Cancer researchers have long suggested that new targeted drugs may work best when paired with other therapies. In a new study published today in Cancer Research, scientists have taken some of the first steps to demonstrate this synergy in mouse and cell line models.
The findings show that two different drugs may work better in a "one-two punch," targeting a cancer development process in two types of cells. The early results are so promising that preliminary testing of the drug combination in humans is now being planned.
"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."