Duke Researchers Report Successful Use of Gene Therapy in Preventing The Growth of Tumors
SEATTLE, WA -– In a series of experiments in mice, Duke University Medical Center researchers have demonstrated that gene-therapy techniques can successfully deliver proteins to block the formation of new blood vessels that are vital for the sustained growth of tumors and their metastases.
In a study presented at the first annual meeting of the American Society for Gene Therapy, the researchers described how they used adenovirus vectors to deliver a protein that blocks the growth of blood vessels to tumors. Although the effect was transitory – it lasted about a week – the rate of tumor growth in animals was decreased by two-thirds in most cases and was completely halted in others.
With refinement, Duke researchers hope to extend the time this type of therapy can be used to slow or halt the growth of tumors, which then could potentially be used in humans to provide more time to treat their cancer.
"We were able to demonstrate that, in this animal model, we could slow the growth of primary tumors and halt the growth of metastasis from the primary tumor to distant sites using gene therapy," said Duke's Charles Lin, Ph.D., a cancer researcher who is presenting the results of the Duke research. "These studies prove in principle that gene therapy administered systemically can inhibit the formation of new blood vessels in tumors."
The work is the first to show that gene therapy can "starve" tumors, said Duke's Dr. Kevin Peters, cancer researcher and the study's principal investigator. Most other researchers have taken the approach of using drug intervention, with agents such as angiostatin and endostatin, to cut tumors off from their blood supply, Peters said.
In order for tumors to grow larger than several millimeters in size, they need to attract new blood vessels to provide nourishment. Not only is this new vessel growth essential for the tumor to increase in bulk, it provides the escape route for individual cancer cells to break off, migrate to other parts of the body and become the seeds for new tumors.
The target of the Duke research, which was supported by a National Cancer Institute Special Program of Research Excellence in Breast Cancer grant, is a protein receptor, known as Tie2, found on the endothelium, or inner surface, of tumor blood vessels. When activated by growth factors that are secreted by tumors, Tie2 triggers a series of biochemical events in blood vessels around the tumor that lead to the formation of new capillaries, a process known as angiogenesis.
The researchers developed a recombinant Tie2 inhibitor protein, which they called "ExTek," and inserted it into the genome of an adenovirus. The adenovirus is an ubiquitous virus commonly used as a carrier, or vector, for gene therapy experiments, and is genetically modified so that it retains its ability to infect tissue, but cannot replicate like a normal virus.
The ExTek-containing virus then was injected into two groups of mice, one with melanoma and one with human breast cancer. The virus then "infected" the animal's liver, according to Peters.
"The livers of these animals act a lot like a factory, producing large quantities of the Tie2 inhibitor protein that is then released into the bloodstream," Peters said. "Importantly, levels of ExTek remained high during that time with no adverse effect on the mice."
In the first experiment, the mice livers produced the protein for more than a week before the animals' immune system cleared the virus. However, during that time, the rate of tumor growth in the mice with breast cancer decreased 64 percent, and decreased 47 percent in the mice with melanoma, the researchers say.
"While the effect was transitory, it was significant," Peters said. "As we find newer and better vectors, we should be able to extend the length of time we are able to slow or halt tumor growth, which provides more time to treat the cancer with other existing agents."
Once the researchers found that they could slow the growth of the primary tumor, they wanted to know what effect their gene therapy approach would have on cancer metastasis. So they mixed the breast cancer and melanoma cell lines together and injected them into the mice. Half the mice received the genetically altered adenovirus and half received a control virus.
"The mice that served as a control developed large and well vascularized lung tumors, while in the other mice we only found microscopic clusters of tumor cells," Lin said. "So not only does this method of therapy slow the growth of the primary tumor, it also appears to halt the growth of metastatic tumors to other regions of the body."
In addition to developing new and more efficient gene therapy vectors, the Duke team is testing the combination of Tie2 inhibitor proteins with a different class of anti-angiogenic proteins known as vascular endothelial growth factor (VEGF).