Targeting mTOR in Glioblastoma: Rationale and Preclinical/Clinical Evidence

Abstract

The mechanistic target of rapamycin (mTOR) drives several physiologic and pathologic cellular processes and is frequently deregulated in different types of tumors, including glioblastoma (GBM). Despite recent advancements in understanding the molecular mechanisms involved in GBM biology, the survival rates of this tumor are still disappointing, primarily due to the lack of efficacious treatments. The phosphatase and tensin homolog (PTEN)/phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mTOR pathway has emerged as a crucial player in GBM development and progression. However, to date, all the attempts to target this pathway with PI3K, AKT, or mTORC1 inhibitors failed to improve the outcome of patients with GBM. Despite these discouraging results, recent evidence pointed out that the blockade of mTORC2 might provide a useful therapeutic strategy for GBM, with the potential to overcome the limitations that mTORC1 inhibitors have shown so far. In this review, we analyzed the rationale of targeting mTOR in GBM and the available preclinical and clinical evidence supporting the choice of this therapeutic approach, highlighting the different roles of mTORC1 and mTORC2 in GBM biology.

Glioblastoma: Pathogenesis and Current Status of Chemotherapy and Other Novel Treatments

“…mTOR forms two complexes which are characterized by different binding partners; mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) [64]. mTORC1 is rapamycin-sensitive and is activated by at least five cues (growth factors, stress, energy status, oxygen, and amino acid concentration), and promotes glial cell growth upon activation by eukaryotic translation initiation factor 4E binding protein 1(E4BP1) and ribosomal protein S6 kinase (S6K) [64,65]. Conversely, mTORC2 is insensitive to rapamycin, which drives the glial cell proliferation, motility, and survival through the activation of AGC protein kinases [64][65][66].…”

“…mTORC1 is rapamycin-sensitive and is activated by at least five cues (growth factors, stress, energy status, oxygen, and amino acid concentration), and promotes glial cell growth upon activation by eukaryotic translation initiation factor 4E binding protein 1(E4BP1) and ribosomal protein S6 kinase (S6K) [64,65]. Conversely, mTORC2 is insensitive to rapamycin, which drives the glial cell proliferation, motility, and survival through the activation of AGC protein kinases [64][65][66]. However, it is found that overactivation of the PI3K/AKT/mTOR pathway reduces in the survival of glioblastoma patients and increases in the aggression of the tumor as it overstimulates processes responsible for cell proliferation, survival and migration in glioblastoma [67,68].…”

Novel mTORC1 inhibitors kill Glioblastoma stem cells

“…The mechanistic or mammalian target of rapamycin (mTOR) is a highly conserved protein kinase that serves as a central regulator of cell growth and connects cellular metabolism with environmental factors (6). It is divided into two distinct complexes labelled mTORC1 and mTORC2, both of which are often dysregulated in cancer, including GBM (7)(8)(9). mTORC1 is made up of a regulatory-associated-protein-of-mTOR (RAPTOR), proline-rich AKT substrate 40 kDa (PRAS40), mammalian lethal with Sec-13 protein 8 (mLST8), and DEP-domain TOR -binding protein (DEPTOR) (9).…”

“…It is divided into two distinct complexes labelled mTORC1 and mTORC2, both of which are often dysregulated in cancer, including GBM (7)(8)(9). mTORC1 is made up of a regulatory-associated-protein-of-mTOR (RAPTOR), proline-rich AKT substrate 40 kDa (PRAS40), mammalian lethal with Sec-13 protein 8 (mLST8), and DEP-domain TOR -binding protein (DEPTOR) (9). It is inhibited by rapamycin which binds to FK506-binding protein that only interacts with mTORC1.…”

Autophagy Modulators Profoundly Alter the Astrocyte Cellular Proteome

“…Pathways like Akt signaling are linked with activating mTOR proteins which in turn not only modulate autophagy but also regulate cell-cycle progression; if something goes awry, cell size and growth can be affected [9]. Since such signaling pathways are so intricately involved in regulating a plethora of other core cellular processes, no single drug or treatment has been identified to date that can target them to prevent glioblastomas from developing and growing [10]. One study that examined the cytotoxic effects of rapamycin in U-251 cells in the presence of temozolomide showed an increase in the level of autophagic glioma cell death, highlighting the importance of autophagy modulation in cancer treatment [11].…”