In the annals of the pharmaceutical industry, it’s hard to find an event more infamous than the thalidomide scandal.
The drug, originally developed by German drugmaker Grünenthal, was marketed in 1957 in Europe, Australia and parts of South America to treat morning sickness in pregnant women. But soon thereafter, it was blamed for severe birth defects in more than 10,000 babies across dozens of countries and an untold number of miscarriages, leading to a 1961 ban. Meanwhile, the US, the Food and Drug Administration did not approve it, and FDA scientist Frances Oldham Kelsey, who played a key role in keeping the drug from reaching American shores, died in 2015 at the age of 101.
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Despite the drug’s notoriety, the underlying mechanism for its infamous fetal toxicity had been poorly understood. But now, a team of researchers at the Dana-Farber Cancer Institute in Boston may have resolved the question. In addition, their research may also point the way forward in the development of future drugs.
In a paper published online Wednesday in the journal Elife, Dana-Farber researcher Eric Fischer and others zeroed in on a transcription factor – a protein that switches genes on and off – called SALL4. Thalidomide, they found, promotes degradation of several transcription factors, including SALL4, whose degradation in particular interferes with aspects of fetal growth like limb development.
“We don’t have absolute, definitive proof that SALL4 is the sole cause of thalidomide syndrome,” Fischer said in a phone interview. However, the genetic similarity between dozens of patients with SALL4 and the defects they have appear to make degradation of the transcription factor a likely culprit, he said.
Research on thalidomide’s ability to inhibit the growth of blood vessels in tumors in the 1980s led to the FDA granting Celgene approval for the drug to treat the blood cancer multiple myeloma in 1998. Since then, Celgene, which markets it under the name Thalomid, has developed two more multiple myeloma drugs derived from Thalomid, namely Revlimid (lenalidomide) and Pomalyst (pomalidomide), which are collectively known as immunomodulatory drugs, or IMiDs.
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A general term for the mechanism of action that IMiDs use is targeted protein degradation, and understanding the way that IMiDs cause fetal toxicity will benefit development of drugs that use similar mechanisms, Fischer said, not only in cancers but also in neurodegenerative conditions like Alzheimer’s disease, he said. Fischer pointed to New Haven, Connecticut-based Arvinas, which is developing drugs using its protein-degradation platform. Arvinas has an androgen receptor degrader in preparations for clinical development as a treatment for prostate cancer. The article publication has also generated interest from other drugmakers, but Fischer declined to identify them for confidentiality reasons.
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