In addition to its benefits for molecular subgrouping and copy number analysis of brain tumors, DNA-methylation based classification is a highly reliable tool for the assessment of MGMT promoter methylation status in glioblastoma patients.
Some of these genetic alterations are currently believed to have clinical significance and are more related to secondary GBMs: TP53 mutations, detectable in the early stages of secondary GBM (found in 65%), isocitrate dehydrogenase 1/2 mutations (50% of secondary GBMs), and also O6-methylguanine-DNA methyltransferase promoter methylation (75% of secondary GBMs).
LC-MS/MS plasma stability assays were conducted in mice to further explore the stability profile of TMZ@Calix <i>in vivo</i> The therapeutic efficacy of TMZ@Calix was compared with that of unbound TMZ in GBM cell lines and patient-derived primary cells with known O6-methylguanine-DNA methyltransferase (<i>MGMT</i>) expression status and <i>in vivo</i> in an intracranial U87 xenograft mouse model.
The absence of systematic and clinically relevant changes in HRQOL and neurocognitive function combined with the survival benefit of lomustine-temozolomide versus temozolomide alone suggests that a long-term net clinical benefit exists for patients with newly diagnosed glioblastoma with methylation of the MGMT promoter and supports the use of lomustine-temozolomide as a treatment option for these patients.
We showed that ionizing radiation and temozolomide reduced the viability of cancer stem cells from GBM patients, as well as modified MGMT gene and miRNA-181d expression in cancer stem cells, suggesting that miRNA-181d interferes in the glioblastoma cancer stem cell response to treatment with temozolomide and ionizing radiation.
The purpose of this study was to determine the effect of disulfiram (DSF), an aldehyde dehydrogenase inhibitor, on in vitro radiosensitivity of glioblastoma cells with different methylation status of O6-methylguanine-DNA methyltransferase (MGMT) promoter and the underlying mechanism of such effect.
GTR and MGMT promoter methylation are independent prognosticators for improved overall and progression-free survival in a homogeneous cohort of newly diagnosed patients with IDH wild-type glioblastoma.
Temozolomide (TMZ) is the first-line chemotherapy drug for glioma, but whether TMZ should be withheld from patients with GBMs that lack O6-methylguanine-DNA methyltransferase (<i>MGMT</i>) promoter methylation is still under debate.
Although the two classical molecular markers of glioblastoma including isocitrate dehydrogenase 1 or 2 (IDH1/2) mutation and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation are associated with overall survival rate of glioblastoma patients, they are not specific to the survival outliers.
Surprisingly, integrative analyses demonstrated that O6-methylguanine-DNA methyltransferase methylation and isocitrate dehydrogenase mutation status were equally distributed among glioblastoma metabolic profiles.
In addition, because temozolomide did not cause phosphorylation of cPLA<sub>2</sub> in MGMT high-expressing glioblastoma T98G cells, phosphorylation of cPLA<sub>2</sub> may be caused by DNA alkylation of temozolomide.
To determine whether there is a threshold for the TMZ-induced DNA damage response and exploring the factors regulating the switch between p53 dependent survival and death, the glioblastoma lines LN-229 (deficient in MGMT) and LN-229MGMT (stably transfected with MGMT) were exposed to different doses of TMZ. p53 protein expression and phosphorylation levels of p-p53ser15 and p-p53ser46 were determined by Western blotting.