New Targeted Therapies for Children's Low-Grade Brain Tumors: A Comprehensive Guide

Table of Contents

• Introduction: Understanding Pediatric Low-Grade Gliomas
• Key Genetic Discoveries Driving New Treatments
• Targeted Therapy Breakthroughs
• Detailed Treatment Response Data
• Understanding Potential Side Effects
• Treatment Challenges and Considerations
• Alternative Treatment Options
• Emerging Technologies and Approaches
• Conclusion: The Future of Pediatric Brain Tumor Treatment
• Source Information

Introduction: Understanding Pediatric Low-Grade Gliomas

Pediatric low-grade gliomas are the most common central nervous system tumors in children and young adults, accounting for up to one-third of all brain tumors in these age groups. These tumors typically grow slowly but can cause serious symptoms depending on their location, including increased intracranial pressure in up to 25% of patients and seizures in another significant portion.

While many tumors are surgically removable with high cure rates, studies show that up to 50% of patients may have some remaining tumor after surgery, and approximately 30% will require additional non-surgical treatment. Traditional approaches have included conventional chemotherapy and radiation therapy, but these treatments come with significant side effects and long-term consequences, especially for developing children.

The recent World Health Organization classification system now divides these tumors based on both histological features and molecular characteristics, with most driven by alterations in the MAPK signaling pathway. This improved understanding has opened doors for targeted therapies that specifically address the genetic abnormalities driving tumor growth.

Key Genetic Discoveries Driving New Treatments

Groundbreaking research over the past two decades has identified that most pediatric low-grade gliomas are driven by abnormalities in the MAPK (mitogen-activated protein kinase) pathway. The most common alterations include BRAF V600E point mutations (found in 15-20% of cases) and BRAF fusion events, particularly with the KIAA1549 gene.

Researchers have identified three classes of RAF mutations that drive these tumors. Class I mutations are activating point mutations that cause persistent BRAF activation. Class II mutations involve RAF fusions that work independently of RAS signaling. Class III mutations enhance RAF activation through inappropriate binding to RAS proteins. Understanding these distinctions is crucial because they determine which targeted therapies will be effective.

Beyond BRAF alterations, scientists have discovered numerous other genetic drivers that offer additional therapeutic targets:

• FGFR (fibroblast growth factor receptor) fusions
• MYB/MYBL1 (myeloblastosis family of transcription factors) alterations
• MN1 (meningioma 1 tumor suppressor) fusions
• NTRK (neurotrophic receptor kinase) fusions
• KRAS (Kristen RAS oncogene homolog) mutations
• ROS1 (Receptor tyrosine kinase ROS proto-oncogene 1) mutations
• PRKCA (protein kinase C alpha) alterations
• PDGFR (platelet-derived growth factor receptor) amplification

These discoveries have fundamentally changed how doctors approach treatment, moving from one-size-fits-all chemotherapy to precision medicine based on each tumor's specific genetic profile.

Targeted Therapy Breakthroughs

The most significant advancement has been the development of BRAF and MEK inhibitors that specifically target the MAPK pathway abnormalities driving these tumors. Clinical trials have demonstrated remarkable success with combination therapy using dabrafenib (a BRAF inhibitor) and trametinib (a MEK inhibitor).

In a landmark phase I/II study (NCT02124772), researchers treated 13 patients with trametinib alone and 36 patients with the combination of dabrafenib plus trametinib. The results showed dramatically different outcomes: progression-free survival was 16.4 months in the trametinib-only group compared to 36.9 months in the combination therapy group.

This was followed by an even larger phase II trial (NCT02684058) that directly compared the combination therapy to conventional chemotherapy. The trial randomized 110 patients in a 2:1 ratio to receive either dabrafenib plus trametinib or standard chemotherapy with carboplatin and vincristine. The results were practice-changing and have established a new standard of care for eligible patients.

For tumors with BRAF fusions rather than V600E mutations, newer agents like tovorafenib have shown impressive results. This pan-RAF inhibitor recently received FDA approval for relapsed/refractory pediatric low-grade gliomas with BRAF fusions based on a phase 2 trial showing a 51% overall response rate.

Detailed Treatment Response Data

The clinical trial results provide compelling evidence for the superiority of targeted therapies over conventional chemotherapy. In the phase II trial comparing dabrafenib plus trametinib to chemotherapy, the overall response rate at 18.9 months was 47% in the targeted therapy group versus just 11% in the chemotherapy group.

Perhaps even more importantly, responses in the targeted therapy group occurred mostly within 4 months of starting treatment, meaning families saw results relatively quickly. Progression-free survival was significantly longer at 20.1 months in the targeted therapy arm compared to 7.4 months in the chemotherapy arm.

For patients with tumors affecting the optic pathways, visual outcomes were dramatically better with targeted therapy. Visual acuity improved in 34% of patients receiving dabrafenib plus trametinib compared to only 11% of those receiving chemotherapy. This represents a crucial quality-of-life improvement for children who might otherwise face permanent vision loss.

Other targeted agents have shown promising results in specific situations:

• Selumetinib achieved a 3-year progression-free survival of 84% in neurofibromatosis type 1 patients with inoperable plexiform neurofibromas
• Trametinib monotherapy showed effectiveness in prolonging time to progression in progressive low-grade gliomas and glioneuronal tumors
• Everolimus, targeting the mTOR pathway, showed a median progression-free survival of 11.1 months in recurrent or progressive low-grade glioma

Understanding Potential Side Effects

While targeted therapies generally have more favorable side effect profiles than conventional chemotherapy, they still present unique challenges that families should understand. The most common side effects of MEK inhibitors include weight changes - with up to 57% of patients experiencing weight gain and 19% experiencing weight loss.

Other frequently reported side effects include:

• Paronychia (nail inflammation) due to drug-induced neutrophilic lobular panniculitis
• Diarrhea and gastrointestinal discomfort
• Elevated CPK (creatine phosphokinase) levels
• Dry skin and skin rashes
• Hair color changes (particularly with tovorafenib)
• Fatigue and decreased energy levels
• Anemia and other blood count changes

Interestingly, doctors have noted decreased growth velocity in some children receiving these medications, which requires careful monitoring and potential dosing adjustments. It's important to note that while cardiomyopathy has been reported in adults receiving these medications, this side effect has not been observed in pediatric patients to date.

For FGFR inhibitors like erdafitinib, additional unique side effects have been observed including hypophosphatemia (low phosphate levels) and specific concerns about bone development, with one study reporting slipped capital femoral epiphyses in 3 of 7 children and increased linear growth velocity.

Treatment Challenges and Considerations

Despite the exciting progress, several important challenges remain with targeted therapies. Resistance develops in up to 28% of patients during treatment, often through activation of parallel pathways or recruitment of immune-suppressive cells in the tumor environment.

Perhaps the most concerning phenomenon is what experts call "rebound growth" - rapid tumor regrowth after stopping therapy. Studies show that 76.5% of patients experience rapid progression (defined as >25% growth within three months of stopping therapy), with a median time to progression of just 2.3 months. However, the encouraging news is that up to 90% of patients respond again if the same therapy is restarted.

Researchers are working to understand why this rebound occurs. Early laboratory studies suggest it may be due to accumulation of upstream activators when MAPK inhibition is withdrawn. There's also evidence of immune system involvement, with increased microglial activity in the tumor environment after stopping treatment.

The medical community is developing standardized definitions for these phenomena:

• Resistance: Tumor growth (>25% increase) while on MAPK inhibitor therapy
• Rebound: >25% growth of existing lesion within 3 months of stopping therapy
• Regrowth: >25% growth or new lesion 6 months after stopping therapy

These distinctions are important because they likely represent different biological mechanisms and may require different management approaches.

Alternative Treatment Options

While targeted therapies represent the most exciting recent advancement, other treatment options remain important, particularly for tumors without identifiable MAPK pathway alterations or when targeted therapies aren't accessible.

Bevacizumab, a medication that inhibits VEGF (vascular endothelial growth factor), has shown effectiveness in refractory or progressive cases. Meta-analyses indicate that up to half of patients achieve disease stability with bevacizumab, with only 8% showing progression during treatment.

For optic pathway gliomas specifically, bevacizumab has demonstrated impressive results for vision preservation. In one study of 17 patients with progressive optic pathway tumors, 14 showed stable or improved visual acuity or visual field, with improvement typically seen within 2.7 months. A larger multicenter trial with 33 patients found visual acuity stabilized in 74.4% and improved in 20.5% of cases.

Progression-free survival rates with bevacizumab were 70.9% at 18 months and 38% at 36 months in these studies. For cervicomedullary brainstem low-grade gliomas, all six patients in one retrospective review showed radiographic response and improvement in cranial nerve deficits, remaining clinically stable at 7-month follow-up.

Conventional chemotherapy regimens, particularly carboplatin/vincristine and vinblastine-based protocols, continue to have a role in treatment, especially while targeted therapies are being further studied in frontline settings through ongoing clinical trials.

Emerging Technologies and Approaches

Beyond pharmaceutical advances, new technologies are improving how we diagnose and treat pediatric low-grade gliomas. Liquid biopsies are being explored as a noninvasive method for both initial diagnosis and monitoring treatment response. This approach is particularly promising for tumors with common genetic alterations like BRAF fusions or V600E mutations.

Laser interstitial thermal therapy (LITT) represents another innovative approach for local tumor control. This technique involves stereotactic placement of an optic fiber that delivers focused laser energy to destroy tumor tissue. While currently available at only limited centers, this approach may be particularly helpful for deep-seated, non-cystic small tumors that are difficult to access surgically.

Focused ultrasound technology is being investigated for its potential to disrupt the blood-brain barrier temporarily, enhancing drug delivery to specific brain regions. Early research suggests this approach may also facilitate obtaining liquid biopsy samples from the tumor environment.

These technological advances, combined with the molecular understanding of these tumors, are creating unprecedented opportunities for personalized treatment approaches that maximize effectiveness while minimizing side effects.

Conclusion: The Future of Pediatric Brain Tumor Treatment

We are witnessing a paradigm shift in how we approach pediatric low-grade gliomas, moving from non-specific chemotherapy to precision medicine based on each tumor's genetic profile. The development of targeted therapies like BRAF and MEK inhibitors has dramatically improved outcomes for children with specific genetic alterations in their tumors.

While questions remain about optimal treatment duration, combination strategies, and long-term effects, the progress to date is extraordinary. Current clinical trials are exploring newer generation inhibitors, combination approaches, and how best to integrate these novel therapies with traditional treatment modalities.

Perhaps most importantly, these advances are improving not just survival statistics but quality of life for children with brain tumors. The preservation of vision, cognitive function, and normal development are becoming realistic goals rather than hopeful aspirations.

As research continues, we can expect even more refined treatment approaches, better understanding of resistance mechanisms, and ultimately more cures with fewer long-term consequences. The era of precision medicine for pediatric brain tumors has truly arrived, bringing new hope to children and families facing these diagnoses.

Source Information

Original Article Title: Novel therapies for pediatric low grade glioma

Authors: Dardan Demaliaj and Sharon L. Gardner

Publication: Current Opinion in Neurology 2024, 37:702–707

DOI: 10.1097/WCO.0000000000001319

This patient-friendly article is based on peer-reviewed research and aims to make complex medical information accessible to patients and families while preserving all scientific data and findings from the original publication.