Steven R. Pirie-Shepherd, Ph.D.

Harvard University Children's Hospital
Cleaved Serpins as Anti-Angiogenic Therapeutics in the Treatment of Cancer

Angiogenesis-the formation of new blood vessels-is critical to the growth and survival of many tumors, and occurs at a much accelerated pace in tumors compared to normal tissue. Angiogenesis inhibitors, investigational agents that starve out tumors by cutting off their blood supply, hold out great hope as effective and relatively non-toxic anticancer treatments. Most angiogenesis inhibitors work by slowing the growth of endothelial cells: endothelial cell growth is a key step in angiogenesis. Dr. Stephen Pirie-Shepherd has identified several structurally related proteins (called serpins), normally involved in the body's blood clotting system. These proteins are believed to contain fragments capable of inhibiting endothelial growth, and thus, angiogenesis. Interestingly, it has been suggested that cancer cells may themselves produce enzymes capable of cleaving-or splitting-these proteins to generate anti-angiogenic molecules, as part of the body's own defenses aga inst cancer. To investigate whether these cleaved molecules can ultimately be harnessed as novel cancer treatments, Dr. Pirie-Shepherd proposes to cleave these anti-angiogenic molecules in the laboratory and study their effects on endothelial cells. Cleaved serpins that demonstrate anti-endothelial activity will then be tested as anti-tumor drugs against human cancers in a mouse model system, which is the first step on the road to clinical trials in humans.