Human peptide derivatives against cancer with poor prognosis

Despite all the progress in the design of cancer therapy there is no cancer treatment yet that is 100% effective against disseminated or resistant cancer. Besides occurrence of resistance, potential toxicity and other side effects of chemotherapeutics, which are mainly due to inadequate specificity for tumor cells, still represent a major limitation of this type of therapy. Therefore, the development of new anticancer drugs based on novel mode of actions with improved cancer cell selectivity and hence less toxicity is urgently needed. Furthermore, cancer with poor prognosis and treatability, like glioblastoma, a tumor to the brain, or malignant melanoma, metastatic skin cancer, demand for new effective treatment and will be the focus in this project. Increasingly the retrieval of more specific targets generally expressed within a certain tumor is a major issue in anticancer research. In the preceding project (FWF-P20760-B11) we were able to demonstrate that the negatively charged lipid phosphatidylserine that is specifically exposed by cancer cells and metastases represents such a uniform and novel target for cancer therapy. This yielded the important basis for the design of cationic antitumor peptides derived from human Lactoferricin. The follow up project will continue and finalize this promising new approach in cancer therapy based on host defense peptides, effector molecules of innate immunity. In the follow up project the aim is to use the knowledge gained in the in model and in vitro optimization process of the preceding project to finally select two lead compounds derived of human Lactoferricin that are highly active and selective for glioblastoma and melanoma. A basis for the selection will be the adoption of a specific secondary structure of the peptides. Structure activity relationship and mechanistic studies will be performed to gain information on the mode of action of cancer selective and non-selective peptides. Furthermore elucidation of the target in vitro and final peptide localization of the peptide on or in the target cell will be studied to learn about characteristic features of a highly potent antitumor drug. The influence of other membrane components, as mucines or the role of cholesterol and rafts will be studied regarding their influence on peptides` activity. Activity studies of the peptides on cell lines and primary cultures of human glioblastoma and malignant melanoma in vitro are followed by in vivo studies in mouse xenografts, to prove the biological relevance of the peptide activity. As has been shown in the preceding project and the work of other groups the putative peptide target PS is also present on many other cancer types and therefore the peptides are multiply applicable. The project aims at delivering sufficient in vitro and in vivo data for patent application and further development of the lead compound(s) by pharmaceutical industry.

The project FWF-P24608-B23 enabled the strong improvement of antitumor activities of derivatives of the human host defense peptide Lactoferricin, e.g. found in breast milk, against poorly treatable cancers of skin and brain, malignant melanoma and glioblastoma, respectively. Cancer is still one of the leading causes of death worldwide. In 2012 14.1 million people in the world were diagnosed with cancer, 8.2 million died therefrom. Existence or formation of resistance during treatment with chemotherapy, toxicity on normal cells and other side effects mainly derived from insufficient specificity, and reoccurrence and distantly localized metastases that cannot be reached by therapy so far, are still the main reasons, why the contemporary treatments are often not successful enough. Hence, the development of new anticancer therapies, based on novel and selective killing mechanism are of urgent need. In the preceding project FWF-P20760-B11 we were able to prove that cancer cells and metastases, as well as chemo-resistant cancers present a specific target on their surface in the form of the negatively charged lipid phosphatidylserine (PS). This delivered the important basis for the design and optimization of cationic antitumor peptides derived from human host defense.The developed peptide derivatives showed strongly increased activity against cells of different cancer types, as malignant melanoma and glioblastoma and even their metastases. Especially effectivity against so far not treatable metastases, stability in presence of blood components and ability to pass the blood brain barrier are of great advantage. Further toxicity against non-cancer cells is negligible at concentrations exhibiting high toxicity against cancer cells, a characteristic that benefits from derivation of natural human host defense. In that respect cancer toxicity of two peptides against melanoma was increased by 10-fold compared with its natural parent peptide Lactoferricin found in breast milk, with consistent low toxicity against healthy cells. We were also able to clarify the mechanism by which the peptides selectively interact with PS exposed by cancer cells, enter the cell via the PS key, localize within the cell where they induce cell suicide, so called apoptosis. This ability to die on command if necessary is a feature that most cancer cells have lost during their lifetime, a fact that causes the main problem with cancer. Of great impact on the success of the project were results concerning studies performed in a mouse tumor model of human melanoma and glioblastoma that showed that the peptides are not only able to inhibit tumor growth in cell culture but also in the living system (in vivo). After treatment the tumors showed strong regression or even completely disappeared. Application would be possible for all cancers, since the specific target PS is uniformly present on cancer surfaces independent on type. However in the described project the focus was laid on human malignant melanoma and glioblastoma, two cancers hardly treatable so far with poor prognosis.