This study examined the mouse double minute 2 (MDM2) inhibitor RG7388 together with radiotherapy and analyzed strategies to overcome acquired MDM2 inhibitor resistance in glioblastoma.
<b>Conclusion</b>: MTBP regulates the cell survival and treatment sensitivity of TP53wt GBMs through MDM2-dependent post-translational modification of p53.
Our results suggest that the ADAMTS9-AS2/FUS/MDM2 axis may represent a suitable prognostic biomarker and a potential target in TMZ-resistant GBM therapy.
It was concluded that MDM-2 antagonists are improved therapy against GBM but evidential proof with more experimental studies is needed to standardize this therapy in near future.
The objective of this study was to investigate the impact of modulating MDM2 function in combination with front-line temozolomide (TMZ) therapy in GBM.
The knock-out of HAX-1 leads to the inactivity of the Ak1t/MDM2 axis, which leads to increased levels of p53, and finally generates cell cycle arrest and results in the apoptosis of glioblastoma cells.
Carnosol (CAR), a natural inhibitor of MDM2/p53 complex, has been attracted attention for its anti-cancer effects on several tumor types, including GBM.
Recently, a dual-target indol-3ylglyoxyldipeptide derivative, designed to bind to the Translocator Protein (TSPO) and reactivate p53 function via dissociation from its physiological inhibitor, murine double minute 2 (MDM2), has been developed as a potent GBM pro-apoptotic agent.
Congruently, growth inhibition upon normalization of mutant p53 by a small molecule, Prima-1, in human GBM cultures also requires p14(ARF)/MDM2 functionality.
Our findings suggest that targeting of the MEK-ERK-MDM2-p53 pathway in combination with temozolomide could be a novel and promising therapeutic strategy in the treatment of glioblastoma.
Gene expression-based prediction of genomic copy number aberrations in the chromosomal region 12q13 to 12q15 that is flanked by MDM2 and CDK4 identified Wnt inhibitory factor 1 (WIF1) as a candidate tumor suppressor gene in glioblastoma.
Multivariate analysis showed that MDM2 SNP309 G/G allele was significantly associated with favorable outcome in female glioblastoma patients (hazard ratio 0.54; 95% CI = 0.32-0.92).
Although there was no association between the MDM2 SNP309 and overall survival, the GG genotype was associated with development of GBM at a younger age in patients with tumors harboring wild-type p53, which may mitigate the effect of the MDM2 SNP.
In addition, this set of human GBM cell lines may constitute a suitable model for evaluating MDM2-targeted therapies in the context of various accompanying genetic alterations.