MTOR!

I want to give our community a little background on the potential use of mTOR inhibitors like rapamycin for EHE. There has recently been renewed interest and some practical experience in the clinic that shows some promise, so here’s a  little summary to let know a bit of the rationale behind that. Note to the cognoscenti: For the sake of simplicity, I am going to use ‘mTOR’ to refer generically to what might be considered the classic regulatory functions of mTORC1.

mTOR, the mammalian target of rapamycin (or mechanistic target of rampamycin) is a protein complex that integrates information about cell status (especially nutrient levels and energy status) to regulate cell growth and division (proliferation). Sensing the levels of various nutrients is an important job of mTOR which is activated when these are high; essentially mTOR says, ‘It’s OK to start making proteins because we have enough nutrients and energy”.

A brief glossary note is indicated: inputs are considered ‘upstream’; effects exerted are ‘downstream’; and the specific signal molecules (usually proteins) are called ‘effectors’. The classic upstream inputs for mTOR are (positive) insulin signaling (occurs when insulin binds a cell surface receptor) and (negative) AMPK, an important sensor of cell energy status that is activated when the cell energy level is down – this puts the brakes on mTOR signaling. Effects of mTOR activation include protein synthesis and progression through cell cycle that together allow the cell to grow and divide. Mutations in upstream regulators of mTOR that leave it constitutively (always) ‘on’ result in growths and tumors that can be treated with mTOR inhibitors. You can look up tuberous sclerosis for example to learn more. This is why rapamycin might be considered a potential generic treatment for all sorts of cancers, including EHE.

However, there is theoretical (and serious) concern with a general application of this approach since the downstream targets of mTOR play a role in regulating and controlling growth responses through ‘negative feedback’ to upstream systems. To engineers, this is called a servo-mechanism; to the rest of us, this is just a way to keep things from getting out of control. The problem is that when mTOR is inhibited indiscriminately, many upstream systems become active or very sensitive; this could turn on other growth systems parallel to mTOR, essentially defeating the purpose of mTOR inhibition. However, there is now circumstantial evidence that suggests mTOR is specifically turned on in EHE, thereby providing a rationale for using rapamycinin EHE.   

The amino acid, leucine, is one of the key upstream activators of mTOR. Teleologically, it makes sense that a high intracellular concentration of an important amino acid means the cell is ready to synthesize proteins (which after all are made of amino acids). Going even more upstream, both YAP and TAZ are potent stimulators of the amino acid transporters that bring specific amino acids, including leucine, into the cell. This means that YAP and TAZ are both indirect stimulators of mTOR. So, when either of them is turned on all the time, leucine levels will be high and mTOR should be activated, too. This might provide an explanation for a possible benefit of mTOR inhibition in EHE. We should also look at the possibility of using specific inhibitors of the leucine transporter. More on this at a latter blog.