It is estimated that ninety percent of deaths from breast cancer are due to complications from metastasis, a process in which cancer cells break away from where they first formed, travel through the blood or lymphatic circulatory system, and form new metastatic tumors in other parts of the body.
With no effective treatment to prevent this process, there is a need to target not only the primary tumour, but also its metastatic potential when highly invasive. Types of breast cancer and/or breast cancer at an advanced stage.
Cancer cells use foot-like protrusions called invadopodia to break down underlying tissue, enter the bloodstream and form metastases in other organs. Nearly four years ago, Dr. Hava Gil-Hen and researchers from the Azrieli School of Medicine at Bar-Ilan University in Israel revealed two important clues about the formation of invasives: the cellular level of the proteins Pyk2 and cortactin increased suspiciously when the cell entered its malignant stage, but when the cell was lost Its ability to produce Pyk2, no metastasis was ever observed.
In a recent study expanding on this finding, Dr. Gil Henn and Professor Jordan Chill, of the Department of Chemistry at Bar-Ilan, described the interaction between partner proteins and demonstrated that this interaction is a prerequisite for the formation of metastasis to cancer cells. Moreover, they identified the mechanism by which the cortactin-Pyk2 interaction affects the formation of invasins and determined the structure of the complex between these two proteins. And published in the journal the results of the research team, which included d. Shams Tawfara and Dr. Shana Sokolik. Oncology.
In the latest study, the researchers determined the exact fraction of the protein involved in the interaction between Pyk2 and cortactin. The small fragment, known as the peptide, was synthesized in the laboratory and given to mice with breast cancer. The synthesized peptide successfully competed with the natural Pyk2 protein for the ‘attention’ of cortactin and prevented Pyk2 from accessing it. This prevented the formation of foot-like invasions of the legs, and as a result, the mice’s lungs remained healthier, with very few, if any, metastases.
We were very excited to see that the idea of using a cortactin-binding motif of Pyk2 as an inhibitor of ligand invasion worked in vivo very good. This helped demonstrate the clinical potential of the newly discovered interaction inhibition.”
Dr.. Hava Gil Henn, co-author of the study
Amazingly, all of this was achieved using a very small fragment of Pyk2, spanning only 19 of its 1009 amino acid building blocks. This, as observed, resulted in reduced lung metastasis in a murine model of breast cancer. In addition, it significantly reduced the invasiveness of breast tumor cells, stopped the maturation of invasives in tumor cells, and decreased the rate of actin polymerization, which is essential for the progression of invasive formation. All these results together provided unequivocal evidence that the 19 amino acid peptide does indeed prevent malignancy.
Professor Jordan Chill, who specializes in determining the three-dimensional structure of proteins, joined the research team to determine how the peptide prevents metastasis. “The process of developing a successful drug from an inhibitory peptide is very tedious and almost impossible to complete without structural insight into the complex between the peptide and its target, which in this case is cortactin,” says Professor Chell. Through a nuclear magnetic resonance experiment known as NOESY, each of the 881 atoms of the cortactin protein and 315 atoms of the peptide were located, creating a 3D image of the structure. The spatial location of the atoms is the secret to understanding the strength of the bond between proteins, which is critical to creating a drug that effectively blocks this bond. To illustrate, he found that amino acid #10 in the peptide fits right into the “hole” in cortactin and should not be altered, while amino acid #11 faces out and its exact identity is less important.
Dr. Gil-Hin and Professor Schell are now focusing on turning the peptide into a better drug candidate. Different amino acid sequences are being tested to produce a product that provides stronger and more specific binding at the target site of cortactin. Specificity is critical because the site in cortactin where binding occurs, known as SH3, is similar to SH3 sites in other proteins, and any unwanted binding to another protein may cause side effects.
The combination of cellular biology (discovering the two proteins and demonstrating that we can effectively prevent metastases) and structural biology (giving us the how and why of this binding event) brings science very close to combating breast cancer in a way that has not been possible before. Researchers hope that this advance will lead to the development of a drug that inhibits metastasis and become part of available therapeutic approaches to improve survival and quality of life for patients diagnosed with invasive breast cancer and other metastatic cancers.
This research was funded by the Israel Cancer Research Fund and the Israel Cancer Society (Dr. Gil-Hin) and grants from the Israel Science Foundation (to Dr. Gil-Hin and Prof. Chell).
Availability, s. et al. (2022) A novel peptide derived from Pyk2 inhibits breast cancer metastasis. Oncology. doi.org/10.1038/s41388-022-02481-w.