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Midline Low-Grade Gliomas of Early Childhood: Focus on Targeted Therapies
Ludmila Papusha1, Margarita Zaytseva1, Agnesa Panferova1
1Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.
Purpose:
Midline low-grade gliomas (mLGGs) of early childhood have a poorer prognosis compared with tumors of other localizations and in older patients. LGGs are associated with aberrant activation of RAS-RAF-MEK pathway, and pharmacological inhibition of the pathway has therapeutic promise. The aim of this study was clinical and molecular characterization of infantile mLGGs, with emphasis on the efficacy of targeted kinase inhibition.
Patients And Methods:
This study enrolled 40 patients with mLGG age <3 years. The majority of the patients (30/40) received first-line chemotherapy (CT) as per International Society of Paediatric Oncology LGG 2004 guidelines. In all patients, molecular genetic investigation of tumor tissue by polymerase chain reaction and RNA sequencing was performed. The median follow-up was 3.5 years.
Results:
First-line CT failed in 24 of 30 recipients. The identified molecular profiles included KIAA1549::BRAF fusions in 26 patients, BRAF V600E in six patients, FGFR1::TACC1 fusions in two patients, and rare fusion transcripts in four patients. At disease progression, targeted therapy (TT) was initiated in 27 patients (22 patients received trametinib) on the basis of molecular findings. TT was administered for a median of 16 months, with partial response achieved in 12 of 26 (46%) patients in which response was evaluated. Severe adverse events were detected only on trametinib monotherapy: acute damage of GI or urinary mucosa complicated by hemorrhage and development of transfusion-dependent anemia in four patients and grade 3 skin toxicity in three patients.
Conclusion:
mLGGs of early childhood are often aggressive tumors, resistant to CT, and frequently require alternative treatment. The majority of patients harbor druggable molecular targets and respond to molecular TT.
Insights
Infantile midline low-grade gliomas (mLGGs) are aggressive and often resistant to chemotherapy. Targeted therapy shows promise, with many patients responding to molecularly-guided treatments.
Area of Science:
- Pediatric Oncology
- Molecular Diagnostics
- Neuro-oncology
Background:
- Midline low-grade gliomas (mLGGs) in young children present a significant clinical challenge due to their poorer prognosis compared to other localizations or older patients.
- Aberrant activation of the RAS-RAF-MEK pathway is a hallmark of low-grade gliomas (LGGs), suggesting potential therapeutic benefit from pathway inhibition.
Purpose of the Study:
- To perform a clinical and molecular characterization of infantile mLGGs.
- To evaluate the efficacy of targeted kinase inhibition in this patient population.
Main Methods:
- Enrolled 40 patients with mLGGs aged under 3 years.
- Conducted molecular genetic investigations including polymerase chain reaction and RNA sequencing on tumor tissues.
- Administered first-line chemotherapy to 30 patients and targeted therapy to 27 patients upon disease progression.
Main Results:
- First-line chemotherapy demonstrated limited efficacy, failing in 24 out of 30 patients.
- Common molecular alterations included KIAA1549::BRAF fusions (26 patients) and BRAF V600E mutations (6 patients).
- Targeted therapy, particularly trametinib, resulted in partial responses in 46% of evaluable patients, though some severe adverse events were noted.
Conclusions:
- Infantile mLGGs are frequently aggressive and chemoresistant, necessitating alternative treatment strategies.
- The presence of druggable molecular targets in the majority of these tumors supports the use of molecularly-guided targeted therapy.
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