A One-two Punch For Tumors: Double Drug Combo Attacks Tumor And Blood Vessel Development

"Anti-angiogenesis" drugs which inhibit vast networks of blood vessels that feed tumors have thus far failed to make the anticipated dramatic impact on targeted tumors when used singly in human clinical studies, say Johns Hopkins Kimmel Cancer Center investigators. Previous evidence by the Hopkins scientists and others suggest that a new class of drugs which helps normalize how DNA is wrapped around a scaffolding of proteins called histones also has secondary effects on limiting blood vessel development.

"Combining these two types of drugs may have a greater impact on cancer development than using them alone," says Roberto Pili, M.D., assistant professor of oncology at the Kimmel Cancer Center. "Our idea is to attack the way cancers form new blood vessels by disrupting the angiogenesis process in two different cells."

Cancer cells inappropriately remove small molecules called acetyl groups from histones, forcing the DNA to remain tightly coiled and restricting gene activation. This error may be reversed by using drugs called histone deacetylase (HDAC) inhibitors to block the enzymes that remove the acetyl groups allowing the DNA to unwrap itself and make necessary gene products.

To test the combination, the Hopkins scientists chose an anti-angiogenesis drug (called PTK787/ZK222584) that blocks the effect of a protein called VEGF, for vascular endothelial growth factor, which is responsible for triggering a cascade of cell signals that promote blood vessel formation.

"Such VEGF inhibitors are known to have most effect on endothelial cells, the bricks and mortar of blood vessels," explains Pili. "However, HDAC inhibitors target both endothelial and epithelial cells, which line organs, and are the origin of many cancers."

In this Hopkins study, the VEGF inhibitor combined with an HDAC inhibitor called NVP-LAQ824 reduced the number of endothelial cells in culture dishes by 51 percent, compared with approximately half the effectiveness using the two drugs alone. In mouse models, the combination controlled 60 percent of new blood vessel formation compared to 50 percent using the agents alone.

Tumor growth in mice with prostate cancer was reduced by 35 and 75 percent for the VEGF and HDAC inhibitors, respectively. The combination of drugs reduced tumor development by 85 percent.

Mice with breast cancer showed similar inhibition of tumors with 54 and 60 percent growth reduction for the VEGF and HDAC inhibitors alone. In combination, the drugs slowed tumor growth by 80 percent.

The team also profiled gene activation patterns in tumor and endothelial cells treated with the HDAC inhibitor. They noted additional action on blood vessel development by its ability to decrease activation of several critical angiogenesis-related genes and proteins, including HIF1a (hypoxia inducible factor), VEGF, survivin, angiopoietin-2 and its receptor, Tie-2.

Based on these results, the team is planning a clinical trial at the Johns Hopkins Kimmel Cancer Center, sponsored by the National Cancer Institute, using similar VEGF and HDAC inhibitors.

###The research was funded by the American Cancer Society, the Commonwealth Foundation for Cancer Research, and a Sidney Kimmel Foundation Research Award.

David Z. Qian, Ph.D, is the first author on this research and additional participants include Xiaofei Wang, Sushant K. Kachhap, Yukihiko Kato, Yongfeng Wei, and Lu Zhang from Johns Hopkins; and Peter Atadja from the Novartis Institute for Biomedical Research.

Qian, D., et al., "The Histone Deacetylase Inhibitor NVP-LAQ824 Inhibits Angiogenesis and Has a Greater Antitumor Effect in Combination with the Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor PTK787/ZK222584," Cancer Research 64:18, 2004.

Links:

Johns Hopkins Kimmel Cancer Center: http://www.hopkinskimmelcancercenter.org

The Sidney Kimmel Foundation: http://www.kimmel.org