Dr. Dennis E. Hallahan
Signal blocking improves radiation
Blocking a specific signaling pathway with drugs can make blood vessels more susceptible to the effects of radiation and improve tumor control, Vanderbilt-Ingram Cancer Center scientists have demonstrated.
The study, published this month in the journal Cancer Research, shows a potential way to overcome an ironic discovery in radiation therapy found in the study. The radiation therapy intended to kill the blood vessels that feed cancer cells can actually trigger a chemical pathway that makes the vessels more resistant to therapy.
“We know that if vascular endothelium is destroyed, tumor control can be improved,” said principal investigator Dr. Dennis Hallahan, chairman of Radiation Oncology. “However, the blood vessels are often resistant to the therapy. Our initial hypothesis was that the cell survival pathways that allowed the blood vessels to survive were activated by growth factors from the tumor cells. We were surprised to find that cell survival pathways were activated not only by these growth factors but by the therapy itself.”
Blood vessels probably developed this mechanism, Hallahan said, to protect themselves against the day-to-day exposure to so-called “free radicals” produced as a byproduct of inflammation and other normal biologic processes.
The researchers found that radiation activates a biochemical signaling pathway involving the proteins known as PI3K and Akt. This pathway then makes the endothelial cells lining the blood vessels resistant to radiation by activating a cell survival pathway.
“We tested whether we could reverse the blood vessels’ resistance to radiation therapy by inhibiting this pathway,” Hallahan said. “We found inhibitors made tumor blood vessels more sensitive to radiation.”
The scientists investigated two selective enzyme inhibitors that target this pathway, wortmannin and LY294002. In cell cultures, the researchers found that use of these drugs enhanced radiation-induced cell death and cytotoxicity in endothelial cells. In animals, these agents enhanced destruction of tumor blood vessels.
Hallahan pointed out that this approach to cancer therapy, though based on the same notion that cutting off the tumor’s supply lines will defeat the tumor, is different from the field of anti-angiogenesis that has received so much attention in the past few years. Anti-angiogenesis uses agents to prevent the development of these blood vessels in the first place, with the goal of keeping tumors from growing and spreading. The approach Hallahan’s group is testing is “angiolytic,” meaning that it aims to destroy existing blood vessels and thus helps destroy the tumor.
The next step in the research will be to develop clinical trials using these or similar agents to inhibit the PI3K/Akt pathway in conjunction with radiation therapy. Wortmannin is in clinical trials already, though not yet with radiation, Hallahan said.
It is expected to be at least a year before such clinical trials are ready to begin.