Novel drug targets aggressive form of non-Hodgkin lymphoma

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A new experimental drug therapy has been developed to target activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL). The experimental small molecule agent MI-2 irreversibly inactivates MALT1, which is a key protein responsible for driving the growth and survival of ABC-DLBCL cells.

DLBCL is the most common subtype of non-Hodgkin lymphoma and the seventh most frequently diagnosed cancer. ABC-DLBCL remains a major therapeutic challenge. MALT1 is highly active in ABC-DLBCL and plays an important role in lymphoma cancer cell growth and survival. MALT1 is a protease, meaning it cuts apart other proteins, and when it slices proteins in ABC-DLBCLs, growth-promoting molecules are activated and growth-inhibiting proteins are stopped.

“In essence, MALT1 turns off the brakes and presses the gas pedal to accelerate cell growth and survival in this aggressive cancer,” said the study's lead investigator, Ari Melnick, MD, of Weill Cornell Medical College.

The researchers developed an activated form of MALT1 to study the structure of the molecule. They searched for small molecule agents to shut it down by screening libraries of chemicals to find one that bound tightly to MALT1, preventing it from cutting other proteins. The agent, MI-2, also inactivated MALT1 in human samples of ABC-DLBCL.

“In our study we show the drug MI-2 we developed inactivates any MALT1 protein it touches, and without any apparent toxicity in animal models,” said Melnick.

When the agent was tested in mice, it stopped cancer growth without toxicity in normal tissues. This is because MALT1 is not required for biologic processes essential for life. If tested successfully in human clinical trials, MI-2 could have benefits for other diseases, including MALT1 lymphoma, which is a lower-grade type of lymphoma. It could also possibly play a role in a variety of inflammatory disorders and autoimmune disorders.

“MALT1 is a bona fide therapeutic target, and with the discovery of MI-2 we have provided a lead compound that forms the basis of a new class of therapeutic agents,” said Melnick.

This study was published in Cancer Cell (2012;22[6]:812-824).

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