Unveiling Novel Avenues in mTOR-Targeted Therapeutics: Advancements in Glioblastoma Treatment
Abstract
:1. Introduction
2. The mTOR Signaling Pathway in Glioblastoma
3. The mTOR Inhibitor and Its Limitations
4. Potential Biomarkers for mTOR Inhibitor Response
5. Strategies for Targeting mTOR in Glioblastoma
5.1. Combination Therapies
5.2. Personalized Medicines
5.3. Nanotechnology-Based Drug Delivery
5.4. Extracellular Vesicle as Drug Delivery Vehicle
6. Preclinical and Clinical Studies
6.1. Preclinical Studies and Outcome
6.2. Ongoing and Completed Clinical Trials
7. Challenges for Targeting mTOR in Glioblastoma
8. Future Perspectives and New Therapeutic Approaches
8.1. Potential of Novel mTOR Inhibitors
8.2. Targeting Specific Downstream Effectors of mTOR
8.3. Potential of Immunotherapy in Combination with mTOR Inhibitor
8.4. Targeting Crosstalk of mTOR with Other Signaling Pathways
9. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
References
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mTOR Inhibitors | Target | Activity | Limitations | References |
---|---|---|---|---|
Rapamycin | FKPB12/mTORC1 | Inhibits lymphocyte activation and induces cell cycle arrest |
| [35] |
RAD001 (Everolimus) | mTORC1 | Reduces VEGF expression and inhibits glycolysis | [36] | |
CCI-779 (Temsirolimus) | Inhibits mTOR activity and regulates cell division | [37,38] | ||
AP23573 (Ridaforolimus) | Inhibits PTEN-independent tumor cell proliferation and AKT activation |
| [39] | |
PP242 PP30 | mTORC1 and mTORC2 in an ATP-competitive manner | Affects cell cycle, cell proliferation, and cap-dependent translation | [40] | |
WYE-354 WAY-600 WYE-687 | mTOR/PI3K | Reduces mTORC1 and mTORC2 substrate phosphorylation in response to amino acids, and growth factors and induces PI3K-AKT |
| [41] |
Torin-1 | mTOR | Inhibits mTORC1 and mTORC2 complex, impairs cell proliferation, suppresses rapamycin-resistant functions of mTORC1 | [42,43] | |
Ku-0063794 | mTOR in an ATP-competitive manner | Inhibits AKT activation and hydrophobic motif phosphorylation |
| [44] |
AZD8055 | mTOR | Inhibits mTORC1 and mTORC2/AKT activity, promotes proteasomal degradation | [45] | |
XL388 | mTORC1 and mTORC2 | Induces apoptosis, suppresses autophagy | [46] | |
NVP-BEZ235 (Dactolisib) | Dual PI3K/mTOR | Inhibits AKT activity, S6RP (S6) and 4E-BP1 phosphorylation, induces FKHRL1 nuclear translocation and cell cycle arrest | [47] | |
PQR309 (Bimiralisib) | Dual PI3K/mTOR | Inhibits proliferation, and induces apoptosis and G1 cell cycle arrest | [48] | |
PKI587 (Gedatolisib) | Dual PI3K/mTOR | Increases DNA damage | [49] | |
JR-AB2-011 | mTORC-2 | Inhibits rictor-mTOR association, reduces migration and invasion | [50] | |
RapaLink-1 | mTORC1 and mTORC2 | Reduces chemotherapeutic drug resistance | [51] |
Drugs | Nanocarrier | Particle Size (nm) | Entrapment Efficiency (%) | Effects | References |
---|---|---|---|---|---|
Rapamycin | α,β-Poly(N-2-hydroxyethyl)-D,L-aspartamide (PHEA)-g-RhB | 100 | 82 | Efficient release and protection of Rapamycin from degradation | [85] |
PI-103 | Supramolecular polysaccharide nanotheranostic (SPN) | 200 | - | Kinase inhibition and caspase-mediated apoptosis | [86] |
Rapamycin | Biomimetic nanoparticle (Leukosome) | 108 | - | Decrease macrophage proliferation and proinflammatory cytokines | [87] |
Rapamycin | Lipid nanocapsule (LNCs) | 110 | 69 | mTORC1 signaling inhibition | [80] |
Rapamycin | P80-Par-PLGA-NPs or P80-CLD-PLGA-NPs | 110 | 69 | Anti-glioma activity | [88] |
Rapamycin | NP-conjugated pericardial patche | 370 | 86 | Reduction of smooth muscle cell proliferation | [89] |
Rapamycin | PLGA-LTTHYKL peptide | 122–130 | 88–91 | Phospho-S6 Inhibition | [90] |
Sirolimus | Cholesterol-PEG-NH2 or Cholesterol-PEG-amine | 12–14 | 77–82 | Scleral permeation and retention | [91] |
Sirolimus | D-α-tocopheryl polyethylene glycol succinate (TPGS) | 11 | 97 | Improve oral absorption | [92] |
Rapamycin | O-octanoyl-chitosan-polyethylene glycol (OChiPEG) | 44 | 86 | Scleral permeation and retention | [93] |
Rapamycin | Pluronic block copolymer | - | - | Increase solubility and oral administration, enhance absorption | [94] |
Sirolimus | Polymeric nanoparticle (PNP) | 35–38 | - | Increase radiosensitivity | [95] |
Rapamycin +Tacrolimus | Poly(ethylene glycol)-poly(pro-pylene sulfide) (PEG-PPS) | 39 | 41 | Allograft survival | [96] |
Rapamycin | Poly(ethylene glycol)-block-poly(2-methyl-2-benzoxycar-bonyl-propylene carbonate) (PEG-b-PBC) | 66–76 | 15–88 | Toxicity reduction | [97] |
Rapamycin | PLGA | 180 | 88 | Reduce neointimal hyperplasia | [98] |
Rapamycin + Paclitaxel | Methoxyl-poly(ethylene glycol)-succinic acid | 56–94 | - | Reduce multi-drug resistance | [99] |
Rapamycin + Piperine | PLGA | 150 | - | Improve oral bioavailability | [100] |
Rapamycin + Cisplatin | PLGA | 12–75 | 93 | Alteration of tumor microenvironment | [101] |
17-AAG + Paclitaxel | PEG-PLA | 37–44 | - | Increase apoptosis | [102] |
Therapy Category | Therapeutic Class | Therapeutic Agent | EV Source | EV Type | Packaging Method | Effects | References |
---|---|---|---|---|---|---|---|
Small molecules | mTOR inhibitor | Rapamycin | MSC | Small EV | Ultra sonication | Autoimmune response inhibition | [108] |
Sirolimus | Fibroblast | Exosome | Electroporation and ultra sonication | Arterial restenosis inhibition | [109] | ||
Rapamycin | Macrophage | Exosome | Extrusion (EB-AM) | Reduce proliferation and induce apoptosis | [107] | ||
Rapamycin | 4T1-breast cancer | Exosome | Co-culture of 4T1-with Rapamycin | Increase M1 marker and decrease M2 marker expression | [106] | ||
Chemotherapy | Doxorubicin | MSC | Exosome | Electroporation | Tumor growth inhibition | [110] | |
Paclitaxel | PC-3 | Exosome | Co-culture | Induce cytotoxicity | [111] | ||
Cisplantin | Macrophage | Exosome | Co-culture | Tumor growth inhibition | [112] | ||
Curcumin | PANC-1 | Exosome | Co-culture | Induce apoptosis | [113] | ||
TMZ | Glioma cell | Exosome | Co-culture | Tumor growth inhibition | [103] | ||
Camptothecin | 4T1 | Apoptotic body | Co-culture | Tumor growth inhibition | [114] | ||
Kinase inhibitor | TGFβRI | FBS | Exosome | Electroporation | Tumor growth inhibition | [115] | |
Immune inhibitor | TLR7/8 | FBS | Exosome | Electroporation | Tumor growth inhibition | [115] | |
Lapatinib | MCF10A | Exosome | Electroporation | T cell activation | [116] | ||
CpG | EL4 | Apoptotic body | Co-culture | Prevent tumor metastasis and recurrence | [117] | ||
cGAMP | Breast cancer cell | Apoptotic body | Active loading | STING activation and antigen representation | [118] | ||
Antibodies | A33Ab | LIM125 | Exosome | Co-culture | Tumor targeting | [119] | |
MHC, CD86, αCD3, αEGFR | DC | Exosome | Co-culture | Tumor growth inhibition | [120] | ||
CD3, CD28 | HEK293T | Exosome | Transfection | T cell activation | [121] | ||
RNA | miRNA | miR-138-5p | ADSCs | Exosome | Transduction | Tumor growth inhibition | [122] |
miR-497 | HEK293T | Exosome | Transfection | Tumor growth inhibition | [123] | ||
miR-199a | AMSC | Exosome | Transduction | Doxycycline sensitivity | [124] | ||
miR-146b | MSC | Exosome | Electroporation | Tumor growth inhibition | [125] | ||
miR-21 | HEK293T | Exosome | Electroporation | Tumor growth inhibition | [126] | ||
siRNA | siS100A4 | Breast cancer cell | Exosome | Co-culture and Extrusion | Tumor growth inhibition | [127] | |
siSTAT3 | RAW | Exosome | Ultra-sonication | Tumor growth inhibition | [128] | ||
siCDK1 | Sk-hep1 | EV | Electroporation | Tumor growth inhibition | [129] | ||
mRNA | PTEN | MEF and DC | Exosome | Nanaoporation | Tumor growth inhibition | [130] | |
UPRT | HEK293 | Microvesicle | Co-culture | Tumor growth inhibition | [131] | ||
Anti-sense | STAT6 | HEK293/M2 macrophage | Exosome | Co-incubation | Tumor growth inhibition | [132] | |
Gene editing tool | CRISPR-Cas9 | CRISPR-PARP1 | SKOV3 | Exosome | Electroporation | Induce apoptosis | [133] |
CRISPR-WNT10B | HEK293 | EV | Ultra-sonication | Tumor growth inhibition | [134] | ||
Protein | Transferrin receptor binding peptide | MDA-MB-231 | Exosome | Co-incubation | Tumor growth inhibition | [126] | |
Tlyp-1 | M1 macrophage | Exosome | Co-incubation | Tumor growth inhibition | [135] | ||
CD63/EGFR | M1 macrophage | EV | Electroporation | Tumor growth inhibition | [136] | ||
Combination | CPPO/Ce6/Dox-EMCH | THLG-HEK293 | EV | Electroporation | Induce drug sensitivity | [137] | |
Dox/Cho-miR-159 | THP-15 | Exosome | Co-incubation | Tumor growth inhibition | [138] | ||
5-FU/miR21 | HEK293 | Exosome | Co-incubation | Tumor growth inhibition | [139] | ||
CPT-SS-PR104A | HEK293 | Exosome | Co-incubation | Tumor growth inhibition | [114] | ||
siGPX4/Fe3O4 | Tumor cell | Apoptotic body | Active loading | Tumor growth inhibition | [140] |
Drugs | Registration No. | Stage | Disease Type | Target | Status |
---|---|---|---|---|---|
Afatinib Dasatinib Palbociclib Everolimus Olaparib | NCT05432518 | Early Phase I | Glioblastoma Recurrent disease Recurrent glioblastoma | mTOR and Tyrosine kinase | Not yet recruiting |
AZD2014 | NCT02619864 | I | Glioblastoma multiforme | mTOR | Completed |
AZD8055 | NCT01316809 | I | Glioblastoma multiform Anaplastic astrocytoma Anaplastic oligodendroglioma Malignant glioma Brain stem glioma | mTOR | Completed |
XL765 (SAR245409) | NCT00704080 | I | Mixed gliomas Malignant gliomas Glioblastoma multiforme | Dual PI3K and mTOR | Completed |
Everolimus Temozolomide | NCT00387400 | I | Brain and central nervous system Tumors | mTOR | Completed |
XL765 (SAR245409) XL147 (SAR245408) | NCT01240460 | I | Glioma Glioblastoma Astrocytoma grade IV | Dual PI3K and mTOR | Completed |
CC-115 | NCT01353625 | I | Glioblastoma multiforme | Dual pan-PI3K and mTOR | Completed |
DEC-205/NY-ESO-1 fusion protein CDX-1401 Sirolimus | NCT01522820 | I | Glioblastoma Anaplastic astrocytoma | mTOR | Completed |
GDC-0084 | NCT03696355 | I | Brain and central nervous system Tumors | Dual PI3K and mTOR | Active, Not recruiting |
RMC-5552 | NCT05557292 | I | Glioblastoma Recurrent glioblastoma | mTOR | Not yet recruiting |
MLN0128 | NCT02142803 | I | Adult glioblastoma | mTOR | Active, Not recruiting |
Perifosine Temsirolimus | NCT02238496 | I | Brain tumor, Recurrent glioblastoma Anaplastic astrocytoma Anaplastic oligodendroglioma Mixed glioma | Dual Akt and mTOR | Active, Not recruiting |
PQR309 | NCT02850744 | II | Glioblastoma multiforme | Dual pan-PI3K and mTOR | Terminated |
Everolimus | NCT00515086 | II | Glioblastoma multiforme | mTOR | Terminated |
CC-223 | NCT01177397 | I/II | Multiple myeloma Diffuse large B-Cell lymphoma Glioblastoma multiforme Hepatocellular carcinoma Non-small cell lung cancer Neuroendocrine tumors of non-pancreatic origin Hormone receptor-positive breast cancer | Dual PI3K and mTOR | Completed |
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Singh, S.; Barik, D.; Lawrie, K.; Mohapatra, I.; Prasad, S.; Naqvi, A.R.; Singh, A.; Singh, G. Unveiling Novel Avenues in mTOR-Targeted Therapeutics: Advancements in Glioblastoma Treatment. Int. J. Mol. Sci. 2023, 24, 14960. https://doi.org/10.3390/ijms241914960
Singh S, Barik D, Lawrie K, Mohapatra I, Prasad S, Naqvi AR, Singh A, Singh G. Unveiling Novel Avenues in mTOR-Targeted Therapeutics: Advancements in Glioblastoma Treatment. International Journal of Molecular Sciences. 2023; 24(19):14960. https://doi.org/10.3390/ijms241914960
Chicago/Turabian StyleSingh, Shilpi, Debashis Barik, Karl Lawrie, Iteeshree Mohapatra, Sujata Prasad, Afsar R. Naqvi, Amar Singh, and Gatikrushna Singh. 2023. "Unveiling Novel Avenues in mTOR-Targeted Therapeutics: Advancements in Glioblastoma Treatment" International Journal of Molecular Sciences 24, no. 19: 14960. https://doi.org/10.3390/ijms241914960