Immunomodulatory drugs improve the achievement pace of cancer therapy

Overview

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• Source: Technical University of Munich (TUM)


• Date: 15 Feb,2021

Immunomodulatory drugs, for example, Contergan derivatives lenalidomide and pomalidomide, have significantly improved the treatment of hematologic malignancies such as multiple myeloma.

Researchers at the Technical University of Munich (TUM) have now further decoded the mode of action within this class of drugs. At exactly the exact same time, they identified new revolutionary targeted cancer therapies.

The drug thalidomide was sold as a sedative under the trade name Contergan in the 1950s and 1960s. At the time, its side-effects triggered one of the biggest pharmaceutical scandals in history: The drug had been taken from the market after it became known that using Contergan during pregnancy had resulted in over 10,000 cases of severe birth defects.

Using lenalidomide and pomalidomide has considerably enhanced the success rate of treatments and patient survival, particularly for hematological malignancies such as multiple myeloma. Since these substances can influence the immune system, they are referred to as immunomodulatory drugs (IMiDs).

Many membrane proteins affected
Previous studies have shown that IMiDs bind to a protein called cereblon, which leads to the malfunction of a protein complex on the surface of tumor cells, thus inhibiting tumor development.

A research team led by Prof. Florian Bassermann and Vanesa Fernández of the university hospital Klinikum rechts der Isar of TUM has deciphered the specific mechanism and the scope of this dysregulation in a new study.

They found that cereblon supports the protein HSP90 as what’s called a co-chaperone; HSP90 is responsible for the correct folding of numerous proteins in human cells. The scientists were able to show that the support function of the co-chaperone cereblon is specific for membrane proteins.

These proteins, which are anchored on the surface of a cell, are essential for tumor cells to grow: They enable cells to communicate with neighboring cells, pass on growth signals, and take in nutrients that are important.

Upon IMiD-treatment, cereblon can no longer bind to the HSP90 machinery, and because of this, loses its supportive role in the quality control of membrane proteins.

In multiple myeloma, the proteins CD98hc and LAT1 are especially affected. Together these proteins usually ensure that cancer cells are supplied with amino acids. Since cancer cells in the case of multiple myeloma have an especially high need for nutrients such as amino acids, CD98hc and LAT1 are extremely abundant proteins in these cells.

The research team has now shown that IMiD-treatment significantly reduces the uptake of essential amino acids and so inhibits the growth of the tumor cells. “This literally starves out the cancer cells,” explains Michael Heider, first author of the study.

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.”

Florian Bassermann, Oncologist, Technical University of Munich

New targeted therapeutic choices
The discovery that multiple myeloma cells can be attacked by targeting the proteins CD98hc and LAT1 open up new possibilities for advanced treatments in this currently incurable cancer. Together with Wolfgang Weber, TUM Professor for Nuclear Medicine, the researchers analyzed a molecule which is aimed at CD98hc, Called an anticalin.

The molecule was developed by Arne Skerra, Professor for Biological Chemistry at TUM.

This anticalin could therefore be used for targeted therapy and diagnosis in the future.