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Novel drug approach could improve outlook in high risk leukemia

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In the United States, about 2,600 children and 1,900 adults develop B-cell acute lymphoblastic leukemia (B-ALL) annually. B-ALL is an aggressive cancer that originates from a type of white blood cell called the B lymphocyte. Due to improvements in chemotherapy in the last five decades, survival rates have improved. However, an estimated 1,000 Americans still die from the disease every year, largely from a subtype called high-risk B-ALL.

Medicine

A new way to enhance and restore cancer suppressor activity in B-cell acute lymphoblastic leukemia, resulting in better outcomes in a pre-clinical model of the disease has been discovered by researchers at the Penn State College of Medicine, working with Chinese and American colleagues. The researchers are hopeful that the finding could pave the way for a new class of drugs for this and other forms of leukemia. The findings of the study were published in the journal Blood.

It has been observed that patients with high-risk B-ALL relapse after treatment. Dr. Sinisa Dovat, associate professor of pediatrics opined that most of them have one thing in common: impaired activity of a protein called Ikaros that prevents the development and progression of leukemia. He explained that normally, there are two copies of this gene in our DNA. However, in patients with high-risk B-ALL, one copy of the Ikaros gene gets deleted or mutated. Till date, it was not considered possible to enhance the function of Ikaros if one copy was missing or mutated. Present therapies for high-risk B-ALL are aimed at targeting the pathways that promote rather than those that fight leukemia.

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In order to gain a better understanding of how impairments in Ikaros function occur in B-ALL, Dovat’s team set out to gain a better understanding of how impairments in Ikaros function occur in B-ALL. They hoped that if this part of the mystery was understood, it could help them develop a drug to target and improve the protein’s activity.

The research team identified one of the mechanisms used by Ikaros to prevent leukemia. Ikaros bind DNA and regulate the activity of a large number of genes in cells. It was found that the ability to control gene activity allows Ikaros to act as a master regulator of the function of blood cells. The protein normally keeps blood cells in check, preventing them from multiplying indefinitely. Dovat explained that if Ikaros’s function is impaired, blood cells escape its control and begin to multiply rapidly, which ultimately leads to high-risk leukemia.

In the study, functional Ikaros protein produced from the remaining normal Ikaros gene was restored with a novel class of drugs that target a specific enzyme called casein kinase 2 or CK2. It is seen that CK2 highly elevates the activity in leukemia and in other types of cancers. Also, it is observed that CK2 directly impairs the function of Ikaros.

Dovat said that high-risk B-ALL is characterized by a missing or mutated Ikaros and the protein produced from the other copy of the Ikaros gene not functioning well due to the high level of CK2.

In the novel strategy designed by Dovat and his team, the new drug also known as the CK2 inhibitor restored Ikaros function and resulted in a strong therapeutic effect in cancer cells from B-ALL patients. The drug also significantly reduced cancer cell proliferation and survival.

Dovat said that the strategy to enhance the function of proteins that flight leukemia is a never-used-before approach. The next step is to study the optimal dose for CK2 inhibitors and determine ways to incorporate the novel drug into current treatments.

References:

http://news.psu.edu/story/384849/2015/12/14/research/novel-drug-approach-could-improve-outlook-high-risk-leukemia

http://medicalxpress.com/news/2015-12-drug-approach-outlook-high-risk-leukemia.html