Researchers identify target for cancer drugs
CAMBRIDGE, Mass. (Feb. 14, 2005) — For nearly
a decade, scientists have been trying to fully understand
a particular communication pathway inside of cells that
contributes to many malignant brain and prostate cancers.
While scientists have identified elements of this pathway,
other key components have remained a mystery. Researchers
at Whitehead Institute now have discovered a missing
puzzle piece, a finding that may present drug makers
with a significant new cancer target.
"We believe that we have identified a component
that researchers have been looking for since 1996,"
says Whitehead Associate Member David
Sabatini, who is also an Assistant Professor of
Biology at MIT.
At the heart of this new research is a protein called
Akt, an important player in the regulation of cell division
and survival. Abnormally high activation of Akt has
long been implicated in a variety of cancers. If Akt
travels to the cell membrane, it is switched on and
promotes cell division, often contributing to tumor
growth as a result. However, as long as it stays within
the cell cytoplasm, it remains relatively inactive.
That's because the tumor-suppressor protein PTEN keeps
Akt in check by destroying lipids in the cell membrane
that normally draw Akt to the surface. In a sense, PTEN
keeps a leash on Akt and thus suppresses cell division.
But when PTEN is mutated and unable to function, Akt
breaks free. It makes its way to the cell membrane where
other proteins activate it, thereby enabling Akt to
contribute to tumor growth. "When a cell loses
PTEN through, say, a mutation, Akt goes gangbusters,"
says Sabatini.
The exact means by which Akt switches on when it reaches
the cell membrane has only been partially understood.
As a result, researchers have lacked a clear idea about
how to prevent the process. However, in the February
18 issue of the journal Science, researchers from the
Sabatini lab report on discovering an important missing
piece of the activation process.
This missing component, a molecule called mTOR, is
a protein that influences a cell's ability to expand
in size. mTOR has been widely studied as the target
for the immunosuppressant drug rapamycin (in fact, mTOR
is an acronym for "mammalian target of rapamycin").
In July of 2004, Dos Sarbassov, a scientist in Sabatini's
lab, discovered a new protein that mTOR interacts with
called rictor, but he wasn't yet sure of what these
two proteins do together. In this latest paper, Sarbassov
reports that when mTOR and rictor bind and form a complex,
they help activate Akt by adding a phosphate group to
a sequence of its amino acids (a process called "phosphorylation").
This process occurs not only in human cells but in
other organisms such as the fruit fly. Finding this
complex conserved in species as diverse as flies and
humans supports the claim that the mTOR/rictor complex
is indeed a missing piece of the puzzle.
According to Sarbassov, "If we find a molecule
that can block the mTOR/rictor complex, then we may
be able to prevent Akt from becoming active and contributing
to tumor formation."
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