Devastating Pediatric Malignant Brain Tumor Could Be Disabled At The Cellular Level

Basic Research Director Believes Key is “Sonic Hedgehog”

Medulloblastomas, the most common malignant brain tumors in children, can be treated through surgery, chemotherapy and radiation—and such therapies result in about a 60 percent survival rate.

But surviving the treatments often means children have lifelong side effects that can be devastating— including cognitive damage, seizures, developmental delays and premature aging.

The Aflac Cancer Center of Children’s Healthcare of Atlanta director Anna M. Kenney, of the Pediatric Neuro-oncology Basic Research Program at Egleston, is seeking more precise ways to attack and treat these tumors by dismantling them at the molecular level.

“Often pediatric patients survive,” said Kenney, who holds a PhD in neuroscience from Yale University and completed a fellowship in pediatric oncology at the Dana-Farber Cancer Institute at Harvard Medical School,  “But some face such long-term problems from the treatments, they don’t fare well.  And those who don’t fare well just keep facing more challenges—they’re chronically unemployed, they can’t live beyond their parents’ home. It’s really bad.”

She wants to fix this by discovering exactly how to dismantle the growth of medulloblastomas—which can be divided into four molecular distinct subclasses.

One of those subclasses is marked by the activation of a pathway called Sonic Hedgehog or (Shh) – named after the iconic video game character because of its appearance that mimics “bristles clumped on the back.” More importantly, Shh is linked to tumor proliferation through its interactions with other pathways – such as the Hippo pathway (“Hippo” logically named because researchers have found it regulates the size of organs and cells) and the insulin-like growth factor (IGF) pathway.

Each of these pathways is tied to the complex metabolic development of the tumors—and Kenney and others believe that if they can determine the exact relationship between each factor, they can undermine the tumors’ development. Or at the very least, they can make the cells more vulnerable to such therapies as targeted radiation.

Already, drugs have been developed that block the activity of the Sonic Hedgehog—but unfortunately, cellular growth seems resistant to the pharmaceuticals. Kenney said that’s because many of the activities that lead to tumor development are automatically switched on before treatment occurs. “It’s a classic case of where we’re shutting the barn door after the horse is already gone,” she said.

To combat this, Kenney’s lab is studying brain cultures derived from mouse models. With the addition of purified Shh, researchers are then able to manipulate the cells either through genetic or pharmaceutical changes—and then observe what happens to the cells’ abilities to proliferate.

Right now, current projects involve deactivating components of Hippo and the IGF pathways which researchers have found to work with Shh in aiding the tumors’ growth and survival. 

Kenney, also an associate professor at Emory University, said an immense boost for her research is the fact that the Aflac Cancer Center, Children's and Emory have a large “bio bank” of primary tumor cells from pediatric patients—something that allows her to evaluate differences between mouse and human models of metabolic interaction.

In addition, her lab is working closely with Canadian researchers who are also studying similar pathways with humans—with everyone seeking more customized treatment plans for each of the four tumor subclasses.

A master networker (Kenney actually was wooed from Vanderbuilt University after learning about Children's pediatric oncology program through a researchers’ skiing club), she believes that such collaboration will be critical to solving the molecular mysteries of these deadly medulloblastomas.

“Right now, patients are often treated the same,” she said, “ But I think we can tailor the treatments and get a much better long-term prognosis.”