New study finds kinder, more targeted approach to treating aggressive childhood brain cancer

Researchers have identified a critical group of medulloblastoma, a form of brain cancer in children, which is near incurable using current therapies.

The discovery of an aggressive genetic group will lead to better patient management of this form of tumor, which urgently requires new treatment approaches.

Their findings of two major studies, one of which was led by Northumbria’s Dr. Ed Schwalbe, are published in the journal NeuroOncology on October 8.

They provide critical evidence to help guide diagnosis and consider appropriate treatment dependent on the genetic make-up of the tumor.

This paves the way for more effective targeted approaches to treating these tumors, aimed at better prognosis, minimizing long-term side effects and improving quality of life.

Medulloblastoma is among the most common malignant brain tumors of childhood cancer and is responsible for about 5% to 10% of childhood cancer deaths.

The two-phase £5 million INSTINCT program set out to identify key genetic defects and find effective targeted approaches to treating Group 3 medulloblastomas, which occur primarily in young children and are effectively incurable, contributing significantly to overall childhood cancer death rates.

The tumor is driven by the presence of a gene called MYC which triggers rapid disease growth and often results in treatment failure.

Bringing together the largest cohort of MYC amplified tumors ever studied, the researchers were able to assess clinical and molecular data to see which factors affected survival and found critical variation in the clinical outcomes within this group.

The defect is only found in around 8% of medulloblastomas, with their rarity making them difficult to study.

Dr. Ed Schwalbe, Associate Professor in Bioinformatics and Biostatistics in Northumbria University’s Department of Applied Sciences, led the research in the first paper of the INSTINCT study, which focused on diagnosis. The second paper of the study focused on targeted therapies.

Dr. Schwalbe identified a group of patients with a “dismal prognosis,” having tumors with many copies of the MYC gene—typically between 10 and 40 copies, rather than the usual two, alongside other high-risk disease features such as metastasis.

Patients with such tumors are essentially incurable using current chemotherapy and radiotherapy.

The ability to more easily diagnose this group of patients will have an immediate impact, with clinicians having more information to know what they are dealing with and being able to have the right discussions with families.

Dr. Schwalbe also identified other patient groups whose tumors do not have the additional high-risk features, meaning their disease is curable using current treatments.

“The definition of near-incurable groups of patients has the potential to immediately impact their clinical management,” he said.

“The delivery of chemo and radiotherapy is very grueling for the patients and their families, and we now know that this is providing little, if any, benefit for those in this high-risk group, who urgently require new treatment approaches.”

Dr. Schwalbe added, “I’d like to thank those parents and patients who consented to take part in this study. Understanding that children with MYC medulloblastomas have different outcomes helps us to select the best treatments and paves the way for new approaches to treat this devastating disease.”

The INSTINCT research program began in 2015 and is led by Professor Steve Clifford, Director of Newcastle University Center for Cancer. He explained, “Medulloblastomas with MYC gene amplifications are one of the biggest challenges in pediatric oncology. In our latest studies, we have identified an important group of these tumors which are essentially incurable using current therapies, and how to recognize them diagnostically.

“New therapies are urgently required to treat these tumors, but there has been a lag in their development. In our second new paper, we report our discovery that MYC tumors are dependent on a critical metabolic pathway—the serine/glycine synthesis pathway—for their growth and development, and that we can target this pathway using PHGDH inhibitor drugs in experimental models to slow tumor growth.

“Together, these studies provide the essential diagnostic characteristics that can immediately be used to identify this critical tumor group in the clinic, as well as an important targetable mechanism for the development of new therapies aimed at improving their outcomes.”