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 proteins associated with them.
Beclin: Beclin -1, the mammalian orthologueof the yeast Atg6/Vps30 gene, is an essential mediator of autophagy and also has a role as a tumor suppressor. Beclin-1 forms a multimeric complex with Atg14, Vps34/class 3 phosphatidylinositol 3--‐kinase (PI3k), and Vps15; the formation of this complex is necessary for the formation of the autophagosome and contributes to the regulation of autophagy. The human Beclin-1 gene is monoallelically deleted or is underexpressed in breast, ovarian, prostate, and gastric cancer, and most malignant brain tumors. Reduced expression ofautophagic marker LC3B-II and Beclin-1 in glioblastoma multiforme indicates a downregulated autophagic capacity that relates to the progression of astrocytic tumors. p62: Recent studies have identified some level of specificity of the cargo for degradation through autophagic receptors containing the Atg8‐family Interacting motif: p62 (also Known as sequestosome‐1), Atg19, Atg32, NBR1 and Nix. Autophagy‐relat...
... middle of paper ...
...activity in gliomas in preclinical models by eliminating activation of Akt often observed with mTOR inhibitors. Therapies targeting components of the RTK-PI3K-Akt-mTOR axis typically promote autophagy induction, which has been suggested to play a cytoprotective role. Therefore, combining late stage autophagy inhibitors with agents promoting autophagy induction could enhance cytotoxicity in gliomas by inducing autophagic stress. In fact, this concept was tested when combining PI3K-mTOR / AKT inhibitors (PI-103 and AKT-1/2), with the lysosomotrophic agent chloroquine (CQ), which inhibits lysosomal protease activity, accelerated cell death in gliomas. A dual PI3K and mTOR inhibitor, NVP-BEZ235, which is currently in clinical trials for use in solid tumors induces autophagy and works synergistically in combination with choloroquine by inducing apoptosis in glioma cells.