Targeting mTOR as a Therapeutic Approach in Medulloblastoma

Abstract

Mechanistic target of rapamycin (mTOR) is a master signaling pathway that regulates organismal growth and homeostasis, because of its implication in protein and lipid synthesis, and in the control of the cell cycle and the cellular metabolism. Moreover, it is necessary in cerebellar development and stem cell pluripotency maintenance. Its deregulation has been implicated in the medulloblastoma and in medulloblastoma stem cells (MBSCs). Medulloblastoma is the most common malignant solid tumor in childhood. The current therapies have improved the overall survival but they carry serious side effects, such as permanent neurological sequelae and disability. Recent studies have given rise to a new molecular classification of the subgroups of medulloblastoma, specifying 12 different subtypes containing novel potential therapeutic targets. In this review we propose the targeting of mTOR, in combination with current therapies, as a promising novel therapeutic approach.

Keywords: MBSCs; Medulloblastoma; mTOR.

Figure 1

Mechanistic target of rapamycin (mTOR) signaling pathway. mTOR is part of two different complexes, mTOR complex 1 (mTORC1) and complex 2 (mTORC2). mTORC1 is activated by the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway, and its downstream effectors activate cell growth, lipid synthesis, and metabolism, whereas it inhibits the autophagy. This complex can be inhibited by rapamycin. mTORC2 activates AKT, thus activating also mTORC1. Furthermore, mTORC2 activates the metabolism, cytoskeletal organization, and cell survival.

Figure 2

The Sonic Hedgehog (SHH)/Patched (PTCH1) and WNT signaling pathways. (A) The SHH ligand inactivates the PTCH1 receptor allowing Smoothened (SMO) to become active. Red cross represents the release of the inhibition exerted by PTCH1 on SMO when SHH is present. The SMO activates the GLI proteins, a family of transcription factors that turn on the expression of different target genes, giving raise to cell proliferation and tumorigenesis (activation of the pathway represented with black arrows). (B) The binding of WNT to the Frizzled receptor activates a cascade of downstream events, resulting in the inactivation of the β-catenin destruction complex. The red cross represent the release of the inhibition exerted by the β-catenin destruction complex on β-catenin. In consequence, β-catenin activates and promotes the transcription of genes that promote cell proliferation and tumorigenesis (represented with black arrows). Adapted from [21,23].

Figure 3

Schematic representation of a possible new approach to target medulloblastoma stem cells (MBSCs)s and MB. Medulloblastoma has an intracellular heterogeneity, having different cell types, such as normal tumor cells and MBSCs. With the classic treatment, the elimination of normal tumor cells is achieved, and the surviving MBSCs can form the tumor again. With the proposed new approach, the MBSCs are eliminated using mTOR inhibitors and the tumor cells are eliminated using the conventional therapy, achieving total tumor regression.