Potential New Drug Target For Chronic Leukemia Identified By UCSD Researchers

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Potential New Drug Target For Chronic Leukemia Identified By UCSD Researchers

25 Nov 2008

Researchers at the University of California, San Diego (UCSD) and the s

UCSD Cancer Center have discovered what could be a novel drug target for an

often difficult-to-treat form of leukemia. The investigators have identified a

unique " signature " or pattern of a specific family of enzymes in patients with

chronic lymphocytic leukemia (CLL), the most common form of adult leukemia.

Insel, M.D., professor of pharmacology and medicine at the UC San Diego

School of Medicine and his co-workers compared white blood cells in patients

with CLL to those of healthy adults. They found that one form of the group of

enzymes, collectively known as cyclic nucleotide phosphodiesterases, was 10

times higher in CLL patients than in normal individuals. The specific type of

enzyme, phosphodiesterase 7B (PDE7B), controls the levels of cyclic AMP (cAMP),

a molecule that can promote programmed cell death, a process that is defective

in CLL. The team reports its findings this week in the Proceedings of the

National Academy of Sciences.

Whereas most cancers have out-of-control cell growth, CLL is characterized by an

overabundance of white blood cells that do not die when they should, Insel

explained.

The scientists subsequently tested the effects of drugs that blocked PDE7B in

CLL cells, and found that this raised cAMP levels and caused CLL cells to

undergo cell death. He explained that since PDE7B degrades cAMP, blocking PDE7B

in essence takes the clamp off of programmed cell death, enabling CLL cells to

die.

" PDE7B is thus a new drug target for CLL, " he said. " We have preliminary data

from patient samples studied in the laboratory showing that we can increase the

killing of CLL cells even more if we block PDE7B and also add other drugs used

to treat CLL. "

He noted that a test for PDE7B might also potentially be used as a way to detect

CLL, though this has yet to be proven. CLL, which usually strikes adults over

age 35, has two major forms. One form progresses slowly, with few symptoms for

years, and can be difficult to detect. The other form is more aggressive and

dangerous. No one knows what makes one form different from the other. Current

therapies have limited effectiveness, especially once the disease is in its

aggressive phase.

The researchers are planning to screen potential drugs to treat CLL based on the

PDE7B-cAMP connection. They are also exploring other potential treatment

strategies to increase cAMP or disrupt its breakdown.

" We think that CLL cells may have found ways to help keep themselves alive by

preventing cAMP from increasing, " Insel said. " This paper provides a validation

of the importance of the cAMP pathway as a target for drugs that might be used

to treat CLL. "

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