Scientists discover how thalidomide-like drugs fight cancer
Despite its tragic legacy of causing birth defects 50 years ago, thalidomide — and newer drugs derived from it — has been reborn as an effective treatment for multiple myeloma and other cancers. How they act to slow cancer's spread, however, has long defied explanation.
In a new report, scientists at Dana-Farber Cancer Institute say they have discovered that the drugs kill multiple myeloma cells by a mechanism that's different from the way that they cause birth defects.
As a result, "It may be possible to develop better thalidomide-like drugs that retain the anticancer activity but not the activity that causes birth defects," said William G. Kaelin, Jr., MD, senior author of the report in Science Express.
Safer drugs of this type, he said, would be useful not only for multiple myeloma, but "could be explored for treating other B-cell malignancies such as certain types of lymphoma, some of which affect young women." The thalidomide drugs also can also dampen immune system activity and new versions could be tried in women with autoimmune diseases like lupus, said Kaelin.
The findings may have another important implication for cancer treatment.
The researchers demonstrated that lenalidomide — a more powerful derivative of thalidomide — killed multiple myeloma cells by disabling overactive switches called transcription factors that drive the cells' excessive growth. Transcription factors are proteins that bind to genes and increase their activity, and cancers are often driven by overactivity of these molecular switches. For example, a transcription factor called c-Myc appears to be overactive in many different types of cancer.
It has proved difficult to target or "drug" transcription factors, noted Kaelin, but the new study suggests that lenalidomide's ability to disable transcription factors "could be a template for targeting other transcription factors linked to cancer."
Thalidomide was developed by German scientists as drug with many potential uses such as calming anxiety, promoting sleep, and alleviating nausea. In the late 1950s and early 1960s, an estimated 10,000 to 20,000 babies with shortened limbs and other severe, often fatal birth defects were born in the United States, Europe, and Australia to women who had taken thalidomide as a morning sickness remedy in the first trimester of pregnancy. Thalidomide was not approved by the U.S. Food and Drug Administration and was banned worldwide in 1962.
Research interest in the drug continued in the 1960s and thalidomide was found to be useful in treating complications of leprosy. The drug's anticancer activity was discovered in research beginning in the 1990s, and in 2006 the combination of thalidomide and dexamethasone was approved for treating multiple myeloma. More powerful derivatives, lenalidomide (Revlimid) and pomalidomide, are now approved, under strict regulations, for use in multiple myeloma patients.
How the drugs worked remained a mystery, but in 2010, scientists in Japan reported that thalidomide binds to and inactivates a protein, cereblon, which is important in normal development of limbs. Cereblon is a component of a protein complex called an E3 ubiquitin ligase, which tags proteins that need to be destroyed for the cell's health, and is a key to embryonic development. The researchers found that thalidomide's inactivation of cereblon disrupted development and explained the drug's tendency to cause birth defects, but not its ability to block cancer growth.
The new report describes research by Kaelin, along with first author Gang Lu and other Dana-Farber investigators, showing that when lenalidomide binds to cereblon, it can trigger the destruction of two transcription factors, IKZF1 and IKZF3, that are overactive in multiple myeloma cells. The result: cancer growth is shut down, halting the progress of the disease.
"The anticancer mechanism is that lenalidomide binds cereblon and allows the ubiquitin complex to degrade the transcription factors," Kaelin explained. "This is a different mechanism from the way lenalidomide binds and inactivates cereblon, leading to birth defects."
A companion report in Science containing similar findings about the anticancer mechanism of lenalidomide is being published simultaneously by a team led by Benjamin Ebert, MD, PhD, at Brigham and Women's Hospital.
The research was supported by a grant 2R01CA68490-16 and F32 fellowship from the National Institutes of Health, and by the Leukemia & Lymphoma Society, the Multiple Myeloma Research Foundation, and the Howard Hughes Medical Institute.