Breast milk as a weapon against cancer
Many types of cancer respond well to treatment if detected early and treated with effective chemotherapy. But types that are poorly treatable include skin cancer and brain cancer (glioblastoma) as well as metastases, i.e. tumour cells spreading to remote parts of the body via the bloodstream. But even the most malignant cancer cell has a weak spot, an Achilles heel. Unlike healthy cells, the membrane enveloping cancer cells carries on its outer side negatively charged molecules, the lipid phosphatidylserine (PS). This means that PS can serve as a marker for cancer. With the support of the Austrian Science Fund FWF, a team from the Department of Molecular Biosciences at the University of Graz has developed a new weapon that selectively targets this Achilles heel.
Peptide arrow carved from breast milk
In a preceding FWF project, the team of principal investigator Dagmar Zweytick had already ascertained that the PS cancer marker was an appropriate target for anti-tumour medication, since it was detectable on membranes of various types of cancer and even metastases. In the present follow-up project, the team has now managed to hone a human defence peptide into an arrow that targets cancer cells. A modified and strengthened active part of the peptide lactoferricin, which is found in a precursor in breast milk, identifies various types of cancer cells, including melanoma and glioblastoma. The positively charged peptide arrows selectively locate the negatively charged PS-exposed on the surface of cancer cells, dock on to them and within a few hours induce cell death (a command that is otherwise blocked in cancer cells). The peptide variants do not, however, interact with healthy cells of the body.
Killing cancer without harming healthy cells
"The biggest challenge in the design process was to find the right balance of toxicity and specificity. If the peptides are made too active, they will also attack healthy cells. In control tests we always made sure that the peptides locate only cancer cells and leave normal cells untouched", explain principal investigator Dagmar Zweytick and postdoc researcher Sabrina Riedl. The biophysicist has been working on lactoferricin since 2002. A precursor of the small protein molecule is present in breast milk, a substance that not only nourishes a new-born child but also helps it build a strong antimicrobial defence system. As part of the innate immune system, lactoferricin is the body’s first defence reaction against negatively charged non-host cells such as bacteria and fungi, but also against mutated body cells, such as cancer cells. Before the defence peptide can be used as an anti-tumour weapon, it has to be rebuilt in a directed manner to be improved in its activity. Between July 2012 and June 2016, a team of five members worked on the ideal arrangement of the chemical building blocks (amino acids) of the active peptide constituent which is shaped like a hairpin. The team started the design process by simulating variants of promising activity levels in a computer model. About fifteen variants of the substance were synthesised on the basis of these designs and then tested on membrane models and "in vitro" on cancer cell lines.
Tumour regression in the mouse model
In collaboration with Beate Rinner from the Medical University of Graz, the two most auspicious variants were tested "in vivo". The researchers compared peptide-treated and untreated mouse xenotransplants (mice growing human cancer cells). In the cancer mice treated with peptide, the researchers observed a strong or even complete regression of the tumours, achieving an average of 85% regression in the case of melanoma and up to 50% in the case of glioblastoma when compared with untreated cancer mice. A third control group of healthy mice remained unharmed when treated with the agent. The modified variants showed an effectiveness about ten times greater than the original breast milk peptide.
The active peptide variants with an anti-tumour effect have already been patented in the EU and the USA (respectively are patent pending). The team around Dagmar Zweytick is now collaborating with a pharmaceutical company in the context of a project financed by the Austrian Research Promotion Agency FFG in preparation of pre-clinical studies. The new anti-tumour agent should preferably be administered intravenously so as to reach metastases as well. Issues being currently tested include how stable the peptide arrow is in the blood system, whether it can cross the blood-brain barrier and how the arrowhead can be sharpened further.
Dagmar Zweytick (https://molekularbiologie.uni-graz.at/en/research/areas-of-research/biophysics/), assistant professor at the Institute of Molecular Biosciences (https://molekularbiologie.uni-graz.at/en/) at the University of Graz, heads the anti-tumour-peptide research group in the biophysics division. She studied technical chemistry and acquired her PhD in biochemistry and food chemistry at the University of Technology in Graz. During ten years as a senior scientist at the Austrian Academy of Sciences she already focused on defence peptides.
Riedl S., Leber R., Rinner B., Schaider H., Lohner K. and Zweytick D.: "Human lactoferricin derived di-peptides deploying loop structures induce apoptosis specifically in cancer cells through targeting membranous phosphatidylserine", in Biochim. Biophys. Acta 1848 (11) (2015) 2918-2931. http://doi.org/f3sxf9
Riedl S., Rinner B., Schaider H., Lohner K. and Zweytick D.: "Killing of melanoma cells and their metastases by human lactoferricin derivatives requires interaction with the cancer marker phosphatidylserine", in Biometals 27 (5) (2014) 981-997. http://doi.org/f3sqdp
Riedl S., Rinner B., Asslaber M., Schaider H., Walzer S., Novak A., Lohner K. and Zweytick D.: "In search of a novel target – Phosphatidylserine exposed by non-apoptotic tumor cells and metastases of malignancies with poor treatment efficacy", in Biochim. Biophys. Acta 1808 (2011) 2638-2645. http://doi.org/d5zsdk
Image and text will be available as of Monday, 10th April 2017, from 9.00 am CET at: http://scilog.fwf.ac.at/en
Ass.-Prof. Dr. DI Dagmar Zweytick
University of Graz
Institute of Molecular Biosciences
8010 Graz, Austria
T +43 / 316 / 380 4988
Austrian Science Fund FWF
Haus der Forschung
1090 Vienna, Austria
T +43 / 1 / 505 67 40 - 8117
PR&D – Public Relations for Research and Education
1090 Vienna, Austria
T +43 / 1 / 505 70 44
The purpose of the FWF is to support the ongoing development of Austrian science and basic research at a high international level. In this way, the FWF makes a significant contribution to cultural development, to the advancement of our knowledge-based society, and thus to the creation of value and wealth in Austria.
Austrian Science Fund FWF
Haus der Forschung
1090 Vienna, Austria
T +43 / 1 / 505 67 40 - 8117
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