The Story of MTOR
How an expedition to an exotic island and a scientist who ignored his bosses led researchers to this master regulator of growth and metabolism.
The story of MTOR starts with a thimbleful of dust from Easter Island, the outpost in the South Pacific that’s famous for the giant stone heads scattered around the landscape – and for being thousands of miles from anywhere. In 1964, a group of mostly Canadian scientists and doctors, known as the Medical Expedition to Easter Island, stepped ashore to learn as much as possible about the health of the inhabitants and about their environment. When the expedition sailed away just over two months later, its scientific haul included samples of the islanders’ blood, casts of their teeth, 2500 pickled fish specimens, and dozens of vials of Easter Island dirt.
By the early 1970s, 73 of the soil specimens had made their way to Ayerst Research Laboratories in Montreal, where Suren Sehgal was a senior scientist. He and his colleagues had been sifting through exotic soil from various locations, looking for microorganisms that could be sources of new drugs. They hit paydirt, so to speak, when they analyzed one of the Easter Island samples and found a new type of bacterium that was pumping out a chemical poisonous to yeast and other fungi. Many of our antibiotics, including penicillin, were derived from chemical weapons that microorganisms use against their
enemies and rivals, so this new compound was just the type of substance Sehgal and his team had been searching for. They dubbed it rapamycin after the Easter Island inhabitants’ name for their home, Rapa Nui, and in 1975 they introduced it to the world in a scientific paper.
Sehgal not only helped to discover rapamycin; he also saved it from going down the drain when the lab where he worked closed in the early 1980s due to corporate cutbacks. As part of the shutdown procedure, Sehgal and his colleagues were supposed to dispose of their supply of rapamycin. “For all intents and purposes, rapamycin was a lost cause,” he recalled in 2001. But he had the foresight to squirrel away a few vials of the compound in a freezer at his home.
Although research on rapamycin eventually resumed, thanks partly to lobbying by Sehgal, scientists who wanted to turn it into a drug still faced a big problem – they didn’t know how it worked. Michael Hall of the University of Basel in Switzerland and colleagues decided that the way to answer that question was to track down yeast strains that were unfazed by rapamycin and figure out which genes were different in these fungi. In 1991 the researchers homed in on two genes that were altered in yeast that could survive rapamycin. They named the genes “target of rapamycin 1” (TOR1) and TOR2.
Sehgal died from colon cancer in 2003, but other researchers have filled in the details of how the proteins produced by the TOR genes function. Although yeast carry two different TOR genes, humans have only one, known as MTOR, which stands for mechanistic target of rapamycin (or mammalian target of rapamycin). Our cells use this gene to make the protein MTOR. If you wrote a to-do list of all of the tasks a cell has to complete during its day-to-day existence, MTOR would be crucial for many of them. Researchers often refer to it as the master regulator of cell growth and metabolism. Its connections help make it so powerful; MTOR interacts with other proteins, such as members of the AKT family and PTEN, that orchestrate key cell functions.
MTOR takes its cues from the cell’s environment. It responds to messages sent by other cells, including growth factors and hormones such as insulin, and it senses how much food is available. MTOR also weighs other indicators of the cell’s condition, such as whether it is stressed out. After balancing all these
influences, MTOR directs the cell’s next move. If food is plentiful, for instance, MTOR might ramp up production of proteins, which are essential for almost all cellular activities, including growth and division. MTOR also spurs cells to make other kinds of essential molecules, and it stimulates cells to stay alive.
In short, mTOR enables cells to survive, grow, and divide. The catch is that it provides its services not just to healthy cells, but also to cancer cells. Researchers have found that mTOR often works too hard in cancer cells and helps foster the abnormal growth of tumors. Sometimes this hyperactivity occurs because of mutations in MTOR. Researchers used to think these mutations were extremely rare – they’d only identified two – but in 2014 scientists discovered more than 30 others in several kinds of cancers, including kidney tumors. More commonly, however, MTOR malfunctions because of mutations in genes such as PTEN, KRAS, or PIK3CA, which produce proteins that MTOR directly or indirectly interacts with.
Here rapamycin re-enters the story. Rapamycin thwarts some of MTOR’s activities, and it was the first inhibitor of the protein that researchers tested in patients. The drug (marketed as Sirolimus) has proven useful for treating people who have received organ transplants. Rapamycin suppresses immune system cells and prevents them from destroying the organ, and the U.S. Food and Drug Administration approved it for kidney transplant recipients in 1999.
Given that it stifles the immune system, rapamycin might sound like a terrible choice for a tumor therapy. Cancer patients want their immune systems to vigorously attack and destroy tumor cells. But the drug’s effects are complex, and doctors now prescribe rapamycin’s chemical cousins everolimus (marketed as Afinitor) and temsirolimus (marketed as Torisel) to treat a type of kidney cancer known as renal cell carcinoma. Researchers are now testing whether rapamycin and its relatives work against several other kinds of tumors, including pancreatic, bone, and bladder cancers.
So far, though, the members of the rapamycin family don’t have stellar records as cancer treatments, possibly because they only curb some of MTOR’s effects. The drugs also have serious limitations. They can leave patients susceptible to infections or other cancers, and they might cause diabetes.
That’s why researchers are working to develop new types of drugs that block MTOR, the so-called next-generation MTOR inhibitors. None of these compounds has been approved for treating patients, but some of them have shown promise in clinical trials. One group of new compounds essentially shuts down MTOR’s power supply by preventing it from coupling with ATP, the molecule that fuels cellular activities. An example of these compounds is MLN0128, which clinical trials are testing in patients with the brain tumor glioblastoma, thyroid cancer, lung cancer, and other tumor types.
And maybe one day one of Sehgal’s scientific successors will uncover an even better MTOR blocker in a dollop of dirt from the Amazon rain forest or the highlands of Madagascar.