Pediatric diffuse midline glioma: Understanding the mechanisms and assessing the next generation of personalized therapeutics.
Nicolina JovanovichAhmed HabibJeffery HeadFarrukh HameedSameer AgnihotriPascal O ZinnPublished in: Neuro-oncology advances (2023)
Diffuse midline glioma (DMG) is a pediatric cancer that originates in the midline structures of the brain. Prognosis of DMG patients remains poor due to the infiltrative nature of these tumors and the protection they receive from systemically delivered therapeutics via an intact blood-brain barrier (BBB), making treatment difficult. While the cell of origin remains disputed, it is believed to reside in the ventral pons. Recent research has pointed toward epigenetic dysregulation inducing an OPC-like transcriptomic signature in DMG cells. This epigenetic dysregulation is typically caused by a mutation (K27M) in one of two histone genes- H3F3A or HIST1H3B -and can lead to a differentiation block that increases these cells oncogenic potential. Standard treatment with radiation is not sufficient at overcoming the aggressivity of this cancer and only confers a survival benefit of a few months, and thus, discovery of new therapeutics is of utmost importance. In this review, we discuss the cell of origin of DMGs, as well as the underlying molecular mechanisms that contribute to their aggressivity and resistance to treatment. Additionally, we outline the current standard of care for DMG patients and the potential future therapeutics for this cancer that are currently being tested in preclinical and clinical trials.
Keyphrases
- blood brain barrier
- small molecule
- end stage renal disease
- papillary thyroid
- clinical trial
- induced apoptosis
- single cell
- ejection fraction
- newly diagnosed
- dna methylation
- healthcare
- gene expression
- cell therapy
- squamous cell
- stem cells
- peritoneal dialysis
- young adults
- spinal cord
- prognostic factors
- high resolution
- squamous cell carcinoma
- signaling pathway
- white matter
- functional connectivity
- resting state
- spinal cord injury
- cerebral ischemia
- cell death
- risk assessment
- randomized controlled trial
- patient reported outcomes
- low grade
- chronic pain
- transcription factor
- free survival
- affordable care act
- rna seq
- current status