Beth Israel Deaconess Medical Center
Massachusetts
NFCR Fellow
2006 Albert Szent-Györgyi Prize winner

Like all living tissues, tumors need a steady supply of blood to survive. Blood vessel formation, or "angiogenesis," is critical for tumors to grow and spread. If cancer researchers know the mechanisms by which tumors acquire additional blood vessels, they may find new strategies to block this process and literally starve tumors to death.

The Discovery of VEGF

In research supported by NFCR, Dr. Dvorak has discovered a molecule called vascular permeability factor/vascular endothelial cell growth factor (VPF/VEGF) that encourages and supports the growth of new blood vessels. According to Dr. Dvorak, cancerous tumors make and secrete VEGF that causes blood vessels to leak plasma fibrinogen, the substance that helps form blood clots. This in turn, enables the formation of new blood vessels that the tumor needs to grow. However, tumors differ from healing wounds in one important aspect. As soon as a wound is healed, VEGF production is turned off abruptly. Tumors, on the other hand, continue to make large amounts of VEGF and in essence keep the body's healing mechanism in the "on position," allowing malignant cells to grow and spread at rapid speed.

This is a groundbreaking discovery that has changed the very face of cancer research. This finding was the first to identify the source that allows tumors to grow, and helped explain how the blood vessels of malignant tumors differ from those of normal tissue in structure and function. Dr. Dvorak's breakthrough had a major influence on the research efforts of many other vascular scientists, and this has led to the development of anti-angiogenic drugs that target VEGF such as AvastinTM by the company GENENTECH. Avastin is the trade name for Bevacizumab and is a monoclonal antibody that recognizes all vascular endothelial growth factor isoforms and blocks angiogenesis. Bevacizumab was the first clinically available angiogenesis inhibitor in the United States.

VEGF is the target of the first clinically available angiogenesis inhibitor

In 2004, Avastin was approved by the U.S. Food and Drug Administration (FDA) for treatment combined with chemotherapy for metastatic (spreading) colorectal cancer and non-small cell lung cancer. In May of 2009, the FDA granted accelerated approval of Avastin for patients with the aggressive brain cancer, glioblastoma multiform, which has progressed following prior therapy (refractory).

Dr. Dvorak was awarded NFCR's Inaugural Annual Albert Szent- Györgyi Prize for Progress in Cancer Research for his groundbreaking discoveries of VEGF and its profound influence in the development of new anti-cancer therapies.

Future Studies

Dr. Dvorak's research suggests that tumor blood vessels are rather heterogeneous and there are presently six subtypes, each with very different structural and molecular properties. His lab has shown that only a few types of tumor blood vessels are sensitive to current anti-VEGF therapies, e.g., Avastin. The team is elucidating additional genes and gene products downstream of VEGF-A which regulate new blood vessel growth and may be "targetable". The Dvorak laboratory has recently discovered that VEGF-A and another vascular endothelial growth factors induce the formation of lymphatic vessels near tumors-another mechanism by which these factors promote cancer growth. The characterization of the molecular players involved in lymphatic vessels growth, or lymphangiogenesis, is important to the discovery of therapies to halt vessel growth.

Impact on Cancer Prevention, Early Diagnosis, and Treatment

To grow beyond minimal size, tumors must induce a new blood supply through angiogenesis. By understanding the many steps and mechanisms involved in tumor angiogenesis, Dr. Dvorak's research has laid fundamental ground for the development of novel anti-angiogenic therapies such as Avastin. His continuing pioneering work in this critical area may provide insights into tumor resistance to Avastin and lead to the development of new therapies that attack the remaining types of tumor blood vessel -an urgent need to improve patient outcomes. NFCR has been supporting Dr. Dvorak's vital research since 1980.