To determine how different drugs affect the cells, scientists use an imaging analysis method developed in collaboration with the Broad Institute. The automated system searches for drugs that decrease the number of leukemic stem cells, which are labeled with a fluorescent red marker. The software also analyzes the structure of the cells. Leukemic stem cells tend to group together to form structures called cobblestones, which Hartwell describes as “a biological readout of stemness.” By evaluating the number of cobblestone formations, the team can find drugs that interfere with the activity of cancer stem cells.
The researchers are currently screening libraries of FDA-approved drugs and known bioactive compounds, as well as RNA molecules. They are also using libraries of compounds, developed by Stuart Schreiber at the Broad Institute, known to prevent the type of DNA alterations seen in leukemia. The team has already identified compounds that can kill off cancer stem cells without affecting stromal cells.
Scadden’s team is also performing parallel tests on normal bone-marrow stem cells, in order to identify compounds that specifically target cancer stem cells without killing their normal counterparts. Scadden says that these studies could also provide potential treatments for diseases beyond cancer by identifying drugs that expand normal stem cells.
Robert Weinberg, a professor of biology at MIT, believes that the overall idea of targeting cancer stem cells is an attractive one because it suggests a path to therapies that are truly curative. But he says that it’s not clear whether the Harvard screening approach will be applicable to solid tumors, rather than to cancers of the blood like leukemia. He also cautions that the approach faces some difficulties. “It’s already clear that cancer stem cells are more resistant to most therapies than the bulk of the cancer cells in the tumor,” he says. Furthermore, if it is possible to wipe out cancer stem cells selectively, it still remains unproven whether doing so will truly eradicate the tumor.
Cancer stem cells were first identified in leukemia in 1994, but in the past several years, the cancer stem-cell hypothesis has gained ground as stem cells have been identified in other types of cancer, including those of the breast, prostate, brain, and pancreas. Although most scientists now agree that cancer stem cells exist, they still debate the cells’ exact role in cancer. Other types of cancer pose a greater challenge for screening than do blood cancers such as leukemia because the cancer stem cells are buried within solid tumors, making them more difficult to access and characterize.