BRD4: New hope in the battle against glioblastoma

The BET family proteins, comprising BRD2, BRD3 and BRD4, represent epigenetic readers of acetylated histone marks that play pleiotropic roles in the tumorigenesis and growth of multiple human malignancies, including glioblastoma (GBM). A growing body of investigation has proven BET proteins as valuable therapeutic targets for cancer treatment. Recently, several BRD4 inhibitors and degraders have been reported to successfully suppress GBM in preclinical and clinical studies. However, the precise role and mechanism of BRD4 in the pathogenesis of GBM have not been fully elucidated or summarized. This review focuses on summarizing the roles and mechanisms of BRD4 in the context of the initiation and development of GBM. In addition, several BRD4 inhibitors have been evaluated for therapeutic purposes as monotherapy or in combination with chemotherapy, radiotherapy, and immune therapies. Here, we provide a critical appraisal of studies evaluating various BRD4 inhibitors and degraders as novel treatment strategies against GBM.

 

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Title: The Role of BRD4 in Glioblastoma: Mechanisms and Therapeutic Potential

Abstract: Glioblastoma (GBM) is a highly aggressive brain tumor with limited treatment options and poor prognosis. The BET family proteins, including BRD2, BRD3, and BRD4, have emerged as important epigenetic readers of acetylated histone marks, playing diverse roles in the tumorigenesis and growth of multiple human malignancies, including GBM. In recent years, BRD4 has gained attention as a promising therapeutic target for GBM treatment. This review aims to provide a comprehensive summary of the roles and mechanisms of BRD4 in the initiation and development of GBM. Additionally, we critically evaluate the efficacy of various BRD4 inhibitors and degraders as novel treatment strategies against GBM, either as monotherapy or in combination with conventional therapies such as chemotherapy, radiotherapy, and immune therapies.

1. Introduction
   - Overview of glioblastoma and its current treatment challenges
   - Introduction to the BET family proteins and their role in epigenetic regulation

2. BRD4 and GBM Pathogenesis
   - Expression and activation of BRD4 in GBM
   - Regulation of key oncogenic pathways by BRD4 in GBM
   - Interplay between BRD4 and other epigenetic regulators in GBM

3. Mechanisms of BRD4-Mediated GBM Development
   - BRD4 and transcriptional regulation in GBM
   - BRD4 and chromatin remodeling in GBM
   - BRD4 and cell cycle progression, proliferation, and apoptosis in GBM

4. Therapeutic Targeting of BRD4 in GBM
   - Overview of BRD4 inhibitors and degraders
   - Preclinical and clinical studies evaluating BRD4 inhibitors in GBM
   - Combination strategies involving BRD4 inhibitors and other therapies in GBM

5. Challenges and Future Perspectives
   - Potential resistance mechanisms to BRD4 inhibition in GBM
   - Identification of biomarkers for patient selection and treatment response
   - Future directions and ongoing research in targeting BRD4 in GBM

6. Conclusion
   - Summary of the current understanding of BRD4's roles and mechanisms in GBM
   - Evaluation of BRD4 inhibitors and degraders as promising therapeutic options for GBM

This comprehensive review aims to provide researchers and clinicians with a comprehensive understanding of the pivotal role of BRD4 in glioblastoma pathogenesis. Additionally, it highlights the therapeutic potential of targeting BRD4 as a novel approach for GBM treatment, either as a monotherapy or in combination with other treatment modalities.

Related Products

Cat.No.	Product Name	Information
S8297	ARV-825	ARV-825 is a BRD4 Inhibitor that recruits BRD4 to the E3 ubiquitin ligase cereblon, leading to fast, efficient, and prolonged degradation of BRD4 and sustained down-regulation of MYC.

Related Targets

Epigenetic Reader Domain PROTAC