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Targeting Errant Immune System Enzyme Kills Myelodysplastic Cells

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Key Points

  • Researchers identified an immune system enzyme called IRAK1 that is highly overexpressed and hyperactivated in about 25% of myelodysplastic syndrome and acute myeloid leukemia cells.
  • Both genetic and pharmacologic inhibition of IRAK1 was effective at selectively targeting and slowing the progression of human MDS cells and in mouse models of the disease.

Scientists have successfully targeted a malfunctioning immune system enzyme to kill diseased cells from patients with myelodysplastic syndrome (MDS), a precursor to acute myeloid leukemia (AML). Reporting their results in Cancer Cell, researchers say their successful laboratory tests in human MDS cells and mouse models of MDS provide a molecular target for designing new drugs to battle a syndrome with few effective treatments.

“There is an urgent need to develop new targeted therapies that can eliminate MDS-initiating clone cells and provide a durable therapeutic response,” said lead researcher Daniel Starczynowski, PhD, of the Division of Experimental Hematology and Cancer Biology at Cincinnati Children’s Hospital Medical Center.  “Not only does our research implicate errant immune system signaling in MDS cells, it strongly indicates that inhibiting the function of this hijacked immune pathway may become an effective treatment option for MDS.”

Dr. Starczynowski and colleagues sought to identify a molecular target that affects MDS-related biologic pathways with the goal of inhibiting the molecule to see if that would suppress the duplication and expansion of MDS cells.

Study Details

Working from past studies that analyzed elevated gene expression in MDS cases, the investigators conducted their own analyses of MDS and AML patient cells. The research team verified that an immune system enzyme called IRAK1 (interleukin receptor associated kinase-1) is highly overexpressed and hyperactivated in about 25% of MDS/AML cells.

The researchers then tested the effect of blocking IRAK1 on human MDS cells, on mouse models of human MDS, and on normal human CD34-positive blood cells. They used both direct genetic inhibition and a small-molecule inhibitor of IRAK1 (called IRAK-Inh) that was developed initially as prospective treatment for autoimmune disease and chronic inflammation.

Both genetic and pharmacologic inhibition of IRAK1 was effective at slowing the progression of human MDS cells and in mouse models of the disease. Inhibiting IRAK1 also had no effect on normal human CD34-positive blood cells, showing it selectively targets MDS cells.

Targeted Drugs Could Benefit Subset of Patients

A possible shortcoming to IRAK-Inh treatment was discovered when researchers noticed it was not effective at overcoming a procancer survival gene called BCL2. In some cell lines treated with IRAK-Inh, BCL2 genes became overexpressed in an effort to compensate for and work around the experimental treatment—a common occurrence in certain cancer therapies.

Researchers responded by testing a collaborative treatment strategy, combining IRAK-Inh with an inhibitor of BCL2 called ABT-263. The combination treatment was effective at selectively targeting and killing MDS cells without harming normal blood cells.

Dr. Starczynowski cautioned that laboratory tests in mouse models and cell cultures do not necessarily translate into treatment for humans. Because IRAK1 is currently thought to be overexpressed in a subset of MDS patients, any prospective drugs targeting the enzyme would in theory benefit only that group.

This work was supported by Cincinnati Children’s Hospital Research Foundation, American Society of Hematology, National Institutes of Health (R01HL111103, P30DK090571), and the U.S. Department of Defense.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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