Introduction
tumor, brainstem glioma, midline gliomas, Diffuse midline gliomas, tumors, IDH, gliomas
ADULT BRAIN TUMOR, TUMOR, DISEASE, TUMORS, GLIOMAS
Diffuse midline gliomas (DMGs) compose a rare subset of adult diffuse gliomas that often harbor histone H3 mutations (H3 K27M mutations). Recent studies have demonstrated median overall survival to be 19.6 months and 25 months in patients who received radiotherapy alone or with temozolomide (TMZ). Adults harboring H3 K27M-mutant gliomas predominate in patients aged < 40 years, and while these gliomas are rare in the entire population of adult IDH wild-type diffuse gliomas, they are frequent among the subset of tumors found within the midline [One of the main attributes of disease progression/proliferation in DMGs is associated with dysregulation of the cell cycle via cyclins and cyclin dependent kinases [While it has shown efficacy in a preclinical brainstem glioma model alone and with combination therapy, details of brainstem drug entry pharmacokinetics and pharmacodynamics are still needed [Efforts to evaluate drug delivery across the BBB in midline gliomas have been restricted to post biopsy specimens. In comparison, intracerebral microdialysis sampling of cortical tissue has been shown to be a highly effective tool in determining cortical neuropharmacokinetics (brain extracellular fluid penetration, accumulation and excretion) intratumorally and peritumorally in adult brain tumor patients [The tumor biology and drug distribution pattern within the midline region is largely unknown [This proposal will specifically measure biopsied tissue and brain interstitial fluid to compare both intracellular and extracellular abemaciclib concentrations. Microdialysis studies will afford the clinical team with information regarding BBB function as it relates to abemaciclib CNS entry and clearance. Additional information afforded from the biopsied tumor tissue will be genomic profiling (whole exome sequencing) to determine molecular targets for treatment and pharmacodynamic evaluations to assess response to abemaciclib treatment. These studies aim to better understand the complex relationship between DMG tumor biology and CNS drug distribution, to more intelligently select therapies for future clinical studies.