Medication prescribed for a certain type of epilepsy may offer a new method for treating malignant infantile brain tumors

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Medication prescribed for a certain type of epilepsy may offer a new method for treating malignant infantile brain tumors.

A specific mTOR inhibitor has the ability to cross the blood-brain barrier to both reach and attack the tumor at source.

This has been demonstrated by researchers from Uppsala University, in collaboration with US and UK colleagues, whose research has now been published in the scientific journal Cell Stem Cell.

Approximately 100 children suffer infantile brain tumors in Sweden each year.

The most common type of malignant brain tumor in infants and children is medulloblastoma. Radiation therapy is part of the standard treatment for medulloblastomas and modern radiation therapy has saved the lives of many children suffering from these often aggressive cancers; however, as it often comes with serious side effects for healthy brain tissue, it is seldom prescribed for infants.

Although a presumably better solution would be to give more targeted treatment, in order to establish such a therapy it would naturally need to be proven to be both more effective and come with fewer side effects than current treatments.

Many infantile medulloblastomas are amplified by MYCN, an oncogene that drives tumor growth and metastasis to the spinal column, leading to a very poor prognosis.

In the study in question, the researchers cultivated a particular type of neural stem cell and were able to demonstrate that MYCN was quickly able to turn these into cancer cells.

This suggests that these cells are likely to be the origin of infantile medulloblastomas.

MYCN activity is controlled by a signal in what is known as the Sonic Hedgehog pathway, which is involved in the normal development of the brain but is upregulated in medulloblastomas.

Although there are a number of drugs available today that inhibit this signal pathway, none have proven effective in children with brain tumors, who often experience serious side effects such as bone growth problems.

“I initially tested whether Sonic Hedgehog pathway inhibitors could knock out the tumor cells, but without success.

The cells attacked another protein instead, Oct4, and another signal pathway called the mTOR pathway, making the tumor more aggressive,” explains Matko Čančer, a researcher at Uppsala University’s Department of Immunology, Genetics and Pathology, who conducted the laboratory studies.

Matko Čančer was later able to show that Oct4 and the mTOR signal pathway interact in infantile brain tumors with a very poor prognosis.

When he then tested a number of drugs with the ability to inhibit this pathway, he saw that the brain tumor was quickly knocked out and that metastasis to the spinal cord was blocked.

“We discovered that one of the mTOR inhibitors that we used crossed the blood-brain barrier, suggesting that it actually reaches the tumor and can attack it in the brain. This is of course a prerequisite for effective clinical treatment,” says Fredrik Swartling, who led the research study.

“At the same time, we realized that similar mTOR inhibitors are often used to treat a certain type of epilepsy in small children with the genetic disease tuberous sclerosis complex (TSC), as they inhibit abnormal cell growth in the brain, and that these drugs have fewer side effects than the Sonic Hedgehog pathway inhibitors we tested.

This is a very promising discovery and, if this precision medicine works on young children with medulloblastomas that do not respond to conventional treatment, it would of course be fantastic,” says Swartling.


utism spectrum disorder (ASD) is characterized by high phenotypic heterogeneity, including deficits in social interaction and communication, as well as repetitive and unusual behaviours1,2.

The aetiology of ASD is still largely unknown, although a complex genetic basis is present3. Some insights have been gained through the study of specific genetic disorders, such as fragile X syndrome (FXS) and tuberous sclerosis (TSC), two monogenic disorders characterized by a high incidence of ASD ranging from 25 to 60%46.

FXS, the most common form of inherited intellectual disability, is caused by the loss or mutation of the fragile X mental retardation protein (FMRP)7,8. FMRP regulates several aspects of mRNA metabolism911. At synapses, FMRP regulates local protein synthesis at different levels9, with one of the characterized mechanisms based on the binding to CYFIP1 (cytoplasmic FMRP interacting protein 1) and eIF4E (eukaryotic translation initiation factor 4E)1215.

TSC is a dominantly inherited multisystem disorder characterized by the formation of hamartomas in different organs and the brain, caused by mutations in the TSC1 or TSC2 genes encoding hamartin and tuberin, respectively. TSC1 and TSC2 form a biochemical complex that inhibits the mammalian (also named mechanistic) target of rapamycin mTOR signalling pathway16. A large majority (85%) of children and adolescents with TSC display epilepsy, 50% cognitive disorders and ~30–40% ASD16,17.

Several forms of syndromic autism and intellectual disabilities (IDs), including FXS and TSC, are associated with mutations in genes that regulate protein synthesis and affect structure, transmission and plasticity of synapses18.

Thus, it has been hypothesized that aberrant synaptic protein synthesis might contribute to ASD and other IDs that share ASD-like clinical features19,20.

In the brain, mTOR and MAPK signalling pathways regulate synaptogenesis and local protein synthesis21.

The MAPK pathway regulates neural progenitor biogenesis, learning and memory22,23 and mRNA translation, by phosphorylation of TSC2 and eIF4E via MAPK-interacting kinase 1 and 2 (MNK1 and MNK2)14,24.

The MAPK pathway is upregulated in patients with syndromic ASD25. Furthermore, the deletion of the 16p11.2 locus, which includes the MAPK3 (mitogen-activated protein kinase 3) gene, is associated with ASD26,27.

The mTOR kinase is part of two functionally distinct biochemical complexes: mechanistic target of rapamycin complex 1 (mTORC1) and mechanistic target of rapamycin complex 2 (mTORC2)24,28. mTORC1 affects protein synthesis by phosphorylation of eukaryotic translation initiation factor 4E-binding protein 1 (eIF4E-BP1) and p70 ribosomal protein S6 kinase (S6K1)21,28.

The mTOR pathway is dysregulated in several human diseases, including cancer and diabetes29,30 as well as intellectual disabilities, such as FXS, Rett syndrome and ASD30.

Thus, there is a wealth of evidence implicating mTOR and MAPK pathways, and ultimately protein synthesis, in syndromic ASD. Surprisingly, however, less is known about the function of these pathways in idiopathic ASD.

Here, we sought to characterize mTOR and MAPK pathways in children with idiopathic autism who had no other identifiable clinical syndromes. We investigated the expression of the above-described two pathways in peripheral blood mononuclear cells (PBMCs) of children with idiopathic autism and in typically developing individuals (TDI).

In addition to performing a global analysis of patients versus TDI, we also analysed the molecular profile according to the clinical severity of ASD to identify a potential molecular signature of the disease severity.


More information: Matko Čančer et al. Humanized Stem Cell Models of Pediatric Medulloblastoma Reveal an Oct4/mTOR Axis that Promotes Malignancy, Cell Stem Cell (2019). DOI: 10.1016/j.stem.2019.10.005

Provided by Uppsala University

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