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Seek and destroy: Wake Forest researchers’ “designer protein” finds and kills brain tumors
08-23-2010
by Amy Swinderman  |  Email the author
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WINSTON SALEM, N.C.—Researchers at Wake Forest University Baptist Medical Center have unveiled what is being called a major breakthrough in cancer research: A method of targeting and destroying glioblastoma multiforme (GBM) cells—the most malignant and aggressive brain cancer cells.

And perhaps even more notably, the researchers say their method can kill these fatal cells without harming healthy cells, an unfortunate side effect of many other cancer therapies.

The finding, published in the June 16 online version of the journal Genes and Cancer, is the latest development in two decades of cancer research efforts led by Dr. Waldemar Debinski, director of the Brain Tumor Center of Excellence at Wake Forest Baptist.

According to Debinski, despite medical advances, treatment of GBM is still a major challenge. Patients with GBM survive an average of 14.5 months after diagnosis, he says.

"Over the last 30 to 40 years, with all the cancer research efforts out there, we have only been able to extend the survival rate in these patients by about one month per decade of research. I don't think anyone would label this satisfactory progress," Debinski says. "It's a very aggressive disease, and one of its hallmarks is that it doesn't metasticize much outside of the brain. Most of the recurring disease takes place within two centimeters of the tumor margin. This is one of the biggest difficulties in managing this disease."

About 20 years ago, Debinski and his colleagues developed what they call a "designer protein," a single-chain protein that is able to seek out and make its way into specific cells, such as cancer cells. But that wasn't enough, Debinski says.

"We had some other ideas about using the protein to travel to the nucleus," he says.

Debibski's team knew that most anticancer therapeutics have defined targets such as
oncogenes, enzymes or DNA, all of which are localized to distinct intracellular compartments like cytosol, mitochondria or nuclei. Reasoning that having direct delivery vectors for therapeutics/labels to these subcellular compartments would lead to an increased specificity and efficacy, and less toxicity, the researchers designed a true multiple- specificity delivery vehicle targeting the interleukin-13 receptor alpha 2 (IL-13Rα2) for efficient transport to the nuclei of GBM cells.

For their nuclear targeting delivery vector, the researchers combined the recognition and transport signals into a single-chain recombinant protein.

"We demonstrated that molecularly targeted, genetically engineered proteins specifically recognize GBM cancer cells, travel to and accumulate in these cells' nuclei," Debinski says. "The protein recognizes GBM cells and then delivers a drug or some other therapy into those cells in a way that will put those active agents inside a specific subcellular compartment, like the nucleus, destroying only that specific cell."

Debinski notes that some radiation has no effect on cancer cells because it can't penetrate far enough into the body to reach its specific site of action in the cells. However, if scientists deliver that same radiation specifically to the nuclei of GBM cells, it can destroy the DNA of the cancer cell, leaving the cell unable to live any longer.

"It dies, while the neighboring healthy cells go untouched," Debinski explains. "We believe this could lead to the development of a therapy that is more effective and less toxic."

The technology office at Wake Forest has applied for a patent on the method, and many commercial parties have expressed an interest in licensing it, Debinski says. The method, he adds, also has potential applications in breast, head and neck and pancreatic cancer, as well as other types of solid tumors.

"As a researcher, one can think and dream about many possible scenarios during the quest to find a way to treat cancer," Debinski says, "This is one that we now know we can actually do. It's feasible—and it's fantastic."

Contributing to the study, "Molecular Targeting of Intracellular Compartments Specifically in Cancer Cells," were Dr. Hetal Pandya, a doctoral student in Debinski's lab and the first author on the paper, as well as research associate Denise M. Gibo.

 
Code: E08251004

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