DISINTEGRINS - EFFECTIVE INHIBITORS OF CANCER INVASION AND DISSEMINATION:
We have been studying a peptide from southern copperhead snake venom that we call contortrostatin (CN). CN is a homodimer with two identical chains held together by two inter-chain disulfide bonds. The peptide possesses potent anti-tumor and anti-invasive activity. CN is a member of a family of peptides called disintegrins that are found in snake venoms. Many members of this family are distinguished by the presence of an amino acid sequence, arginine-glycine-aspartic acid (RGD), that enables them to bind to a subset of cell surface receptors called integrins found on cancer cells and newly growing (angiogenic) blood vessels supplying the tumor. Integrins mediate interactions between cells and their surroundings, and on cancer cells they play important roles in tumor invasion and dissemination. We postulated that since contortrostatin disrupts integrin interactions, it should block both cancer cell and newly growing blood vessel cell integrins and may, therefore, have significant anti-angiogenic and anti-metastatic activity. We have shown that CN acts as an effective inhibitor of breast cancer progression. Importantly, CN displays impressive inhibitory activity on the growth of new blood vessels into the breast cancer. But, there is a problem with CN and that is it is present in snake venom in very small quantities, making its translation to the clinic very difficult. However, we recently succeeded in producing a recombinant version of CN using an E. coli expression system. The recombinant protein is a monomer, called vicrostatin (VCN), purposefully designed with a slightly different amino acid sequence at its COOH-terminus to improve binding affinity to an important member of the integrin family. Using a delivery system in which VCN is encapsulated in unilamellar lipid particles (liposomes), we have shown that intravenous delivery of the liposomal formulation (LVCN) twice weekly in animal models of human, triple-negative, metastatic breast cancer, or human prostate cancer, leads to close to 80% inhibition of tumor growth and angiogenesis. More recently we have been examining the effect of VCN introduced intraperitoneally on the growth of human ovarian cancer cells in mice and have observed potent inhibition of tumor growth and dissemination. Presently we are studying human breast, prostate and ovarian cancer and glioma (a devastating brain tumor) animal models to demonstrate the anti-invasive and anti-tumor activities of VCN. We are also examining the mechanism by which VCN dramatically disrupts the actin cytoskeleton of cancer and angiogenic blood vessel cells leading to an abrupt halt to the locomotor apparatus of these cells. Finally, we are examining the diagnostic activity of VCN as an imaging agent to detect integrin positive cancer in prostate cancer mouse model studies, and then use VCN to treat the tumor.
In separate studies we are examining another class of related proteins derived from members of the ADAM (A Disintegrin and Metalloproteinase domain) family. We are able to recombinantly produce large quantities of the disintegrin domain (DD) of the ADAM proteins using a highly engineered bacterial expression system. One of these ADAM DDs has interesting antitumor activity based on its interaction with integrins on the tumor cell surface. Since members of the ADAM family have different structures of their DDs, we are interested in characterizing the integrin binding specificities and affinities of these ADAM DDs and characterizing their biological activities with potential application to human cancer or other diseases.