Finding new treatments for high-grade pediatric brain tumors

Children diagnosed with high-grade brain tumors, including high-grade glioma and medulloblastoma, historically have fared poorly. Over the past 20 years, the prognosis has improved somewhat, particularly for children with medulloblastoma. Despite enhanced treatments for diseases such as childhood leukemia, brain and central nervous system tumors now represent the most common cause of cancer-related death in children. Unfortunately, for children with diffuse intrinsic pontine glioma (DIPG), atypical teratoid rhabdoid tumor (ATRT) and primitive neuroectodermal tumor, the outlook remains bleak.

Researchers at Mayo Clinic in Rochester, Minnesota, are making progress in the laboratory, possibly finding novel ways to treat high-grade gliomas and other brain tumors in children. Over the past decade new information about the molecular diversity of these tumors has emerged, pointing the way toward targeted therapies tailored to tumor subtypes and highlighting differences between pediatric and adult brain tumors. Pediatric high-grade gliomas are often treated like their adult counterparts, despite this new knowledge that pediatric and adult high-grade gliomas represent different biological diseases.

"For example, midline tumors such as DIPG, which occur in the brainstem, have a very specific histone mutation that is different from the histone mutation found in pediatric hemispheric high-grade gliomas, while adult high-grade gliomas do not have these genetic mutations at all," says David J. Daniels, M.D., Ph.D., a pediatric neurosurgeon at Mayo Clinic's campus in Minnesota. "Pediatric and adult brain cancers are very different. An adult with a diagnosis of a grade IV glioma has a 14-month life expectancy. We have some long-term survivors of pediatric high-grade gliomas, although children with DIPG still have a poor prognosis similar to that of adult glioblastoma multiforme."

"There is plenty of room for hopefulness in pediatric brain cancer," adds Gesina F. Keating, M.D., a pediatric neuro-oncologist at Mayo Clinic's campus in Minnesota. "The news that a child has a high-grade brain tumor is always difficult. But I can tell the family that they are at a top medical center with a team of knowledgeable physicians who will see them today and outline a treatment plan."

Research and compassionate care

At Mayo Clinic, patient consent is sought for obtaining research samples from every biopsy or resection of a brain tumor, including DIPG, medulloblastoma and ATRT. In his research laboratory, Dr. Daniels grows these tumors in cell culture and in mouse xenograft models; he has succeeded in developing more than 20 cell lines or xenografts, including numerous DIPG and medulloblastoma lines.

Groundbreaking research by several groups in 2012 independently discovered the histone mutations that subsequently were shown to drive high-grade gliomas. DIPG tumors, for example, universally harbor an H3K27M histone mutation or equivalent. DIPG is of particular interest in Dr. Daniels' lab because it is a devastating disease, with a life expectancy after diagnosis of nine to 12 months.

Dr. Daniels' laboratory is using several different ways to identify therapeutic vulnerabilities in tumors with the H3K27M mutation. One approach is to reverse the effects that this histone mutation has on the epigenome. Another is to screen libraries of chemotherapeutics approved by the Food and Drug Administration, or compounds that are already in clinical testing, and identify compounds that selectively kill tumor cells with this mutation.The researchers hope that testing clinically relevant compounds will result in identifying compounds that can be fast-tracked for approved use in patients.

"We're homing in on some very specific molecular pathways that are critical for tumors with the H3K27M mutation. Knocking out these pathways kills these tumors in vitro," Dr. Daniels says. Animal models are in development, and Dr. Daniels hopes eventually to move to clinical trials with inhibitors of these pathways.

Alongside this research, Mayo Clinic offers a team approach to clinical care. Expedited referrals and next-day evaluation are available for patients with brain tumors.

"We are able to gather everyone in one room — neurologist, oncologist, surgeon — to discuss the patient's needs," Dr. Keating says. "We have nurses, radiation technicians and social workers who provide ongoing support. Our patients feel well looked after."

After initial treatment, patients have ongoing evaluations through childhood and beyond. "We work with whatever long-term issues arise, whether it's double vision or diabetes insipidus or sleep disorders," Dr. Keating says. "Continuity of care is so important. We can seamlessly transition our patients into care from endocrinologists or neuro-ophthalmologists or whatever they need."

Medulloblastoma progress

In addition to his research on glioma treatments, Dr. Daniels is screening medications for effectiveness in treating the molecularly defined subtypes of medulloblastoma. "As clinicians, we are rewriting the way we treat medulloblastoma," he says. "We used to divide the disease into average risk and high risk. Now we have low, average and high risk.

"Furthermore, at least four molecular subgroups of medulloblastoma have been identified, including Wnt, SHH, Group 3 and Group 4. We know that children with the Wnt subtype tend to do well. Instead of pounding them with high-dose chemotherapy and radiation and even stem cell transplants, we can back off on their treatment." Dr. Daniels' lab is also screening for new drug targets for the Group 3 and 4 tumors, which can be more challenging to treat.

For children with medulloblastoma, proton beam therapy is a new treatment option at Mayo Clinic's campus in Minnesota. Proton beam therapy targets tumors more precisely than conventional radiation therapy, limiting damage to surrounding tissue.

"Proton beam therapy is yet another step forward," Dr. Keating says. "The outlook for kids being treated with medulloblastoma is better now than it was even five years ago. Among the 80 percent who survive to five years after diagnosis, most will probably survive another 20 years and beyond."

To achieve the best results, it is essential that treatment of tumors be tailored to the needs of the developing pediatric nervous system. Historically, about 20 percent of children who undergo medulloblastoma resection developed cerebellar mutism syndrome (CMS), with symptoms including mutism and behavioral and mood changes such as irritability, frequently accompanied by additional neurological signs such as ataxia, flaccid hemiparesis, feeding difficulties and incontinence. The occurrence of CMS can reduce the likelihood of independence as a young adult. Although the cause of CMS isn't fully understood, it might be linked to surgical approaches that can damage a developing brain.

At Mayo Clinic, preventing this devastating complication is of highest importance. "Pediatric neurosurgeons use several techniques to minimize the occurrence of CMS, such as avoiding the vermis, not violating the cerebral peduncles or deep nuclei," Dr. Daniels says. "As a large, tertiary center, Mayo Clinic understands how to manage these risks. Over the last five years, our rate of CMS is under 5 percent, and we are embarking on research to further understand this complication."

Dr. Keating notes that even a teenager with the physical stature of an adult lacks a fully developed brain. "Medulloblastoma is a pediatric disease, and it's important to have a pediatric neurosurgeon," she says. "We want our patients to be adults who can live independently.

"For all of our pediatric patients with high-grade brain tumors, we are committed to a team approach that combines the best of clinical care and research," she adds. "Going from lab bench to bedside and back is the only way we can make progress."