Targeting Tumors

Courtney
McGrath
Research and Care Programs at Kennedy Krieger Work to Minimize the Damage Caused by Brain Cancer

Nicole BahenIf you've ever doubted how quickly your life can be turned upside down, just ask the Bahen family. On Monday, Nov. 14, 2000, the Bahens' 5-year-old daughter Nicole joined her friends for her usual afternoon dance class. By Sunday Nov. 20, Nicole lay in intensive care recovering from surgery, unable to speak, roll over or swallow, nearly paralyzed on her right side. Such is the swift devastation of a pediatric brain tumor.

Each year, more than 2,000 children nationwide are diagnosed with primary malignant brain tumors cancerous tumors that originate in the brain, as opposed to those that spread to the brain from other areas. The five-year survival rate for children with primary brain tumors ranges between 50 and 75 percent, but the lasting effects of tumor treatment can be substantial. Life-saving surgeries, chemotherapy and follow-up radiation can leave patients with motor and cognitive impairments so significant they can set young survivors back months or years in normal development.

Researchers at Kennedy Krieger Institute are working to increase the understanding of the neurological basis of brain tumors through innovative research projects that are bringing scientists here and around the world closer to treatments that could dramatically improve outcomes. The goal of this research, and of Kennedy Krieger's world-renowned rehabilitation continuum, where children recovering from brain tumors are served, is to minimize the impact of the illness and its treatment on children's futures.

"Brain tumors are the leading cause of cancer death in children, now that the treatment of leukemia is very effective," says John Laterra, M.D., Ph.D., a Kennedy Krieger research scientist. "And while it's wonderful to see someone in their 20s who has survived medulloblastoma, the most common childhood brain cancer, it's heartbreaking to see that these adults are functioning at a level that is clearly below what they would have achieved had they not been exposed to these toxic therapies."

Dr. Laterra leads Kennedy Krieger's pediatric brain tumor research efforts. He and his team are working to understand "what makes these tumors tick," he says, by identifying the molecular pathways in the brain that are involved. For the past eight years, researchers have been examining gliomas, the most common brain tumor in adults. They have identified a particular over-active molecular pathway involving two proteins, hepatocyte growth factor and its cell surface receptor known as c-MET, which triggers excessive tumor growth and stimulates the surrounding blood vessels to grow and continue to feed the tumor. "Our goal is to understand how c-MET stimulates brain tumors to be more aggressive and to show that if you inhibit its expression you also inhibit tumor growth," says Laterra. "The ideal scenario is that you can make the tumor quiescent, or more responsive to therapies designed to kill it."

The c-MET pathway that is commonly overactive in adult cancers also has been found to be overactive in pediatric brain tumors. Researchers at Kennedy Krieger now are using gene therapy on laboratory-grown tumors in an attempt to halt their growth and make them more sensitive to radiation therapy. Dr. Roger Abounader, a Kennedy Krieger research scientist, recently received a grant from the Children's Cancer Foundation in support of further investigation of the role c-MET plays in medulloblastoma growth. "To develop urgently needed new therapies, we need to understand the molecular pathways that underlie medulloblastoma growth," says Dr. Abounader. "This grant supports a thorough investigation of the role that a specific pathway plays in medulloblastoma malignancy and an exploration of its value as a new target for therapy. Successful completion of the research will lead to a better understanding of medulloblastoma growth and to the development of new therapies that could cure this devastating disease."

Dr. Laterra and his colleagues hope that the findings from studies like this will justify clinical trials of drugs designed to inhibit c-MET. But those trials are likely years away. Until then, children with cancerous brain tumors and their families must pray for the best using existing treatments which, even when successful, can leave a child with tremendous and sometimes permanent disabilities.

"When Nicole left the hospital two weeks after her surgery, she was completely incapacitated she hadn't made any progress at all in her recovery," says her mother, Mary Bahen. Nicole entered Kennedy Krieger's inpatient Pediatric Rehabilitation Unit on December 3, 2000, although she had to return to the hospital regularly for radiation treatments and to battle septic shock and other medical complications.

Kennedy Krieger Scientists Research Brain TumorsSuch interruptions are common for children recovering from brain tumor surgery. The pediatric rehabilitation unit at Kennedy Krieger provides 24-hour medical and nursing care for children recovering from brain cancer, as well as brain injuries caused by accidents or strokes. The unit also serves children who have had orthopedic surgery, primarily because of cerebral palsy. Children who are medically stable receive at least three hours daily of physical, occupational and/or speech-language therapy, but for children recovering from brain tumor surgery, their therapy schedule often changes in response to their medical needs.

"With children who have had a traumatic brain injury or stroke, the insult to their body is over and their condition usually only improves. Kids who have had tumors are still receiving chemotherapy or radiation, which continue to cause major stress on the brain and the rest of the body. It makes the initial rehabilitation more difficult," says James Christensen, M.D., director of the pediatric rehabilitation unit. "We have to make allowances for the nausea and fatigue that accompany these treatments, and tell the difference between a temporary decline in neurological function caused by radiation-induced swelling and deficits related to the tumor and surgery."

Patients remain on the unit until they are medically stable and until rehabilitation needs can be met in an outpatient setting. Nicole Bahen stayed in the unit for nearly four months before being discharged in March 2001. She began receiving physical therapy at home in April 2001, and also had a shunt inserted to relieve brain pressure. She continued to recover, and her family hoped she'd be able to return to the parochial school she attended before she got sick. But nearly a year later, some difficulties persisted, particularly in Nicole's speech and ability to walk. Nicole entered the Kennedy Krieger Specialized Transition Program in March 2002.

The Specialized Transition Program, a comprehensive rehabilitation day hospital, strives to transition children and adolescents who are undergoing intensive neurorehabilitation services back into home, community and school life. These children, like those on the inpatient unit, typically have suffered traumatic brain injuries or strokes, or are recovering from brain or orthopedic surgery. The program serves children who no longer need constant nursing care, but who are not yet ready to return to traditional school settings. Set up much like a school, the STP offers children between the ages of three and 18 years a daily schedule of physical and occupational therapies, speech-language pathology, neuropsychology, educational services and nursing care.

Program director Joan Carney notes that guiding the recovery of children who have had brain tumors can be complicated by their ongoing medical treatments. But, she says, if the tumor has been removed, or its growth arrested, it it typically easier for the therapists to offer predictions of functional recovery than it is for children who have had traumatic brain injuries.

"Brain tumors are localized, so once you know where the tumor was, the therapist can predict what skills might be affected," she says. "TBIs are usually more pervasive, so you have to assess all the things that might be affected. As devastating as brain tumors are, once you know what area of the brain has been affected, you can give a more confident prognosis for functional recovery"

For some children, the biggest benefit of STP might be the chance it offers them to re-ignite social skills often neglected during the urgency of cancer treatment.

"Nicole had been home for a year and a half, and needed to get out of the house and be around other kids," says Mrs. Bahen. "She went on field trips, did homework and started to feel normal again."

The therapy team in the Specialized Transition Program helped Nicole recover some skills, too. While she still has slight ataxia and impaired speech, her skills improved considerably while she was in STP. Her most dramatic progress occurred in her motor skills. She walked only with a walker when she first arrived in the program, but soon traded it in for a quad cane. Just before leaving, she negotiated a 50-foot hallway on her own, a little unsteadily, but independently.

Nicole is cancer-free now, moving closer to the five-year mark when her parents can truly begin to breathe a little easier about her health. But the trauma she endured has had lasting effects her gait remains unsteady, and she's enrolled in a school for children with special needs. She's thriving, but will face ongoing challenges related to the treatment she received. In time, perhaps the work done by researchers like Drs. Laterra and Abounader will lead to a breakthrough that will make other children's recoveries from cancer more complete.

Nicole Bahen"We need to solidify our findings that suggest a tie between elevated c-MET expression and poor survival in pediatric brain tumors," Dr. Laterra says. "We're showing that if we artificially over-activate this pathway, tumors grow more aggressively. We need to study whether we get a therapeutic effect if we inhibit the pathway. But if we can design a treatment plan that targets this or similar pathways, we can combine that new therapy with existing treatments to reduce toxicity and improve patients' chances for a cure."