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Applying Autophagy and Apoptosis for Strategies to improve treatment of Glioblastoma

Decent Essays
The pathways controlling autophagy and apoptosis should be targeted as the strategies to improve treatment of glioblastoma. The proteins to be targeted are Beclin, p62 and EGFR.
Survival related or anti-apoptotic protein such as Bcl2 were found to be upregulated in glioblastomas whereas autophagy proteins like Beclin were found to be downregulated. The autohagy (Atg) proteins function at several discrete but continuous steps in autophagy which include induction or selection/packaging of cargo, vesicle nucleation, vesicle elongation, vesicle docking and fusion with lysosomes, and degradation of vesicular contents. There is significant evidence showing overlap between these two pathways. Hence, we choose to target these pathways and
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p62 is an autophagy selective substrate and it accumulates when autophagy activity is reduced. Indeed, the level of p62 is often used as an indicator of autophagy activity. Interestingly, p62 levels are commonly upregulated in human tumors and genetic ablation of p62 in various tumor models has been shown to reduce the tumorigenesis occurring because of autophagy‐deficiency.
EGFR: The most common genetic mutations / alterations seen in gliomas are the amplification of EGFR, expression of EGFR VIII mutant and homozygous / hemizygous deletion of PTEN and NF-1. The aberrant signals that result from these mutations interact with the PI3KAkt- mTOR pathway and are responsible for promoting survival and chemoresistance in gliomas. Therefore targeting the receptor tyrosine kinases (RTKs) with either monoclonal antibodies or small molecule inhibitors emerged as a promising therapeutic strategy . Clinical studies with small molecule inhibitors of EGFR, such as erlotinib and gefitinib, have been disappointing in gliomas. Similarly, monoclonal antibodies against EGFR, cetuximab and panitumumab, have only a cytostatic effect in glioma cell lines. The abundance of multiple types of RTKs along with the frequent deletion of PTEN in gliomas may account for the lack of effectiveness of single agent tyrosine kinase inhibitors.
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