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HER2 and the Power of Translational Research: Part II
Continued from the BCC Newsletter, Spring, 2009
BREAST CARE CENTER NEWSLETTER • fall 2009 3
While it had been thought for many
years that the activating partner for
HER2 could be another HER2 protein,
our laboratory research group and others
discovered that this partner is actually
its sister protein HER3. In fact HER2
cannot cause breast cancer without the
help of HER3 and research in our laboratory
has now re-defined the causative
driver of this disease as the HER2-
HER3 dimer, not just HER2.
Too
much HER2-HER3 interaction leads
to uncontrolled and irrational cancer
cell behavior and growth and dysfunction
of the many cellular mechanisms
that ordinarily makes cells respect their
neighbors and not damage each other.
We have found that HER2-HER3
signaling in cancers is much more difficult
to inactivate with the current types
of drugs than would have been predicted.
This is because HER3 brings
to the complex many mechanisms to
protect it, exemplifying how important
the HER2-HER3 complex is in cancer
cells.
Inactivating HER2-HER3 is possible,
but it requires much higher doses
of our current types of drugs, or a new
generation of drugs that acts through
new mechanisms. We are currently testing
the effect of much higher dosing
of a HER2 inhibitor in a clinical trial
at our center with the hope that high
doses can cripple HER2-HER3 signaling.
Ultimately, our studies suggest that
to treat this disease very effectively
we
need to stop the HER2-HER3 complex
either by preventing them from coming
together or preventing HER3 from activating
HER2. Our laboratory is working
on the details of how the HER2-HER3
handshake takes place, how the HER3
key fits into the HER2 ignition, and
what kind of drug it takes to interfere
with the HER2-HER3 interaction and
to completely inactivate this complex.
We believe that the next generation of
therapies that arise from this research
will finally be the ones that will eradicate
this disease in affected patients. We
are working towards this endeavor in
collaboration with numerous other scientists,
including scientists who create
new types of drugs, scientists who study
the structures of proteins, and scientists
who study many of the other signaling
proteins that are affected by HER2 and
HER3.
Nature developed mechanisms
whereby HER2 and HER3 are kept
apart and only allowed to come together
in certain panic situations when cells are
under stress, or under inflammation,
or need help to survive. However, this
restraint is overcome in HER2-positive
breast cancer cells because the massive
amount of HER2 essentially ambushes
HER3, overriding the natural restraints
that limit their interactions and turning
on cell signals that are highly inappropriate
leading to malignant behavior.
These revelations have now made transparent
the inner workings of these
cancer cells, identifying the key culprits
and events, and efforts to intervene are
underway. The dedication of researchers
is absolute, and their will inexhaustible.
As long as people and government
continue to fund these efforts,
and patients continue to participate in
studies, the future holds great promise
that the curse of this disease will eventually
be lifted.
Dr. Moasser is a Medical Oncologist in the
UCSF Breast Care Center and Associate
Professor in Residence, Department of
Medicine, Division of Hematology/Oncology.
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