Bet most of you never heard of mTOR. Well, this is about to change if I am reading my crystal ball correctly. It is the next big thing—the iPad-equivalent of Medicine.
What is mTOR?
mTOR stands for “mammalian Target Of Rapamycin” (pronounced em –tor), and it has a fascinating history. Rapamycin is a molecule isolated from bacteria and was tested as an antibiotic. Instead, as is common in medicine, it turned out to be something completely different—an immunosuppressant. In 1999, temsirolimus (under the brand name Torisel) was approved by the FDA as a treatment to avoid kidney transplant rejection. But nobody really knew how this drug worked, which is also common for new drugs. But now we know.
Biochemical research discovered an intracellular complex of proteins that together formed the target for rapamycin/temsirolimus, hence, the name. There are actually 2 protein complexes, called mTORC1 and mTORC2. We will focus on C1, the biologically more interesting complex. Obviously, this complex of proteins was not in the cell just to bind rapamycin. So what is its natural function? Further research continues to reveal new and amazing functions.
- It regulates protein synthesis in the cell.
- It regulates cell proliferation.
- It regulates cell growth.
- It senses the status of energy and oxygen supply (called redox potential) in the cell.
- It regulates the formation of new blood vessels (called angiogenesis).
How does mTOR “know” to start performing all those functions? As the diagram on the right shows, it gets signals from insulin and other growth factors, from the energy status of the cell, from hypoxia (low oxygen level) in the cell, and the supply of amino acids (which reflects the nutritional status of the cell). In fact, as Dr. Bestermann pointed out, phenformin, an anti-diabetes drug, reduces the insulin signal and consequently reduces the level of mTOR, which in turn should be useful in cancer therapy.
Pretty heady list of functions, but let’s examine what they mean.
Regulation of protein synthesis is the basis for cell proliferation and cell growth. Now, what would happen if there is dysregulation (impaired or dysfunctional regulation) by mTOR? Obviously, there will be unregulated cell proliferation and growth. Voilá! Now we are talking cancer! And sensing low oxygen supply would stimulate new blood vessel formation, to better provide oxygen (and nutrients) to the tissue. That’s exactly what a new tumor requires in order to proliferate and grow. In fact, several anti-angiogenic drugs (Avastin, sunitinib, sorafenib) are used in cancer therapy, trying to deprive the tumor of blood supply and literally starve it of oxygen and nutrients.
So, there you have it. mTOR is a major target for new anti-cancer drugs. By last count, there are about 10 in various stages of development, in addition to temsirolimus, which is already being used in the treatment of kidney cancer.
But wait, there’s more!
For several years, we’ve known that calorie restriction can significantly prolong lifespan in yeast, worms, mice, monkeys, and maybe humans. Have you seen those emaciated individuals on the brutal diet of 800-1,000 calories a day? Even if they fail to extend, their lifespan life will feel long being constantly hungry.
But they don’t have to be. It turns out that in response to calorie deprivation, cells have reduced protein supply, decreased growth, and proliferation—precisely the functions controlled by mTOR. Indeed, mTOR level is significantly depressed in the starving animal. So why go through the torment of severe dieting to prolong lifespan? Why not inhibit mTOR and mimic the metabolic effects of calorie deprivation? A recent experiment with rapamycin indeed prolonged mice lifespan by about 30%. This is equivalent to increasing a person’s lifespan from, say 90 to 120.
The November issue of the Proceedings of the National Academy of Science reported on another surprising function of mTOR. In laboratory studies conducted with mice, researchers led by Dorit Ron, Ph.D, a Gallo Center principal investigator and a professor of neurology at UCSF, measured an increase in mTOR cellular products in the nucleus accumbens of mice that had consumed alcohol—an indication that alcohol activates the mTOR pathway. The nucleus accumbens is a brain region that, in rodents and humans, is part of the reward system that affects craving for alcohol and other addictive substances. They then showed that rapamycin (or temsirolimus), the immunosuppressant drug that blocks the mTOR pathway, decreased excessive alcohol consumption, binge drinking, and alcohol-seeking behavior in the rodents.
If it’s too good to be true…
There is never a free lunch. Remember that rapamycin is a powerful immunosuppressant. That means that a person taking this drug is prone to infections in which, under normal circumstances, could be dealt with by the immune response without much of a problem, but now can be life-threatening. Not to minimize the problem, but we are already dealing with immunosuppressive cancer chemotherapy. I feel we could do the same with mTOR inhibitors. Patients on temsirolimus tolerate the drug quite well.
So, if you stuck with me to the end, you may not live forever, or overcome your fondness for alcohol (I hope not!), but you learned something new—which is cool, don’t you think?