reason for this is that active agents are used that are designed to poison and kill the cancer cells. Since these active agents are not able to distinguish between healthy and cancer cells, all cells in the human body are damaged.
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 (ADC’s). 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, ADC’s 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 (Germany), University of Cologne (Germany), University of Milan (Italy), University of Insubria (Italy), University of Helsinki (Finland), Eötvös Loránd University (Hungary), National Institute for Cancer Research (Hungary) and at the pharmaceutical companies Heidelberg Pharma (Germany) and Exiris (Italy), supported by the industrial partners Italfarmaco, IRBM and Promidis (Italy), Bayer (Germany), Kineto Lab (Hungary), as well as by the Optical Imaging Center Erlangen (Germany) and Fraunhofer-Institute for Toxicology and Experimental Medicine (Germany). Since the beginning of the project in 2015, the doctoral students are meet

Work performed

The compounds synthesized within Magicbullet are aiming at molecules that are specific for tumour cells. One of the most prominent cell adhesion molecules that are addressed is the family of integrins. They are naturally present on the cell surface and are involved in the attachment of the cell to other cells and the extracellular matrix. Moreover, integrins are involved in the regulation of diverse cellular functions including migration, invasion and proliferation. Most notably, some members of the integrin family are usually present at very low levels in most adult cells but can be highly abundant in some tumours, which makes them highly promising targets in cancer therapy. Numerous conjugates with several variations of the integrin targeting peptide sequence L-arginine, glycine, L-aspartic acid have been synthesized. These homing devices are linked to different highly toxic drugs: amanitin, the toxin from the poisonous Green Death-Cap fungus, paclitaxel from the Pacific yew, or the extremely potent cytotoxin crytophycin originating from cyanobacteria (blue-green algae). The homing device and the toxin are connected via a linker moiety that is selectively cleaved once the conjugate has entered the cancer cell. As a result, the drug is only released in the tumour and not in the blood circulation where it could harm other cells. This selectivity could be shown for several conjugates in human cell culture and is currently further investigated. Conjugates possessing more than one targeting device have been synthesized to increase selectivity towards cancer cells and also cell-penetration peptides have been used to raise cell permeability.
Receptors present on the cell surface are a second promising target for directed cancer therapy under investigation in MAGICBULLET. 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 in MAGICBULLET.

Final results

Due to the modular setup of the conjugates, a variety of combinations of toxins, linkers and homing peptides have already been prepared within MAGICBULLET. The synthesized conjugates are tested in human cell culture to determine the selectivity and the efficacy in cancer treatment. Numerous highly active and selective conjugates have been identified and the most promising lead molecules are currently under further optimization. Several optimized conjugates will be patented, published in highly renowned scientific journals, and subjected to further evaluations in the near future.

Website & more info

More info: http://www.magicbullet.de.