Researchers say they have identified the molecular mechanism of thalidomide and other immunomodulatory drugs (IMiDs), a finding that is relevant to the treatment of multiple myeloma and other hematologic malignancies.
Previous research showed that cereblon, a cellular protein, plays an important role in the function of IMiDs.
However, the exact details of how cereblon mediates the effects of IMiDs were not clear.
The new study, published in Nature Medicine, provides an explanation.
Researchers found that, inside cells, cereblon usually binds to the proteins CD147 and MCT1. Among other things, these 2 proteins promote proliferation, metabolism, and the formation of new blood vessels. In cancers such as multiple myeloma, tumor cells contain particularly high levels of CD147 and MCT1.
As a protein complex, CD147 and MCT1 always occur as a pair. However, to find their other half and become activated, the proteins require the help of cereblon.
Binding to cereblon promotes development and stability of the complex, which, in return, stimulates cell growth and facilitates the excretion of metabolic products like lactate.
In diseases such as multiple myeloma, an increased abundance of this protein complex enables tumor cells to multiply and spread rapidly.
If such a cancer is treated with IMiDs, the drug virtually displaces the complex from its binding to cereblon. As a result, CD147 and MCT1 can no longer be activated, and they vanish.
“Ultimately, this causes the tumor cells to die,” said study author Ruth Eichner, MD, of Technische Universität München in Munich, Germany.
But the disruption of the protein complex is also responsible for the severe birth defects that can occur in the children of women who take thalidomide and other IMiDs when pregnant.
“The mechanisms are identical,” said study author Florian Bassermann, MD, PhD, of Technische Universität München.
“A specific inactivation of the protein complex resulted in the same developmental defects observed after thalidomide treatment.”
The researchers said this confirms the prevailing hypothesis that the typical IMiD-induced birth defects are related to the reduced and abnormal formation of new blood vessels. That’s because, without CD147 and MCT1, blood vessels cannot develop properly.
The team also said these findings could be used to assess the efficacy of IMiD treatment before actually giving an IMiD to the patient.
“The disappearance of the protein complex could only be observed in patients that had responded well to this type of treatment,” Dr Bassermann explained.
Therefore, he and his colleagues believe this information could be used to assess a patient’s response before starting an IMiD. A sample of the patient’s tumor cells could be cultured and treated with IMiDs. If the cells showed a disruption of the complex, the patient would most likely benefit from IMiD treatment.
The researchers also think the results of this study could lead to the development of new anticancer therapies.
The team said the CD147-MCT1 protein complex is a particularly attractive target for tumor treatment, as it is mainly found on the surface of cells and virtually links the inside to the outside of the cell.
Therefore, inactivation of the complex might be achieved using specifically produced antibodies and other distinctive drugs—a possibility Dr Bassermann and his team are now exploring.
