Treatment and efficacy monitoring of H3K27M mutant glioma

H3K27M mutant diffuse midline glioma (diffuse glioma, DMG) is a new brain tumor in the 2016 edition of the WHO Central Nervous System (CNS) malignancy classificationDMG occurs in the spinal cord, brain stem, pineal gland and thalamus; Its unique classification is the result of miscue mutations caused by the 27th bit lysine-to methionine displacement in histone variant HET1H3B (H3.1) or H3F3A (H3.3)The mutation leads to a unique relative homogenous phenomenology that has important genetic, epigenetic and clinical implications, unlike wild DMG and other non-middle-level gliomas (high grade glioma, HGG)H3K27M is a common histone mutation in diffuse midline gliomas and is associated with poor prognosisCarl Koschmann of the University of Michigan School of Medicine and others reviewed the latest data and targeted clinical trial results for H3K27M, and described the progress of continual fluid biopsy diagnosis and monitoring treatment of DMG, published online february 2020 in Current Oncology Reportsfindingsexisting studies have shown that both H3.1 and H3.3 mutant tumors are associated with shorter overall survival in patientsThe H3K27M mutant DMG had a poor prognosis and had an overall survival of 12 monthsThe H3K27M mutant DMG is mostly located in the brain bridge, spinal cord or thalamus; In adult patients, the tumor developed in the thalamus, with a median survival of about 16 months, and in children patients, which was mainly in the brain stem, and median survival of about 10 monthsThe median survival of patients with thalamus is longer than in spinal cord patientsCombined with the above results, it is assumed that there are significant differences in clinical behavior between adults and children with H3K27M mutant DMG, which may be attributed to differences in anatomical sitesTreatment of DMG should be as safe as possible as other HGGs, and some mid-line lesions that are difficult to remove on a large scale can attempt a small section of the excisionIn addition to infants, an auxiliary radiotherapy at a standard dose of 57 Gy is given after surgeryStudies have shown that methyloguanine methyl transferase (MGMT) is highly expressed in H3K27M mutant DMG, which may lead to resistance to tamoxifenStereotactic biopsy had a high diagnosis rate of H3K27M histological diagnosis of DMG, which had very little effect on patient mortalityH3K27M inhibited polycomb inhibition complex 2 (polycomb re-complex 2, PRC2) resulted in an overall decrease in total chromatin H3 dimethylation (K27me2) and trimethylation (K27me3), which resulted in increased cell proliferation potential and decreased differentiationTreatment strategies should be developed to include the overall regulation of methylation/acetylation balance, as well as the cascading effects of the restoration of H3K27M in tumor precursors, wherepanite deacetylase-paobinostat, shown to inhibit cell proliferation and induce apoptosis in multiple myelomas, is shown to inhibit cell proliferation and induce apoptosis Panobinostat made H3K27M mutant DMG histone tail acetylation, against PRC2 inhibition, partially saving H3K27M induced overall methylation low There have also been studies exploring the treatment of chimeric antigen receptor (CAR) T-cell treatment sprees targeting H3K27M mutant DMG, but with significant toxicity Up to now, clinical studies of H3K27M mutant DMG have shown that miprodone (imipridone, ONC201) and pyridoxine-2, 3-double-axerase 1 (IDO1) inhibitor synod (IDOximod) have good therapeutic effect on early H3K27M mutant DMG Diffuse endogenous endogenous brain bridge glioma (Diffuse engene eglioma, DIPG) is a subgroup of DMG with significant clinical and radiological improvements in THE treatment of CNS highly permeable anti-tumor drug ONC201 in patients with DIPG, and is currently being studied in clinical trials of H3K27M mutant DMG in adults and children IDO1 is an enzyme that breaks down tryptophan and can form immunosuppressive tumor microenvironments with high expression of IDO1 in hGG patients The iDO1 inhibitor moedgatamynia combined radiation therapy achieved good early clinical results Drugs to treat DIPG must overcome the blood-brain barrier and reach the level of treatment in tumors In addition, CAR T cells with targeted immunocheckpoint conditioning factor B7-H3 or GD2 showed good prospects in preclinical studies to treat HGG monitor ingresss with HGG treatment, the therapeutic response and the severity of the disease can be inferred; During or after treatment, false progression, false retreat and radioactive necrosis can cause changes in a variety of radiology images, such as increased lesions, INCREASEd FLAIR signals or contrast enhancement, etc., and therefore MRI imaging lacks specificity and sensitivity It is important to develop an accurate and minimally invasive method to monitor therapeutic responses The therapeutic effect of H3K27M mutant DMG is being evaluated with the help of body fluid biopsies Brain tumor cells release circulating tumor DNA (circulating tumor DNA, ctDNA) into the surrounding cerebrospinal fluid (CSF), and researchers have sequenced CSF's ctDNA that may help track mutant tumor cells It is of great clinical significance to carry out the diagnosis test, gene analysis and observe the therapeutic effect, and even predict the tumor growth change, through CSF body fluid biopsy conclusions
the final authors point out that histone mutation H3K27M acts as a catalyst in the field of neuro-oncology and can be used to develop new therapeutic pathways In addition, the ctDNA of H3K27M mutant DMG can be detected by CSF body fluid biopsy to accurately and sensitively monitor the effect of treating diffuse midline gliomas.