Undeciphering the mTOR pathway and the Indian scientist who started it all.

 

This 8 year old boy came in with the history of developmental delay and epilepsy. The diagnosis was written on his face. 

The adenoma sebaceum which you see is a misnomer for what are actually angiofibromas. They are a classical skin manifestation of tuberous sclerosis (TS).

Tuberous sclerosis is the classic mTORopathy. Dysregulation in the mTOR pathway is the reason behind the various manifestations including cardiac rhabdomyomas, intracranial hamartomas, subependymal giant astrocytomas and renal angiolipomas.

Overactivation of the mTOR pathway results in giant dysplastic neutrons, abnormal axonogenesis and dendrites, disordered cortical lamination reduced myelination and increased excitatory synaptic currents.

This mechanism has also been implicated in disorders with cortical malformations due to other genes such as STRADa, DEPDC5 and PI3K which act upstream of the mTOR pathway.

Since then there are been great excitement about possible targeted therapy with mTOR inhibitors in TS.

The EXIST-3 was a phase 3 RCT which used Everolimus (an mTOR inhibitor) and showed significant reduction of seizures in patients with TS ( 14.9% in placebo, 29.3% in low dose and 39.6% in high dose group).https://doi.org/10.1016/S0140-6736(16)31419-2

However a recent RCT everolimus failed to improve cognition/ autistic features in children 4-7 years old with TS.

I sat down to understand the mTOR pathway and was pleasantly surprised to find that it all began due to the exemplary work of an Indian scientist Surendra Nath Sehgal. http://www.indianjcancer.com/article.asp?issn=0019-509X;year=2017;volume=54;issue=4;spage=697;epage=698;aulast=Samanta

Surendra Nath Sehgal studied pharmacology from BHU, India; went on to do a PhD from Bristol and finally settled down in a research lab in Canada. He isolated a drug from the soil sample of the exotic Easter Islands in the South Pacific Ocean. 

He called it Rapamycin because the island was called Rapa Nui.

Though initially evaluated as an anti-fungal it was subsequently found to have immunosuppressive actions.

His persistent efforts to further characterize its properties led to the discovery of its significant anti cancer effects. Incidentally, I suppose that's why the commonest side effect of the mTOR inhibitors like everolimus is stomatitis.

Intense research into its mechanisms revealed that it acts on a target (to be later called mTOR) which plays a key role in cell proliferation and cell growth. This pathway is switched on by many oncogenic signalling pathways.

Ironically, Surendra Sehgal developed metastatic colon cancer in 1998 and he was treated with Rapamune which helped him survive till 2003.