Protein stops growth of brain tumor

Herstatin blocks signaling inside cells that leads to deadly glioblastoma growth

A protein developed by scientists at Oregon Health & Science University blocks the growth of glioblastoma, an aggressive and deadly brain tumor, in laboratory rats, a new study shows. Herstatin inhibits the activation of a family of enzymes responsible for signaling inside tumor cells that tells the cells to proliferate and display other malignant properties, said Gail Clinton, Ph.D., professor of biochemistry and molecular biology in the OHSU School of Medicine who co-authored the study appearing this month in the journal Clinical Cancer Research. “The growth is completely blocked in the intracranial model,” said Clinton, a member of the OHSU Cancer Institute.

Over-expression of the epidermal growth factor (EGF) receptors results in a cascade of signals in the glioblastoma cells that drives their growth. But herstatin, a naturally occurring product, blocks growth of the cells by binding to EGF receptors and turning signaling off. Clinton said human clinical trials for herstatin could begin as early as next year. In fact, the technology is part of a patent portfolio that OHSU has licensed exclusively to San Francisco-based pharmaceutical company Receptor BioLogix Inc., which is developing herstatin as a cancer therapeutic for a variety of cancer types under the name Dimercept.

According to the nonprofit Central Brain Tumor Registry of the United States, glioblastomas account for the majority – 52 percent – of all gliomas, which are tumors that arise from glial cells and include astrocytomas, oligodendrocytomas, ependymomas, mixed gliomas, malignant gliomas NOS (nitric oxide synthase), and neuroepithelial tumors. Glioblastomas make up 23 percent of all brain and central nervous system tumors.

Between 1995 and 1999, there were 8,690 reported cases of glioblastomas in the United States. The median age at diagnosis was 65, and men make up the majority of cases. The disease is most deadly within the first year after diagnosis. Study co-author Edward Neuwelt, M.D., professor of neurology and neurological surgery, OHSU School of Medicine and the Portland Veterans Affairs Medical Center, called the results “very exciting.”

Treating glioblastomas, which can be several millimeters to several centimeters wide, has been tricky. Radiation and chemotherapy “help a little bit, but nothing helps very much,” Neuwelt said, and getting chemotherapy drugs past the blood-brain barrier, the brain’s protective wall of tightly knit endothelial cells, always is difficult.

However, herstatin shows promise as a viable alternative to traditional brain tumor treatment methods, he said. “That herstatin gene Gail developed is very powerful on this tumor, as the paper shows,” said Neuwelt, a member of the OHSU Cancer Institute who directs the OHSU Blood-Brain Barrier Program and pioneered a method for getting most drugs past the barrier. “I think this is a very significant approach.”

But Neuwelt added that “One should always view with caution new and exciting results in rodent models since they may or may not translate in humans.” Scientists used herstatin to treat human glioblastoma cells grown in culture and implanted in rats. “We saw a few tumor cells at the injection site, but they never proliferated,” Clinton said.

Herstatin was not effective on a mutant form of the EGF receptor, called EGF receptor delta. The mutant receptor causes even more aggressive tumor growth in a subset of glioma. “We found our inhibitor targets the full-length EGF receptor, but not the mutant EGF receptor,” Clinton said. “So a patient with a glioma generated by the mutant EGF receptor would not be expected to respond to herstatin.”

She added, “This inhibitor we have is a naturally occurring one, and it’s possible that the mutant EGF receptor may have developed to confer resistance to the class of inhibitors that blocks the extracellular domain” on the glioblastoma cells. About a third of all glioblastomas derive from the mutant receptor, Neuwelt said.

Although herstatin is not effective against the mutant EGF receptor, the study’s results demonstrate highly selective molecules can be developed to target pathogen cells, reducing the chance that other complications will crop up when treating diseases. “It gives new information about which tumors to target, what molecular profile is important to look at up front, but it also tells us that herstatin is a specific inhibitor,” Clinton noted. “This is another step in proving it doesn’t kill all cells, and the more specific and tailored it is to a particular molecular profile, the less likely you’re going to have a lot of side effects.”