A tumor-targeting nanomedicine carrying the p53 gene crosses the blood-brain barrier and enhances anti-PD-1 immunotherapy in mouse models of glioblastoma.
We studied the association of immunohistochemical expression of hypoxia inducible factor-1 alpha (HIF-1α), telomerase reverse transcriptase (TERT), isocitrate dehydrogenase 1 (IDH1) and tumor protein p53 with overall survival (OS) in glioblastoma patients uniformly treated by standard of care, with adequate follow-up.
To evaluate the frequency of MGMT methylation status in a single institute series of 134 GBMs and correlate it with clinical (age, sex, location, survival) and other molecular parameters [such as p53 expression, alpha thalassemia/mental retardation syndrome X-linked (ATRX) expression, isocitrate dehydrogenase (IDH) 1R132H mutation, and epidermal growth factor receptor (EGFR) gene amplification].
We found that HR indeed regulates p53 target genes, including those implicated in cell cycle progression and apoptosis in the GBM-derived U87 cell line, and restoring HR expression triggered G2/M arrest and apoptosis.
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.
More than 1700 proteins were quantified, and bioinformatics predicted activations of MYC, NFE2L2, FN1, and TGFβ1 and inhibition of TP53 in GBM-EV stimulated astrocytes that were then confirmed by qPCR.
In this study, biotinylated PAMAM G3 dendrimers substituted with the recognized anticancer agents cyclooxygenase-2 (COX-2) inhibitor celecoxib and peroxisome proliferator-activated receptor γ (PPARγ) agonist Fmoc-L-Leucine (G3-BCL) were tested in vitro on human cell lines with different p53 status: glioblastoma (U-118 MG), normal fibroblasts (BJ) and immortalized keratinocytes (HaCaT).
Quantitative morphological tumor characteristics on post-contrast T1-weighted MRI can to a certain degree provide insights regarding Ki67 and p53 status in patients with glioblastoma.
The Kaplan-Meier survival plot illustrated poor survival in glioblastoma patients with over-expressed LINC-ROR ( P=0.010) and down-regulated p53 ( P=0.002).
We suppose that performing a standard molecular analysis (IDH, EGFR, p53 and Ki67) is not sufficient to predict the behavior of a GBM in regards to overall survival (OS), nor to provide a deeper understanding of the meaning of the different genetic alterations in the DNA of cancer cells.
Correlation analysis of expressions of PTEN and p53 with the value obtained by magnetic resonance spectroscopy and apparent diffusion coefficient in the tumor and the tumor-adjacent area in magnetic resonance imaging for glioblastoma.
Mean Ki-67 labeling index was 29% (range, 1.5%-80%). p53 mutation was present in 20/36 GBs (55%), whereas OLIG2 expression was positive in 29/36 GBs (80.5%).
Specifically, targeting cellular pathways frequently altered in glioblastoma, such as the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR), the p53 and the retinoblastoma (RB) pathways, or epidermal growth factor receptor (EGFR) gene amplification or mutation, have failed to improve outcome, likely because of redundant compensatory mechanisms, insufficient target coverage related in part to the blood brain barrier, or poor tolerability and safety.