Seeking a Kinder Cure

A child can be cured of cancer and still not be well.

Roughly 80 percent of children diagnosed with medulloblastoma—the most common malignant brain tumor in children—are cured. But the treatment that typically includes surgery, chemotherapy and radiation used to kill the cancer growing in a child’s still-developing brain itself often causes life-long damage.

“The problem with current treatments is that most of those children are pretty severely neurologically devastated afterwards. They are ‘cured’, but not really,” says Dr. Robert C. Castellino, a pediatric hematology/oncology specialist and researcher at the Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta, as well as, Assistant Professor of Pediatrics with Emory University School of Medicine.

Many survivors of medulloblastoma, a tumor that develops at the back of the brain, need assistance with activities of daily living such as feeding, bathing and dressing. This means that, often, there are no ballet recitals, no homerun trots at Little League baseball games.

So, when he isn’t caring for young patients at the Aflac Cancer Center, Dr. Castellino is conducting research he hopes leads to a gentler cure for medulloblastoma.

Dr. Castellino’s research focuses on the gene called wild-type p53-induced phosphatase—abbreviated as WIP1 and pronounced as whip one.  “In essence, what I’m trying to do is to see why WIP1 seems to cause medulloblastomas in children,” says Dr. Castellino.

WIP1 seems to disrupt the functions of another gene called TP53. The gene’s role in preventing and fighting cancer is well documented, Castellino notes.

“p53 is probably one of the most studied genes for its role in cancer prevention, and cancer development when p53 is not working properly,” Castellino says.

But for p53 to do its job, phosphates must attach to specific areas on the p53 molecule. High levels of WIP1 remove the phosphates from p53.

“A major role of p53 is to stop cancer,” says Castellino. “Whip one stops p53 from stopping cancer.”

High levels of WIP1 promote the growth of cancer cells, Castellino says.

“My number one goal is to try to understand how that happens,” he says. “We’re also trying to understand why lots of whip one (WIP1) seems to prevent medulloblastoma cells from dying.”

To advance his research, Dr. Castellino has applied for a grant that will allow him to learn more about inhibiting WIP1 in specific models of medulloblastoma, known as "Sonic Hedgehog-activated" models.

Achieving those goals will be helped by a parallel research project—development of a genetically engineered mouse with high levels of WIP1. A steady supply of research subjects is important for several reasons. Medulloblastoma cells for research are hard to come by, Castellino explains. When a tumor is removed from a child it may be just the size of a quarter and there are many competing demands for the limited supply of tissue samples. That means there is a shortage of cells available for research. Working with partners at Emory University, Castellino says, “we have a high expressing WIP1 mouse.”

The goal is to study development of medulloblastoma in mice that express high levels of the WIP1 gene. The grant would also help Dr. Castellino determine if inhibiting WIP1 in these mice can suppress the growth of medulloblastoma.

Castellino may also have a good lead on a treatment.

“We have at least one compound that we found seems to prevent WIP1 from working and it seems to stop the growth of cells in a test tube,” Castellino says. Since drugs often react much differently in a test tube than they do in a living thing, a strain of mice with high levels of WIP1 in the developing brain will also be used to test potential drugs that could be used in treatment of medulloblastoma.

Dr. Castellino has found that targeting a protein designated as Arl13b may be a more effective treatment for medullablastoma than current therapies. A second grant could help him explore this possiblitiy.

“Once compounds are identified that stop WIP1 from working and medulloblastoma tumors from developing and growing,” Castellino says, “I think we will be one step closer to finding drugs that can cure children of medulloblastoma, while preventing bad effects which keep medulloblastoma survivors from growing up as normal, health children.”