A multi-institutional team of Boston-area researchers has
discovered a chemical that works in mice to kill the rare but aggressive cells
within breast cancers that have the ability to seed new tumors.
These cells, known as cancer stem cells, are thought to
enable cancers to spread — and to reemerge after seemingly successful
treatment. Although further work is needed to determine whether this specific
chemical holds therapeutic promise for humans, the study shows that it is
possible to find chemicals that selectively kill cancer stem cells. The
findings appear in today's advance online edition of Cell.
“Evidence is accumulating rapidly that cancer stem cells are
responsible for the aggressive powers of many tumors,” said Robert Weinberg, a
member of the Whitehead Institute for Biomedical Research and one of the
study’s authors. “The ability to generate such cells in the laboratory,
together with the powerful techniques available at the Broad Institute, made it
possible to identify this chemical. There surely will be dozens of others with
similar properties found over the next several years.”
“Many therapies kill the bulk of a tumor only to see it
regrow,” said Eric Lander, director of the Broad Institute of MIT and Harvard,
professor of systems biology at Harvard
Medical School,
and an author of the Cell paper. “This raises the prospect of new kinds of
anti-cancer therapies.”
An emerging idea in cancer biology is that tumors harbor a
group of cells with the unique ability to regenerate cancers. In addition to
promoting tumor growth, these so-called cancer stem cells are largely resistant
to current cancer therapies. If it were possible to identify chemicals that
selectively kill cancer stem cells, such chemicals might become critical
candidates for future drug development.
However, researchers have struggled to study cancer stem
cells directly in the laboratory. The cells’ relative scarcity compared to
other tumor cells, combined with a tendency to lose their stem cell-like
properties when grown outside of the body, have severely limited the amount of
material available for analysis.
To overcome these hurdles, Broad and Whitehead Institute
researchers drew upon recent findings from Weinberg and his colleagues that
suggested a way to generate in the laboratory large numbers of cancer cells
with stem cell-like qualities. The technique works by coaxing adult cells to
undergo a critical change, known as an “epithelial-to-mesenchymal transition,”
that alters their shape and motility. At the same time, the cells also adopt
similar properties as stem cells.
“A critical aspect of our work was to generate relatively
homogenous and stable populations of cancer stem cell-like cells that could
then be used for screening,” said Tamer Onder, a former graduate student in
Weinberg’s lab, research fellow in biological chemistry and molecular
pharmacology at Harvard-affiliated Children’s Hospital, and co-first author of
the study. “We were able to achieve this by inducing the cancer cells into an
epithelial-to-mesenchymal transition using novel reagents that we had developed
in the lab.”
With an ample number of stem cells in hand, the
Broad-Whitehead team undertook a large-scale analysis of thousands of chemical
compounds, applying automated methods to search for ones with activity against
breast cancer stem cells. From a pool of more than 30 promising candidates, the
researchers identified a compound with surprising potency.
The compound, called salinomycin, kills not only
laboratory-created cancer stem cells, but also naturally occurring ones.
Compared to a common chemotherapeutic drug prescribed for breast cancer known as
paclitaxel, salinomycin reduced the number of cancer stem cells by more than
100-fold. It also diminished breast tumor growth in mice.
To further dissect the function of salinomycin, the
researchers also examined its genetic effects. Previous studies of tumors from
breast cancer patients have revealed groups of genes that are highly active in
cancer stem cells. Many of these same genes are linked with particularly
aggressive tumors and poor patient prognoses. The researchers’ studies show
that salinomycin (but not paclitaxel) treatment can decrease the activity of
these genes, revealing a possible molecular basis for the chemical’s biological
effects.
“Our work reveals the biological effects of targeting cancer
stem cells,” says co-first author Piyush Gupta, a researcher at the Broad
Institute. “Moreover, it suggests a general approach to finding novel
anti-cancer therapies that can be applied to any solid tumor maintained by
cancer stem cells.”
Broad Institute Director Eric Lander 
