The Rehabilitation of Thalidomide

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You may have heard of the infamous thalidomide, a morning sickness drug that was patented in the 1950s. Its potent anti-nausea effects made it ideal as a remedy for morning sickness in pregnant women and thalidomide was sold in over 40 countries, going as far as to be made available over the counter. At the time, medicines were not specifically tested for their effect on the developing fetus. Further, the company responsible deemed thalidomide safe for humans after primarily conducting their studies on mice and rats. This turned out to be a mistake which had terrible consequences for many thousands of families around the world. It turned out that while an effective treatment for morning sickness, thalidomide caused severe birth defects for the mother’s child, particularly underdeveloped limbs. Thanks to some truly heroic efforts by individuals such as Claus Knapp and Frances Kelsey, this drug was pulled from shelves by 1961 and was banned in the States. This was a tragic case of inadequate clinical testing and, according to reports describing its availability in some countries up to the 1970s, irresponsible marketing and distribution by the pharmaceutical companies behind thalidomide.

In recent years, however, this once-disgraced medicine has mounted a bit of a comeback, finding a second career as a treatment against multiple myeloma, a blood cancer practically incurable by standard chemotherapy. By the early 1990s, it had become well known that the growth of blood vessels (a process called angiogenesis) was a key part of cancer development, including blood cancers. It made sense then to enterprising researchers: block angiogenesis, block cancer. This strategy has led to a new class of cancer drugs. Surprisingly, a study in 1994 found thalidomide to be one of these angiogenesis inhibitors. This prompted researchers to examine its effects on rabbits and then human cancer patients. Five years later, a seminal paper in the New England Journal of Medicine published the finding that thalidomide “had substantial antitumor activity in patients with advanced myeloma”, with 10% of the patients in the study having a complete or near-complete remission and nearly a third of all patients showing some improvement. Seven years later, the FDA granted approval for a combination multiple myeloma therapy that included thalidomide, giving this compound a new life.

So how does thalidomide actually work in our cells? Only in the last few years have we really begun to understand its exact mechanism of action, which turned out to be quite similar to how PROTACs work. It was first discovered by a Japanese group in 2010 that thalidomide was able to bind onto a protein in our bodies called cereblon. Cereblon is an E3 ligase, a type of protein that marks other proteins for destruction. It was first thought that thalidomide inhibited cereblon by binding to it, but further research revealed that there was more to the story. The avid Oncobites reader may know that PROTACs work to direct E3 ligases to tag disease-causing proteins, making them a target for our cells to destroy them. In a study published in Science, researchers then found that when thalidomide bound onto cereblon, instead of blocking its activity as previously thought, it actually changed its protein targets. Specifically, thalidomide redirected cereblon to target two proteins important for multiple myeloma cells to survive. By taking them down, thalidomide works as an effective therapy.

Furthermore, last year two independent studies were able to pinpoint the cause of the tragic birth defects that it caused when used by pregnant women. In short, thalidomide also directed cereblon to destroy SALL4, a protein important in limb development. As a result, a signature symptom of thalidomide victims was impaired limb growth. So why didn’t it affect rodents? It turns out that mice have a version of SALL4 that cereblon could not recognize, fooling early scientists into believing that it was safe for humans. This serves as an important reminder to researchers that only after testing in multiple models can a new therapy be considered safe.

Today, thalidomide enjoys a second career as cancer therapeutic. Two related compounds have even been developed and approved by the FDA: lenalidomide and pomalidomide. These make up a new class of multiple myeloma treatments known as immunomodulators. Knowing now how thalidomide and its relatives work, researchers are already trying to come up with new ways to redirect cereblon in a bid to hit other disease-causing proteins, and with minimized side effects.

Works Discussed:

D’Amato, R. J., Loughnan, M. S., Flynn, E., & Folkman, J. (1994). Thalidomide is an inhibitor of angiogenesis. Proceedings of the National Academy of Sciences of the United States of America, 91(9), 4082–4085.

Krönke, J., Udeshi, N. D., Narla, A., Grauman, P., Hurst, S. N., McConkey, M., … Ebert, B. L. (2014). Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science (New York, N.Y.), 343(6168), 301–305.

Matyskiela, M. E., Lu, G., Ito, T., Pagarigan, B., Lu, C.-C., Miller, K., … Chamberlain, P. P. (2016). A novel cereblon modulator recruits GSPT1 to the CRL4CRBN ubiquitin ligase. Nature, 535(7611), 252–257.

Rodríguez-Pérez, F., & Rape, M. (2018). Unlocking a dark past. eLife, 7, e41002.

Scott, C. (2015, May 2). The forgotten victims. The Sunday Times. Retrieved from

Singhal, S., Mehta, J., Desikan, R., Ayers, D., Roberson, P., Eddlemon, P., … Barlogie, B. (1999). Antitumor Activity of Thalidomide in Refractory Multiple Myeloma. New England Journal of Medicine, 341(21), 1565–1571.

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