mTor – Drug Discovery Opinion

mTOR Linked to Myelin Repair

MS lesions The axons of nerve cells are sheathed by an insulating layer of myelin which is made up of about 80% lipid and 20% protein. Demyelination, leading to impaired or lost conduction of signals along the nerve, is a hallmark of multiple sclerosis (MS). In relapsing-remitting MS myelin can be replaced but, after repeated attacks, the repair system becomes less efficient. Researchers at the University of Medicine and Dentistry of New Jersey have now identified a key pathway which regulates the production of new oligodendrocytes – the myelin-producing cells of the CNS – and the production of myelin. They found that activation of the mammalian target of rapamycin (mTOR) is essential for oligodendrocyte differentiation at the late progenitor to immature oligodendrocyte transition. The effects were found to be mediated via two distinct signalling complexes, mTORC1 and mTORC2. mTORC2 was found to control myelin gene expression at the mRNA level whereas mTORC1 influenced expression of myelin basic protein via an alternative mechanism.

Although it remains to be determined whether stimulation of the mTOR pathway or removal of some inhibitory mechanism would be most appropriate, allowing the pathway to function normally could provide new treatments for MS and other demyelinating diseases.

The study is published in the May 13th online edition of the Journal of Neuroscience.

mTORC1 and MAPK Inhibitors for Treatment of Cancer

Rapamycin is a macrolide antibiotic used as an immunosuppressant to prevent organ rejection in transplant patients. Rapamycin and analogues have also been found to have anti-proliferative properties and their effects have been studied in a variety of cancers. Despite early promise, however, clinical tests have proved less successful than had been hoped.

Rapamycin

A report in the Journal of Clinical Investigation now suggests a reason for this lack of success. The anti-tumour effects of rapamycin are brought about by inhibition of the mTORC1 (mammalian target of rapamycin complex 1) pathway which is activated in many cancers, but the new study shows that this inhibition leads to activation of the mitogen-activated protein kinase(MAPK) cascade which stimulates the growth of cancer cells. The authors showed that the MAPK inhibitor, PD0325901, enhanced the effect of rapamycin or an analogue, RAD001 in cancer cell lines, and a xenograft mouse model of cancer.

The results suggest that patient stratification based on molecular pathways and combined use of these drug families, both of which are currently used as single agents in the clinic, will provide more effective treatments for cancer.

Rheb is Overexpressed in Certain Cancers

The mTOR (mammalian target of rapamycin) pathway represents a convergence point for signalling pathways commonly disrupted in cancer. The pathway includes several known and putative oncogenes as well as tumour suppressors. Rheb GTPase is the upstream activator of the mTOR Complex 1 (mTORC1) and is itself activated by growth factors and nutrients.

Two independent papers in the August 15th issue of Genes and Development link Rheb activity with particular cancers. Wendel et. al. demonstrate that Rheb activation can produce rapid development of aggressive and drug-resistant lymphomas. The authors further show that activation of mTORC1 is dependent on farnesylation of Rheb and that an inhibitor of farnesyl transferase (FTI) is able to block the activation. It is noted that Rheb is highly expressed in certain human lymphomas.

Pandolfi et. al. show that overexpression of Rheb promotes hyperplasia and a low-grade neoplastic phenotype in the mouse prostate. Additionally, Rheb overexpression combined with Pten haploinsufficiency results in marked promotion of prostate tumorigenesis.

These results suggest potential for Rheb as a therapeutic target in particular oncology indications.