Cancer pathway exposed
CAMBRIDGE, Mass. (January 25, 2007) — In the
mid-1990s when Whitehead Member David
Sabatini, then a graduate student at Johns Hopkins
University, discovered a protein called mTOR, he had
no idea that within a decade this finding would catch
the attention of drug companies worldwide.
Sabatini and others had been investigating the mechanisms
behind the success of rapamycin, a drug that helps prevent
organ rejection in transplant patients. They found that
the drug works by blocking a previously unknown protein,
which was eventually dubbed mTOR (for mammalian target
of rapamycin).
“Discovering this new branch of mTOR
signaling has changed how we think about mTOR’s
role in cancer,” says Whitehead postdoc
David Guertin. |
Scientists soon found that mTOR helps cells detect
environmental nutrients and protein growth factors,
which in turn influence the actual size of a cell. When
rapamycin blocks mTOR, it tricks the cells responsible
for organ rejection into believing that they are starving.
But scientists now realize that mTOR’s significance
reaches beyond its relation to rapamycin. mTOR also
plays an integral role in many cancers, including prostate
and brain cancers.
Reporting in the December issue of Developmental
Cell, postdoctoral scientist David Guertin and
other researchers in Sabatini’s lab describe using
genetic tools to show that mTOR is a critical regulator
of a prominent cancer protein called AKT.
In a previous paper, then-postdoctoral researcher Dos
Sarbassov, Sabatini, Guertin and colleagues showed that
if proteins critical for one aspect of mTOR activity
were inhibited, AKT could not activate. This implied
that blocking mTOR might prevent AKT from driving tumor
growth. “But that paper relied on biochemical
techniques, like RNAi, to interfere with mTOR, and so
not everyone in the scientific community accepted it,”
says Sabatini. “In order to get the conclusive
evidence that mTOR is a major player, you need to knock
it out all together. And that’s what we did here.”
In the recent study, Sabatini’s lab developed
mouse models in which genes necessary for this aspect
of mTOR activity were deleted. Again, AKT was significantly
inhibited in these animal models.
These findings strongly suggest that an inhibitor of
this mTOR activity might have therapeutic value for
a wide range of AKT-related tumors, such as prostate
and brain cancer. Currently, many labs and drug companies
are looking at various ways to block mTOR activity.
(For reasons that are not clear, the original mTOR-blocking
drug, rapamycin, has had limited success in treating
cancer.)
“Discovering this new branch of mTOR signaling
has changed how we think about mTOR’s role in
cancer,” says Guertin. “This work has opened
the door to new therapeutic strategies that could have
a broad impact in the clinic.”
This project was funded by grants from the National
Institutes of Health and by a Damon Runyon Cancer Research
Foundation Fellowship.
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