Developing New Tools

A scalpel is precise. A hammer is not.

Yet the standard treatment for medulloblastoma—the most common malignant brain tumor in children—includes the use of both tools. The exacting precision of neurosurgery to remove the tumor from a small part of the brain is followed by radiation therapy involving the whole brain in an attempt to kill any stray cancer cells. The radiation hammers healthy brain cells as well as what remains of the medulloblastoma, causing damage to a child’s still-developing brain.

Children that survive brain cancer are often in need of life-long medical, educational and psycho-social assistance, while some may be so severely affected that they are left unable to respond to a mother’s touch or a father’s voice. Many will live the rest of their lives needing assistance with activities of daily living such as feeding, bathing and dressing.

That’s why Dr. Tobey MacDonald—a pediatric hematology and oncology specialist at the Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta—is trying to develop tools to replace the hammer.

“My heart is with the kids when I see them after radiation and that is what keeps me going,” says MacDonald, who is also the Director of the Pediatric Brain Tumor Program at the Aflac Cancer Center and an Associate Professor of pediatrics at Emory University School of Medicine.

“The primary focus of my research is trying to uncover the biology of how brain tumors metastasize,” MacDonald says. “My reason for being here is to unlock the keys that drive these cancer cells to move from one point in the brain to another.”

Eight years ago, MacDonald was co-author of a landmark paper establishing a genetic difference between medulloblastoma cancer cells that spread and cancer cells that don’t. Since that time MacDonald has been investigating the key genetic differences that are critical for allowing the tumor cells to spread in the hope that drugs can be developed to target these specific genes and proteins that have been “switched on” by the tumor.

Cancer typically metastasizes—or spreads—when cells break away from the primary tumor and circulate through the bloodstream.

“Medulloblastoma walks along the coverings of the brain—the leptomeninges,” says MacDonald.

And the cell-to-cell migration that makes up newly formed metastatic clump of tumor typically isn’t very far from the site where the tumor started.

“Brain tumors almost never get outside the brain—they like the environment,” says MacDonald.

It has taken the better part of a decade to determine what combination of roughly 30,000 genes trigger medulloblastoma cancer cell migration.

“We’ve been trying to hone down on what are the most critical elements in a cell, so that if you knock out one or two, you stop the tumor from moving,” says MacDonald, who was recruited to Georgia this fall from the Center for Cancer and Immunology Research at Children’s National Medical Center in Washington, D.C.

Research now is focusing on Rho GTPases, a family of proteins that act as a molecular switch in the complex signaling between the components of a single cell to promote and direct the movement of the tumor cell.

“We believe we have honed in on two critical targets and have identified drugs that block the signals,” says MacDonald.

But the molecular switches must be turned on and off in the proper sequence, MacDonald notes, adding, “it’s like when you turn one light switch off, another flips on.”

“Nature is so vastly complicated, we can obviously get thrown for a loop,” he cautions.

MacDonald, however, is optimistic his research will get a boost from the synergetic collaboration working with researchers at the Aflac Cancer Center, Georgia Tech, Emory University School of Medicine and the Winship Cancer Institute.

He is currently working with biomedical engineering researchers at Georgia Tech who are trying to develop a way to attract and kill migrating cancer cells—much like an ant trap attracts and kills ants.

“This is why I’m excited to be here,” says MacDonald. “This situation here is enormously collaborative.”