Overcoming Taxane Resistance in Cancer
Proteomics study reveals a protein that, when suppressed, makes cancers more susceptible to chemotherapy
BOSTON, Jan. 25 /PRNewswire-USNewswire/ -- Taxanes, a group of
cancer drugs that includes paclitaxel (Taxol®) and docetaxel
(Taxotere®), have become front-line therapy for a variety of
metastatic cancers. But as with many chemotherapy agents,
resistance can develop, a frequent problem in breast, ovarian,
prostate and other cancers. Now, cancer researchers at Children's
Hospital Boston report a protein previously unknown to be involved
in taxane resistance and could potentially be targeted with drugs,
making a cancer more susceptible to chemotherapy.
The researchers believe that this protein, prohibitin1, could
also serve as a biomarker, allowing doctors to predict a patient's
response to chemotherapy with a simple blood test. The study was
published online by the Proceedings of the National Academy of
Sciences in its online early edition during the week of January
25.
The study, led by Bruce Zetter, PhD, of Children's Vascular
Biology Program, used proteomics techniques to compare the proteins
present in Taxol-susceptible versus Taxol-resistant human tumor
cell lines. The researchers found that the resistant cell lines,
but not the susceptible cell lines, had prohibitin1 on their
surface. When they suppressed prohibitin1 with RNA interference
techniques, the tumor cells became more susceptible to Taxol, both
in cell culture and in live mice with implanted Taxol-resistant
tumors.
Zetter's lab is still investigating why having prohibitin1 on
the cell surface makes a tumor cell resistant to taxanes. But in
the meantime, he believes that not only could prohibitin1 be
suppressed to overcome taxane resistance, but that it could also be
exploited as a means of targeting chemotherapy selectively to
resistant cancer cells.
"We are working to target various cancer drugs to
taxane-resistant cells by attaching them to compounds that bind to
prohibitin," Zetter explains. One such compound is already known,
and works well in animals to target other prohibitin-rich cells,
but has yet to be tested in humans.
Suppressing prohibitin1 alone probably isn't enough to make a
cancer fully Taxol-susceptible, but could be combined with other
strategies aimed at increasing taxane susceptibility, such as
targeting another protein called GST Pi, the researchers say. Other
mechanisms of resistance are known, but they so far haven't been
shown to present effective targets for therapy.
Zetter's lab is also trying to develop prohibitin1 as a
biomarker for taxane resistance that physicians could use in the
clinic. Since it's on the surface of the cell, Zetter believes
prohibitin1 may circulate in the blood where it could easily be
detected. His lab is in talks with several cancer centers to obtain
serum samples from patients who did and didn't respond to Taxol, so
that prohibitin1 levels could be measured and compared.
Zetter notes that prohibitin1 could easily have been overlooked,
and was found only because the team happened to look specifically
at proteins in the cell membrane, rather than simply doing a
whole-cell proteomic analysis.
"The interesting finding was that prohibitin was not just
another over-expressed protein," Zetter says. "It was up-regulated
primarily on the cell surface. When we looked at the whole cell,
the absolute amount of prohibitin wasn't changed. Instead,
prohibitin was moving from the inside of the cell to the cell
surface. It had shifted from one location to another, and when it
did, the tumor cells became resistant to taxanes. The fact that it
moves to the cell surface also makes it easier to direct drugs to
it."
Children's Hospital Boston has pending and issued international
patents on this technology (for more information, see http://www.childrensinnovations.org/SearchDetails.aspx?id=1247).
Nish Patel, PhD, was the study's first author. The study was
funded by a grant from the National Institutes of Health.
Children's Hospital Boston is home to the world's largest
research enterprise based at a pediatric medical center, where its
discoveries have benefited both children and adults since 1869.
More than 500 scientists, including eight members of the National
Academy of Sciences, 13 members of the Institute of Medicine and 12
members of the Howard Hughes Medical Institute comprise Children's
research community. Founded as a 20-bed hospital for children,
Children's Hospital Boston today is a 396-bed comprehensive center
for pediatric and adolescent health care grounded in the values of
excellence in patient care and sensitivity to the complex needs and
diversity of children and families. Children's also is the primary
pediatric teaching affiliate of Harvard Medical School. For more
information about the hospital and its research visit:
www.childrenshospital.org/newsroom.
CONTACT: Rob Graham Children's Hospital Boston 617-919-3110 rob.graham@childrens.harvard.edu
Source: Children's Hospital Boston
CONTACT: Rob Graham of Children's Hospital Boston,
+1-617-919-3110,
rob.graham@childrens.harvard.edu
Web Site: http://www.childrenshospital.org/
Posted: January 2010
