v4n2 - Disrupting Metastasis

Various approaches have been studied that disrupt the process of metastasis, and a number of drugs that target the steps involved in the spread of cancer cells are in development

• Targeting enzymes—Matrix metalloproteinases (MMPs) are enzymes used by cancer cells to dissolve the supporting structure surrounding a cell, thus allowing it to break free and spread. A number of MMP inhibitors were studied in lung cancer, prostate cancer and a variety of other tumor types, but no significant benefit was shown. Still, there are a number of additional MMP inhibitors in development. Point Therapeutics, a Boston-based biotechnology company, is studying talabostat (PT-100) in metastatic melanoma.

• Targeting growth factor receptors—When an organ such as the lung becomes injured, it repairs itself through the release of growth factors. Under normal cellular development, growth factors bind to receptors on cell surfaces that then activate signaling enzymes, and these enzymes activate transcription factors that regulate cell growth and production. Isaiah Fidler, PhD, explains that when tumor cells relocate to an organ, they take advantage of growth factors intended by the organ for its own growth, repair or maintenance.In order to use a growth factor, though, a tumor cell must have a functioning receptor for it. Transforming growth factor-beta (TGF-beta) has long been thought to be involved in development of metastases. A number of drugs are being developed to block the activity of the TGF-beta receptor. These include SD-208, an inhibitor of the TGF-beta receptor being developed by Scios, a biotechnology company in California. In animal studies, SD-208 reduced invasiveness and meta-static potential of cancer cells.

• Targeting cell adhesion—In order to invade neighboring tissue, cancer cells must loosen their adhesion with other tumor cells. According to Alan Lader, PhD, of Dana-Farber Cancer Institute, a gene called TACSTD1 instructs cells to produce a protein called epithelial cell adhesion molecule. “When it’s there, the cells tend to stick to each other,” he says.Cadherins are other proteins involved in cell adhesion. Just before breast cancer cells become metastatic, the cadherin on their surfaces changes from one type (E-cadherin) to another (OB-cadherin). Breast cancer cells that express OB-cadherin are the ones that metastasize, particularly to bone that expresses high amounts of OB-cadherin. A new drug, ExherinTM, developed by Adherex Technologies in North Carolina, blocks OB-cadherin, and preliminary clinical trials are under way to test whether Exherin can disrupt metastasis. Tetraspanins, cell-surface proteins that anchor cells in place, are usually found in reduced numbers in metastatic tumors. Conversely, cancer cells with excess tetraspanin CD151 are more likely to spread. The presence or absence of tetraspanins may provide another therapeutic target.