Reference Detail

Ref Type

Journal Article

PMID

(38976815)

Authors

Papusha L, Zaytseva M, Panferova A, Salnikova E, Samarin A, Vilesova I, Voronin K, Protsvetkina A, Podlipaeva S, Zakharov I, Usman N, Hwang E, Karachunskiy A, Packer RJ, Novichkova G, Druy A

Title

Midline Low-Grade Gliomas of Early Childhood: Focus on Targeted Therapies.

Journal	Vol	Issue	Date	Pages	Journal Short Title
JCO precision oncology	8		2024 Jun	e2300590	JCO Precis Oncol

URL

Abstract Text

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.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.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.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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF V600E	childhood pilocytic astrocytoma	predicted - sensitive	Vemurafenib	Case Reports/Case Series	Actionable	In a clinical case study, Zelboraf (vemurafenib) treatment resulted in a partial response in a pediatric patient with pilocytic astrocytoma harboring BRAF V600E (PMID: 38976815).	38976815