Molecular Profiling and Targeted Therapies in Gliomas

Purpose of review: Molecular profiling enables the evaluation of genetic alterations for the diagnosis and classification of gliomas and the selection of appropriate therapies. This review summarizes the current role of molecular profiling and targeted therapies for gliomas.

Recent findings: Molecular profiling is an integral part of the 2021 WHO classification of gliomas. Progress in the development of targeted therapies remains limited due to many factors including the presence of the blood-brain barrier and issues of tumor heterogeneity. Nonetheless, advances have been made with the IDH1/2 inhibitor vorasidenib for IDH-mutant grade 2 gliomas, the combination of dabrafenib and trametinib for BRAFV600E mutated gliomas, and the therapies for subsets of patients with fusions and H3K27M-altered diffuse midline gliomas. While there has been progress in the use of molecular profiling for the classification and treatment of gliomas, much work remains for targeted therapies to realize their potential.

 

Comments:

**Title: Molecular Profiling and Targeted Therapies in Gliomas: Current Advances and Future Challenges**

**Abstract:**
Gliomas are a diverse group of brain tumors characterized by significant genetic heterogeneity. Molecular profiling has emerged as a crucial tool for the precise diagnosis, classification, and targeted treatment of gliomas. The 2021 WHO classification of gliomas integrated molecular profiling, reflecting its pivotal role in the field. This review provides a comprehensive overview of the current status of molecular profiling in gliomas and discusses recent advances in targeted therapies. Despite progress, challenges such as the blood-brain barrier and tumor heterogeneity hinder the development of effective treatments. Encouraging developments include the use of vorasidenib, an IDH1/2 inhibitor, for IDH-mutant grade 2 gliomas, the combination of dabrafenib and trametinib for BRAFV600E mutated gliomas, and tailored therapies for patients with fusions and H3K27M-altered diffuse midline gliomas. This review highlights the achievements and limitations of molecular profiling and targeted therapies, emphasizing the need for continued research to fully unlock their potential in glioma management.

**1. Introduction:**
- Brief overview of gliomas and their genetic heterogeneity.
- Importance of molecular profiling in understanding glioma biology.

**2. Molecular Profiling in Gliomas:**
- Explanation of techniques used in molecular profiling (e.g., next-generation sequencing, gene expression profiling).
- Discussion of key genetic alterations analyzed (e.g., IDH mutations, EGFR amplifications, BRAF mutations).

**3. Integration of Molecular Profiling in 2021 WHO Classification:**
- Explanation of how molecular data are incorporated into the WHO classification system.
- Impact of molecular profiling on glioma diagnosis and classification.

**4. Challenges in Targeted Therapies:**
- Overview of challenges, including the blood-brain barrier and tumor heterogeneity.
- Discussion of advancements in drug delivery techniques to overcome these challenges.

**5. Recent Advances in Targeted Therapies:**
- Detailed description of recent successful targeted therapies, including vorasidenib for IDH-mutant grade 2 gliomas, dabrafenib and trametinib for BRAFV600E mutated gliomas, and therapies for fusions and H3K27M-altered diffuse midline gliomas.
- Examination of clinical trials and outcomes.

**6. Limitations and Future Directions:**
- Discussion of limitations in current targeted therapies, such as resistance mechanisms.
- Exploration of emerging therapies and technologies (e.g., immunotherapy, CRISPR-based gene editing) and their potential in glioma treatment.\

**7. Conclusion:**
- Summary of key findings and advancements in molecular profiling and targeted therapies for gliomas.
- Emphasis on the need for continued research and collaboration to overcome challenges and optimize the use of molecular profiling in glioma management.

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S8611	Vorasidenib (AG-881)	Vorasidenib (AG-881) is an orally available inhibitor of mutated forms of both isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2).

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Dehydrogenase