Oncology’s ultimate goal is to develop treatments that destroy cancer cells and prevent them from returning while leaving healthy cells untouched. Researchers recently began trying to thwart tumor recurrence by developing drugs that target “cancer stem cells,” which may survive traditional chemotherapy and spawn new malignancies.
A new kind of tumor drug screen using fruit flies has found that half of these stem cell-targeting drugs—including some that are FDA-approved—cause a side effect that may actually contribute to tumor recurrence.
The experiment revealed that a subset of chemotherapy drugs does kill tumor stem cells but also triggers excess growth of normal stem cells in the flies. Because humans share some key biology with fruit flies, the discovery could explain why human tumors sometimes grow back after treatment. It also could help in the selection or development of safer chemotherapy drugs.
“We found that one group of chemotherapeutics damages the microenvironment where normal stem cells live in the body, and that the stem cells respond by hyperproliferating,” said first author Michele Markstein, who pioneered the work as a postdoctoral researcher at Harvard Medical School and is now an assistant professor at UMass Amherst. “This side effect could contribute to refueling the growth of the very tumors that these drugs are meant to inhibit.”
“Stem cells are acutely sensitive to their environment. Yet drugs that target tumor stem cells are largely tested in vitro, in lab dishes,” said Norbert Perrimon, the James Stillman Professor of Developmental Biology at HMS and principal investigator of the study. “Our findings underscore the importance of studying these drugs in vivo, in real contexts that are more like the environment in the human body.”
“Fruit flies could be a powerful system to do drug screening without oversimplifying the biology,” he added.
The results were recently published online in PNAS Early Edition.
Unexpected Twist
Perrimon’s group created its fruit fly model by accident. The researchers were investigating different cell signaling pathways when they uncovered one that caused the flies to grow tumors in their intestines. They realized they could use those flies to test tumor-suppressing compounds.
Markstein developed a simple screening method that could quickly test hundreds or even thousands of compounds and validated the model by confirming that 14 chemotherapy drugs known to work in people also destroyed the flies’ tumors.
Then she tested the same 14 drugs in normal flies, expecting to find little or no effect. Instead, she discovered what Perrimon called the “unexpected twist” in the story: Some of the drugs induced “incredible stem cell proliferation.”
The team believes those drugs disrupt a biological process in the flies’ intestines—one that has been linked to inflammation in people, which is in turn associated with cancer.
Perrimon and Markstein determined a classification system for stem cell-targeting chemotherapy drugs based on their findings: those that inhibit tumors without affecting normal stem cells, and those that inhibit tumors but also stimulate normal stem cell hyperproliferation. They suggest that the second type of drug could be combined with anti-inflammatory medications to try to counteract the side effect, but say it would be better to use the first type of drug and avoid the side effect altogether.
Next, the team tested a collection of 6,100 drug candidates and identified 10 that decimated the flies’ tumors without the side effect.
“These compounds, which include synthetic kinase inhibitors, known cytotoxics, and natural products extracted from fungi and Chinese medicinal herbs, expand our repertoire of potential cancer-fighting drugs,” said Markstein.
Perrimon’s lab studies fundamental biological processes, so he doesn’t plan to pursue any drug development research, but he hopes others will consider using fruit flies—which, along with screening techniques using other model organisms such as zebrafish, are becoming more popular in labs worldwide for a variety of diseases—to test new drug candidates.
This study was funded by the National Institutes of Health (grant 5RC1CA146268) and the Howard Hughes Medical Institute.
