Compound May Help Fight a Common Leukemia

A substance that specifically disrupts a chemical pathway in chronic lymphocytic leukemia (CLL) cells may hold promise for battling the disorder, a new study revealed. The research, published recently in the journal Blood, found that a substance called CAL-101 wreaks havoc in several chemical pathways that CLL cells need for their viability and multiplication, promoting apoptosis, or natural cell death, among the cells. The work was done by scientists at the Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC-James).

CLL is the most frequently diagnosed form of adult leukemia in the United States. About 15,000 cases a year are diagnosed, and 4,500 people die of it. Nearly 101,000 Americans are living with or are in remission from CLL.

CLL is called “chronic” because it is characterized by a long asymptomatic phase that can last many years without treatment. But the disease slowly progresses until it is symptomatic. At this point, chemotherapy is required, often producing a remission—which, unfortunately, is nearly always temporary. Almost all patients relapse.
   
The OSUCCC-James researchers discovered that CAL-101 obstructs the action of a molecule called PI3K-delta, which is found chiefly in blood-forming, or hematopoietic, cells, the very cells in which CLL arises. CLL cells contain a high degree of PI3K-delta and show strong activity in the PI3K pathway, a cellular series of chemical reactions. PI3K-delta and PI3K are closely related chemically.

Happily, the scientists found that CAL-101 kills CLL cells over normal B cells, a variety of white blood cells affected by CLL. Moreover, they discovered, CAL-101 does not kill other normal white blood cells called T cells and NK cells. Nor does it reduce antibody activity.

“Overall, our findings provide a rationale for the development of CAL-101 as the first in a new class of targeted therapies for CLL,” said principal investigator Amy J. Johnson, assistant professor of hematology and medicinal chemistry, and a CLL researcher in the OSUCCC-James.
   
“A PI3K inhibitor hasn’t been developed yet because this pathway is required for many essential cellular functions, but the identification of PI3K-delta, which is hematopoietic-selective, unlocks a potential new therapy for B-cell malignancies,” she said.


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