Multiple Myeloma: New Treatment Option Discovered

In the 1950s and 1960s, the drug thalidomide was sold as a sedative under the trade name Contergan whose side effects resulted in one of the largest pharmaceutical scandals in history-the medication was taken from the market after it became known that the use of Contergan during pregnancy had resulted in over 10,000 cases of severe birth defects. Successor drugs like lenalidomide and pomalidomide are currently prescribed under strict supervision by experienced oncologists. The active ingredients are mainstay of modern cancer therapies. The use of these drugs has improved the success rate of therapies and patient survival, particularly for hematological malignancies such as multiple myeloma.

These drugs belong to a class called immunomodulatory drugs (IMiDs) that can influence the immune system.

The research led by Prof. Florian Bassermann and Vanesa Fernández of the university hospital Klinikum rechts der Isar of TUM is published in the journal Molecular Cell.

Membrane Proteins

Earlier studies have shown that IMiDs bind to a protein called cereblon that results in the malfunction of a protein complex on the surface of tumor cells, thus inhibiting tumor growth. In the new study, the researchers have now found the exact mechanism and the scope of this dysregulatiion.

They found that cereblon supports the protein HSP90 known as co-chaperone, which is responsible for the correct folding of thousands of proteins in human cells. They were also able to show that the support function of the co-chaperone cereblon is specific for membrane proteins and it helps the tumor cells to grow by communicating with neighboring cells and passing on growth signals and take in important nutrients.

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On administration of IMiD drugs, the cereblon can no longer bind to the HSP90 machinery, and as a result loses its supportive function in the quality control of membrane proteins.

Oncologist Florian Bassermann said, “Using proteome-wide analyses, we were able to show that a large number of essential proteins on the surface of cancer cells are destabilized by IMiD-treatment. This ultimately explains the unusually broad effects of these substances.”

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In multiple myeloma the proteins CD98hc and LAT1 which are affected, ensure that cancer cells are supplied with amino acids. CD98hc and LAT1 are very abundant proteins in these cells as cancer cells in the case of multiple myeloma have an especially high need for nutrients like amino acids. The researchers have shown that IMiD-treatment can significantly reduce the uptake of essential amino acids and thus inhibits the growth of the tumor cells.

First author of the study, Michael Heider said, “This literally starves out the cancer cells.”

Targeted Therapeutic Options

This discovery that the multiple myeloma cells can be targeted by the proteins CD98hc and LAT1 opens up new possibilities for innovative therapies in this currently incurable cancer. The researchers also tested a molecule aimed at CD98hc, known as an anticalin and the results showed that the molecule binds specifically to the cell surface protein CD98hc in both cell culture and mouse models and hence can be used for targeted therapy and diagnosis in the future.

Basserman said, “Early clinical studies to further evaluate the anticalin are already being planned.”

Source-Medindia