Pivotal New Research Fuels Possibilities for Aggressive Pediatric Brain Cancer

Pivotal New Research Fuels Possibilities for Aggressive Pediatric Brain Cancer https://pediatricsnationwide.org/wp-content/uploads/2025/01/Cover-Final-Color-V4-Flat-RGB-web-crop-1024x414.jpg 1024 414 Wendy Margolin Wendy Margolin https://secure.gravatar.com/avatar/?s=96&d=mm&r=g March 4, 2025 March 6, 2025

March 04, 2025
Wendy Margolin

A new umbrella trial of molecularly driven therapies for high-grade gliomas (HGG) and diffuse intrinsic pontine glioma (DIPG) aims to improve quality of live and extend survival rates for these aggressive tumors.

The diagnosis of high-grade glioma (HGG), a type of aggressive, malignant brain tumor, in pediatric patients is particularly heartbreaking. HGGs are one of the leading causes of cancer-related death in children. Most patients with HGG typically have one to two years to live, and although radiation can often prolong survival and help with symptom burden, there are generally no curative therapies.

DIPG (diffuse intrinsic pontine glioma) is a type of HGG located in the pons (brainstem). Because this location is critical in controlling neurologic function, DIPG tumors cannot be surgically removed. The disease can occur in children and adults but most commonly presents in kids around ages five to seven. It’s uniformly fatal.

“As neuro-oncologists, this diagnosis is close to all of our hearts because it can be so devastating to the patient and family. We want to do better to support these patients by offering novel biologically-guided therapy with few side effects,” says Margot Lazow, MD, MS, a pediatric neuro-oncologist in the brain tumor program at Nationwide Children’s Hospital and an assistant professor at The Ohio State University College of Medicine.

A newly opened phase II umbrella trial at Nationwide Children’s Hospital offers researchers, parents, and patients hope by providing molecularly targeted treatment in a precision medicine approach, with goal of prolonging patients’ lives and improving symptoms during treatment.

CONNECT TarGeT Umbrella Trial: Molecularly Targeted Therapy for Pediatric HGG/DIPG

A large team of researchers from around the world focusing on pediatric HGG and DIPG have worked together over recent years to develop TarGeT (Targeted pediatric high-grade Glioma Therapy), a phase II molecularly-guided umbrella trial for children and young adults newly diagnosed with HGG, including DIPG. The trial is open to all pediatric and young adult patients ages 12 months to 39 diagnosed with HGG, including DIPG, who have undergone biopsy or resection. TarGeT will be conducted at multiple sites worldwide as part of the Collaborative Network for Neuro-oncology Clinical Trials (CONNECT) – a global consortium of 24 childhood cancer centers and pediatric neuro-oncology experts leading early phase clinical trials for high risk pediatric brain tumors.

Nationwide Children’s Hospital is the first CONNECT site to open TarGeT (now open to enrollment), with many additional CONNECT sites in the US and internationally expected to open in the near future.

“Our goal is that each patient is offered novel and biologically guided therapy specific for their unique tumor molecular profile,” says Dr. Lazow.

Through the TarGeT trial, all patients will first enroll in an overarching screening protocol (TarGeT-SCR) that includes comprehensive molecular/genetic profiling of each patient’s tumor. In cases where equivalent detailed testing has already been performed, this testing will be submitted for review, with rapid return of results.

All cases will be reviewed by a central study team of genomics, pathology and neuro-oncology experts from around the world to confirm HGG/DIPG diagnosis, review each tumor’s molecular/genetic profile and assign patients to targeted treatment arms individualized to their tumor genetics.

As the founding chair of CONNECT, Nationwide Children’s Maryam Fouladi, MD, MSc, FRCP, has dedicated her career to developing and testing novel therapies in early-phase clinical trials for pediatric cancer. “Within five years, we moved the field forward by decades just by understanding what makes this tumor tick. Now, our job is to understand how we can treat these children better,” says Dr. Fouladi.

Clinical Trial Design

All study participants first undergo upfront radiation for about six weeks, followed by treatment to target specific genetic alterations in the tumor. In some cases, treatments are given concurrently with radiation. Researchers hope that addition of targeted therapy to radiation will lead to more positive outcomes.

“Many of the treatment arms involve combination therapy of either two targeted drugs or a drug in combination with radiation. We recognize this is such an aggressive disease that in most cases a single drug may not be enough,” says Dr. Lazow.

The first targeted treatment arm to open is TarGeT-A in which patients receive the oral targeted therapy combination of ribociclib and everolimus for tumors that have alterations of cell cycle (which ribociclib primarily blocks) or PI3K/mTOR pathway (which everolimus primarily blocks). TarGeT-A has opened to enrollment at Nationwide Children’s and is anticipated to open at many other CONNECT sites in the U.S. and worldwide soon.

Additional treatment arms will open at Nationwide Children’s and other CONNECT sites in the next six months or more. Researchers are recruiting approximately 350-400 patients from around the world to enroll in the TarGeT screening protocol and across all the treatment arms over the next four years or more.

Goal of Improving Outcomes and Quality of Life

The main question researchers aim to answer through each treatment arm in the TarGeT trial is whether molecularly guided treatments can prolong survival of patients diagnosed with HGG and improve their quality of life.

Most therapies being studied in TarGeT are oral medications that can be taken at home and are generally well tolerated, with few side effects. Most treatments are already in clinical use, have pediatric safety/dosing data and are FDA-approved for other patient populations or tumors.

The study will also collect tumor tissue, blood and spinal fluid at serial timepoints, and perform genomic and immune profiling analyses on these specimens. This data will be combined with clinical outcome results as well as advanced imaging measures and health-related quality of life surveys.

“Our hope, in addition to evaluating survival outcomes, is to identify multimodal biomarkers of response and resistance to these targeted therapies – through analysis of genomics, immune profiling, imaging and quality of life measures. We aim to better understand why certain tumors respond or do not respond to these treatments,” says Dr. Lazow.

HGG Treatment and Research at Nationwide Children’s

Although HGG are rare pediatric brain tumors, a higher proportion of patients are referred to Nationwide Children’s and other CONNECT institutions for clinical trials and for support from a multidisciplinary expert team of neuro-oncologists, neurosurgeons, neuro-radiologists and radiation oncologists who are all deeply familiar with these diseases. Additionally, Nationwide Children’s is home to world experts in genomics and molecular characterization of cancers.

Molecular testing for cancer has greatly expanded over the last two decades. Improved knowledge about the genetic makeup of specific tumors today guides new research and treatments – such as through the TarGeT trial – that wouldn’t have been possible in the past.

“If we can demonstrate the feasibility and success of offering precision medicine through TarGeT to pediatric patients newly diagnosed with HGG and DIPG, then this approach could be translated and expanded for many different tumor types,” she says.

Researchers and families of children with HGG and DIPG specifically are hopeful the research will lead to better outcomes for children with this rare pediatric brain cancer.

“My dream is that in 10 years, we could say this disease is no longer a fatal disease and these five and six-year-old kids are now growing up and living a full life,” says Dr. Fouladi.