While TMZ has been FDA approved for two decades, it provides little benefit to patients whose tumors express the resistance enzyme MGMT and gives rise to systemic toxicity through myelosuppression.
Expression of the tumour suppressor genes (TSGs) [MGMT, RARβ, p21, E-cadherin, DAPK1] as well the methylation status of their promoters were examined alongwith the activity levels of DNMT and HDAC enzymes after treatment with genistein.
For this purpose, tumor samples from newly diagnosed and untreated GBM patients with methylated (n = 22) or unmethylated (n = 17) MGMT promoter were simultaneously analyzed for integrin α<sub>v</sub>β<sub>3</sub> expression by an automated immunohistochemical staining platform.
Consistently, patients with MGMT-negative/low tumors had a significantly longer mPFS than others (6.9 versus 2.0 months; hazard ratio = 0.29, 95% CI 0.02-0.41; P = 0.003) and a non-significant trend for longer mOS.MB testing showed similar accuracy.
The 5-year survival rate of patients with GBM is <10%, a colossal failure that has been partially attributed to intrinsic and/or acquired resistance to TMZ through O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status in the tumor.
The incremental value of a radiomic signature beyond molecular (O6-methylguanine-DNA methyltransferase [MGMT] promoter methylation, DNA methylation subgroups), clinical (patient's age, KPS, extent of resection, adjuvant treatment), and standard imaging parameters (tumor volumes) for stratifying PFS and OS was assessed with multivariate Cox models (performance quantified with prediction error curves).
This was evidenced by a decreased level of the following parameters: a proliferation marker (Ki-67), a tumor growth marker (<sup>18</sup>F-fluorothymidine uptake, determined by PET/CT images), and the MGMT enzyme.
The methylation of the MGMT promoter was not associated with clinical stage and tumor grade (OR = 1.46, 95% CI = 0.71-3.02, p = .301; OR = 1.13, 95% CI = 0.51-2.46, p = .767; respectively).
Paraffin-embedded tumor tissues were subjected to FISH analysis, and the corresponding frozen tissues from the same tumors were evaluated for aCGH and/or WES for 1p/19q co-deletion and other genetic parameters, which included IDH1-R132H, ATRX, TP53, CIC, and NOTCH1 mutations and MGMT methylation status.
After adjusting for age, sex, Karnofsky Performance Scale score, MGMT promoter methylation, and extent of tumor resection, and time to surgery, the hazard ratio for the steroid-free group of patients was 0.46 (95% confidence interval, 0.28-0.77) compared with steroid-dependent patients.
CWs may represent an effective and safe first-line treatment for patients with HGG that exhibit complete tumor resection and harboring a methylated MGMT promoter.
The developed biosensor has a dynamic range from 3.9 to 500 pm and a limit of detection of 1.2 pm for the methylated synthetic sequence of the tumor suppressor gene O-6-methylguanine-DNA methyltransferase (MGMT) promoter region.