Alex's Lemonade Stand Foundation for Childhood Cancer

Brain and spinal cord tumors, collectively known as central nervous system tumors, are the most common solid tumors in children—and the most common cause of cancer deaths in children. Brain tumors claimed this top spot in 2016, surpassing leukemia. It wasn’t that brain tumors had suddenly became more lethal; it was that research had improved outcomes in pediatric leukemia.⁸²

There are several things that make brain tumors so deadly. The location within the critical structures of growing brains not only causes the tumors to jeopardize normal function but also makes treatment risky. Mainstays of treatment, like tumor resection (surgery), radiation, and chemotherapy, all come with high risks. And those high risks are important to consider as other less risky treatments, such as immunotherapy, emerge.⁸³

Why Brain Tumor Counts Vary

Brain tumor counts can vary depending on what is included. Data from the Centers for Disease Control and Prevention (CDC), which this report uses, focus on malignant tumors, while the Central Brain Tumor Registry of the United States (CBTRUS) includes both malignant and non-malignant tumors. As a result, CBTRUS

reports higher totals. For example, an estimated 4,860 children and adolescents will be diagnosed with a primary brain or other CNS tumor in 2025. Although this report uses CDC data for consistency, non-malignant tumors remain an important part of the overall burden because they can still be serious and require intensive treatment and research for kids to be cured.

Breakthroughs and Research Milestones:

1. Proton radiation for pediatrics (2007-present)
   In 2007, proton radiation became available in the U.S. as a treatment for pediatric brain tumors. The benefit of this treatment: no exit dose of radiation which minimizes damage to surrounding brain tissue (see more on proton radiation in Section 3).⁸⁷
2. Innovative drug delivery systems (2010-present)
   The blood-brain barrier, which is a natural protective system that keeps toxins and other bad things out of the brain, can also keep cancer drugs out. Researchers are developing new ways to deliver treatments and bypass this natural defense. New drug delivery technologies being studied include:
   • Nanoparticles: Tiny particles used to package drugs so they can slip through the blood-brain barrier.⁸⁸
   • Convection-enhanced delivery: Surgical placement of small tubes (catheters) into the brain to allow for drug delivery.⁸⁹
   • Focused ultrasound: The use of sound waves to produce microbubbles that temporarily disrupt the blood-brain barrier, allowing for drugs to bypass this protective layer and enter brain tissue.⁹⁰
   • Intranasal delivery: Drugs that are made into particles that can be sprayed into the nose and enter the brain through nasal tissues.
3. Approval of targeted therapies (2010-present)
   The search for targeted, tumor-specific treatments began in the mid-20th century, but the approvals for pediatric brain tumors only began in 2010. These types of therapies bring the promise of being targeted killers: They attack cancer cells and leave healthy cells alone. For children with developing brains and bodies, this is particularly critical. A few examples of novel targeted therapies for brain tumors are:
   • Everolimus
     Targets mTOR, a pathway essential for tumor cell growth and survival.
     Approved for: astrocytoma in 2010^91,92 
   • Dabrafenib and trametinib
     Targets BRAF, which is essential for tumor cell survival.
     Approved for: certain types of low-grade gliomas in 2023⁹³ 
   • Vorasidenib
     Targets a protein called IDH, which is responsible for tumor growth through the regulation of cellular metabolism.⁹⁴
     Approved for: oligodendrogliomas and astrocytomas⁹⁵
   • Tovorafenib
     Tovorafenib Targets BRAF fusion or rearrangement or BRAF V600 mutation.^97,98
     Approved for: patients 6 months of age and older with relapsed or refractory pediatric low-grade glioma (LGG) in 2024
   • Larotrectinib, Entrectinib, and Repotrectinib
     Targets the NTRK fusion protein that is present in rare cases in gliomas.⁹⁹
     Approved for: NTRK fusion solid tumors, including CNS in 2018, 2023, and 2024 respectively
   • ONC201¹⁰⁰
     Targets a protein-coupled receptor called DRD2, leading to tumor cell death.¹⁰¹
     Approved for: diffuse midline glioma in 2025¹⁰²
4. Medulloblastoma reclassification (2016)¹⁰³
   Advances in medulloblastoma research led to the 2016 classification of four molecular subtypes based on genetic and molecular features, allowing clinicians to better tailor treatment and improve outcomes. These include WNT-activated (~10% of cases, best prognosis), SHH-activated (~25–30%), Group 3 (~20–25%, generally poorest prognosis), and Group 4 (~35–40%).^104,105
5. Immunotherapies (2017-present): Immunotherapy—a type of treatment that harnesses the body’s immune system to fight cancer cells—has shown promise in brain tumor treatment. A few examples of immunotherapies include:
   • Immune stimulating agents, such as PD-1 or CTLA-4 inhibitors, have shown success in treating adult cancers and are currently being explored in clinical trials for pediatric brain tumors, such as high-grade gliomas.¹⁰⁶
   • CAR T-cell therapy, which trains a patient’s own immune cells to attack cancer cells, is being explored across many pediatric cancer indications. Some current studies are focusing on a tumor-specific protein called GD2 as the target agent for these CAR T-cells in DMG and DIPG.¹⁰⁷
   • Cancer vaccines are currently being tested against pediatric brain tumors, with ongoing clinical trials for the treatment of medulloblastoma, high-grade glioma, ependymoma, and DIPG. These vaccines are designed to train the immune system to recognize and attack tumor cells.¹⁰⁸
   • Oncolytic viruses, which are re-engineered human viruses that can effectively deliver cancer treatments to tumors, have shown promising results in clinical trials against pediatric CNS tumors.¹⁰⁹