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. 2021 Dec 31;23(1):464.
doi: 10.3390/ijms23010464.

Deficiency in the Treatment Description of mTOR Inhibitor Resistance in Medulloblastoma, a Systematic Review

Hajar Alammar  1 , Rayan Nassani  2 , Mana M Alshehri  2 , Alaa A Aljohani  1 , Bahauddeen M Alrfaei  1   2
Affiliations

Deficiency in the Treatment Description of mTOR Inhibitor Resistance in Medulloblastoma, a Systematic Review

Hajar Alammar et al. Int J Mol Sci. .

Abstract

Medulloblastoma is a common fatal pediatric brain tumor. More treatment options are required to prolong survival and decrease disability. mTOR proteins play an essential role in the disease pathogenesis, and are an essential target for therapy. Three generations of mTOR inhibitors have been developed and are clinically used for immunosuppression and chemotherapy for multiple cancers. Only a few mTOR inhibitors have been investigated for the treatment of medulloblastoma and other pediatric tumors. The first-generation mTOR, sirolimus, temsirolimus, and everolimus, went through phase I clinical trials. The second-generation mTOR, AZD8055 and sapanisertib, suppressed medulloblastoma cell growth; however, limited studies have investigated possible resistance pathways. No clinical trials have been found to treat medulloblastoma using third-generation mTOR inhibitors. This systematic review highlights the mechanisms of resistance of mTOR inhibitors in medulloblastoma and includes IDO1, T cells, Mnk2, and eIF4E, as they prolong malignant cell survival. The findings promote the importance of combination therapy in medulloblastoma due to its highly resistant nature.

Keywords: mTOR; medulloblastoma; resistance; targeted therapy.

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Conflict of interest statement

The authors have declared that no competing interest exist.

Figures

Figure 1
Figure 1
PRISMA flow diagram. The diagram shows preferred reporting items for systematic reviews and meta-analyses. The diagram is a modified version of described PRISMA [7].
Figure 2
Figure 2
Schematic view of mTOR complexes and relevant pathways. The depiction shows mTOR complexes that induce downstream pathway activation. The activation involves either or both cascade cellular activities and/or embryonal processes under development.
Figure 3
Figure 3
mTOR inhibitors and their targets. The depiction illustrates specific inhibitors and their targets used for mTOR-targeted therapy.
See this image and copyright information in PMC

References

    1. Ostrom Q.T., Patil N., Cioffi G., Waite K., Kruchko C., Barnholtz-Sloan J.S. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2013–2017. Neuro. Oncol. 2020;22:IV1–IV96. doi: 10.1093/neuonc/noaa200. - DOI - PMC - PubMed
    1. Northcott P.A., Robinson G.W., Kratz C.P., Mabbott D.J., Pomeroy S.L., Clifford S.C., Rutkowski S., Ellison D.W., Malkin D., Taylor M.D., et al. Medulloblastoma. Nat. Rev. Dis. Prim. 2019;5:11. doi: 10.1038/s41572-019-0063-6. - DOI - PubMed
    1. Diamandis P., Aldape K. World Health Organization 2016 Classification of Central Nervous System Tumors. Neurol. Clin. 2018;36:439–447. doi: 10.1016/j.ncl.2018.04.003. - DOI - PubMed
    1. Chen Y., Zhou X. Research Progress of mTOR Inhibitors. Eur. J. Med. Chem. 2020;208:112820. doi: 10.1016/j.ejmech.2020.112820. - DOI - PubMed
    1. Wen J., Hadden M.K. Medulloblastoma Drugs in Development: Current Leads, Trials and Drawbacks. Eur. J. Med. Chem. 2021;215:113268. doi: 10.1016/j.ejmech.2021.113268. - DOI - PMC - PubMed

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