Abstract
IntroductionGlioblastoma multiforme (GBM) is the most common primary central nervous (CNS) system malignancy with a poor prognosis. The standard treatment for GBM is neurosurgical resection, followed by radiochemotherapy and adjuvant temozolomide chemotherapy. Predictive biomarkers, such as methylation of the promoter region of the O6-methylguanine DNA methyltransferase (MGMT) gene, can successfully distinguish subgroups with different prognosis after temozolomide chemotherapy. Based on multiomics studies, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), BRAF V600E mutation, neurotrophic tyrosine receptor kinase (NTRK) fusions and other potential therapy targets have been found.MethodsWe have reviewed the preclinical and clinical evidence for NTRK fusions and TRK inhibitors therapy in cancers with NTRK fusions in pan-cancer and gliomas.ResultsSeveral NTRK1/2/3 fusions have been reported in GBM and preclinical studies have proven that NTRK fusions are potential driver mutations in some high-grade gliomas. Tropomyosin receptor kinase (TRK) inhibitors have shown efficacy as targeted therapies for extracranial tumors with NTRK fusions in recent clinical trials, with potential CNS tolerability and activity. However, whether NTRK gene fusions can affect survival status, the efficacy and resistance of TRK inhibitors in GBMs are lacking high-level evidences.ConclusionsFor GBM patients, NTRK fusions and TRK inhibitors are potential target therapy strategy but remain biological mechanism and clinical significance unclarified. More clinical data and future clinical trials are needed to provide more evidence that supports targeted therapy for GBM with NTRK fusions.
Highlights
Glioblastoma multiforme (GBM) is the most common primary central nervous (CNS) system malignancy with a poor prognosis
- Detection at transcriptome level and fusion transcripts caused by alternative splicing; - Detection of novel fusions and identification of gene partners; - Detection of more than 1 gene fusions and mutilple therapy targets simultaneously; - Focus on coding sequences but not introns; - Expensive; - Depend on RNA quality of specimens; - Difficulty in results interpreting and bioinformatics analysis; IHC Immunohistochemistry; FISH Fluorescence in situ hybridization; RT-PCR Reverse transcription-polymerase chain reaction; NGS Next-generation sequencing; RNA-seq RNA sequencing; DNA-seq DNA sequencing; *sensitivity and specificity were evaluated in populations of pan-cancer; neoadjuvant therapy [55]
This study reported 1 patient with glioneuronal tumor and BCAN-NTRK1 fusion and 1 patient with brain metastases from lung cancer and SQSTM1-NTRK1 fusion, and both patients showed an evaluable response to entrectinib, which supports the central nervous system (CNS) activity of entrectinib [45]
Summary
Glioblastoma multiforme (GBM) is the most common primary central nervous (CNS) system malignancy with a poor prognosis. The standard treatment for GBM is neurosurgical resection, followed by radiochemotherapy and adjuvant temozolomide chemotherapy. Predictive biomarkers, such as methylation of the promoter region of the O6-methylguanine DNA methyltransferase (MGMT) gene, can successfully distinguish subgroups with different prognosis after temozolomide chemotherapy. Epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), BRAF V600E mutation, neurotrophic tyrosine receptor kinase (NTRK) fusions and other potential therapy targets have been found
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