Cancer researchers have long suggested that new
targeted drugs may work best when paired with other
therapies. In a new study published 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 that 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
Cancer Center investigators. Previous evidence from the
Johns Hopkins scientists and others suggests that a new
class of drugs that 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, 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 HDAC (for
histone deacetylase) 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
"Such VEGF inhibitors are known to have most effect on
endothelial cells, the bricks and mortar of blood vessels,"
Pili says. "However, HDAC inhibitors target both
endothelial and epithelial cells, which line organs, and
are the origin of many cancers."
In this Johns 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 percent 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 Kimmel Cancer Center, sponsored by
the National Cancer Institute, using similar VEGF and HDAC
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 is the first author on this research,
and additional participants include Xiaofei Wang, Sushant
K. Kachhap, Yukihiko Kato, Yongfeng Wei and Lu Zhang, all
from Johns Hopkins; and Peter Atadja, from the Novartis
Institute for Biomedical Research.