HOLLI W. HAYNIE

Continued discovery about brain pathways and the roles proteins play in cell growth is bringing scientists at St. Jude Children’s Research Center closer to targets for the prevention and treatment of medulloblastoma tumors. A paper published in the March 15 issue of Genes and Development reports that a specific pathway which produces proteins called BMPs can actually inhibit the growth of tumors while provoking malignant cells to develop into normal neurons. This discovery suggests a safer way to treat medulloblastoma, the most common malignant brain tumor in children, accounting for 20 percent of all pediatric brain tumors.

Medulloblastoma occurs in the cerebellum. This cancer strikes about 350 young children in the United States annually. Although treated patients have an overall five-year survival rate of 70 percent, conventional therapies combining surgery, irradiation and chemotherapy frequently lead to permanent neurocognitive impairment.

“We think we have identified a pathway that can be used to prevent tumor formation and a potential target for therapy,” said the paper’s senior author, Martine F. Roussel, PhD, member of the St. Jude department of genetics and tumor cell biology.

This new discovery compliments a previous finding made by the St. Jude team in 2004 that determined BMPs induce differentiation, or maturation, of normal neuron progenitor cells. According to St. Jude reports, the significance of this is related to ongoing research into the intricate signaling mechanisms that govern the proliferation, or division, of cells. These signaling mechanisms, called granule neuron progenitors (GNPs), go on to develop into neurons in the cerebellum during the first year of life. The disruption of this differentiation process can trigger medulloblastoma, which points to GNPs as a potential therapeutic target.

Previous research had shown that provoking the differentiation of GNP cells into neurons requires that BMPs bind to a set of receptors on the cell surface, known as the Sonic hedgehog pathway.

“What was not known, and what we now find, is that the effect of BMPs on normal GNP cells is almost exactly mimicked in GNP-like tumor cells,” Roussel explained.

In the latest study, it was uncovered there is yet another link affecting the viability of BMPs as a novel therapeutic treatment, a protein called Math 1. Using mice models, researchers identified that when BMPs bind to the progenitor cells, it causes the rapid degradation of the Math 1 protein. The new challenge is in decoding the purpose and location of this protein. It’s only present in dividing GNPs, but not in neurons that are non-proliferated.

The precise way Math 1 works is unknown. If the protein is enforced in a cell,
said Roussel, it becomes completely resistant to BMP induced differentiation.
Mice that were genetically altered to not carry the gene for Math 1 failed to develop cerebellums, which illustrates that the protein is fundamental to the formation of a normal animal brain.

In the mean time, scientists performed gene transfer experiments in mice to test BMPs as a potential medulloblastoma treatment. As explained by St. Jude reports, using a genetically altered virus, scientists inserted the BMP gene into cancer cells. The transfer not only halted tumor growth, but induced the cancer cells to change into neurons. The down side; BMPs are incredibly expensive to purify. To bypass this obstacle, researchers are searching for tiny, less expensive biological molecules that might mimic the action of BMPs in medulloblastoma.

The use of BMPs, coupled with an earlier discovery in the 2004 study, could offer a combination treatment, suggests Roussel. In the previous study, the St. Jude team reported that an experimental drug called HhAntag, a syndicate antagonist which inhibits Sonic hedgehog signaling, led to the deaths of tumor cells and the elimination of these tumors in treated mice. Yet, the treatment was also found to interfere with bone development in animals, which suggests yet another undesirable side effect for children.

While Sonic Hedgehog and BMP pathways play roles in regulating cell division, their differences are distinct and offer the opportunity for synergistic treatment. Roussel explained how using a lower dose of the HhAntag, the Sonic hedgehog inhibitor, in combination with BMP, “gives the same therapeutic effect as high doses of the hedgehog inhibitor,” she said.

“We hope that by reducing the levels of both compounds, we might prevent the secondary side effects on bone of this potential therapy.”

The next step for Roussel and her team is to understand all the mechanisms within these pathways. “We still don’t know exactly where (the target) is between Math 1 and Sonic Hedgehog,” Roussel said. “If you understand how everything is wired, you may have access to other therapeutic targets. We want to find out how Math 1 is regulated, and downstream, what Math 1 regulates, to (determine) if there are other potential therapeutic targets that would be easier to access.”


July 2008