Molecular Mayhem

Targeted agent shows promise for chronic lymphoid leukemia

Amy JohnsonResearchers at the OSUCCC – James have identified an experimental agent that targets chronic lymphocytic leukemia (CLL) and perhaps other proliferative disorders of lymphocytes.

A study of cells from patient tumors shows that the small-molecule inhibitor CAL-101 promotes apoptosis in CLL cells and disrupts several external survival pathways needed for CLL cell viability and proliferation. The agent blocks the PI3K-delta molecule, an isomer of the P13K (phosphatidylinositol-3 kinase) pathway, which is activated mainly in hematopoietic cells.

“Our findings provide a rationale for developing CAL-101 as the first in a new class of targeted therapies for CLL,” says principal investigator Amy Johnson, PhD, assistant professor of Hematology and Medicinal Chemistry. “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 therapy for B-cell malignancies.”

CLL is the most common adult leukemia in the United States. Patients with the asymptomatic phase can live for many years even without treatment. Once the disease reaches the symptomatic phase, treatment is required, usually chemotherapy that often induces remission. But current therapies are not curative; nearly all patients relapse.

The PI3K pathway is essential for survival of cells generally. This made it an unsuitable target for small molecule inhibitors until recently when research showed that PI3K-delta expression occurs mainly in hematopoietic cell types. Preclinical studies suggest that blocking this molecule may kill B cells with little toxicity to other hematopoietic cells.

The OSUCCC – James study found that: CLL cells show high PI3K pathway activity and PI3K-delta expression; CAL-101 preferentially kills CLL cells compared with normal B-cells; CAL-101 inhibits PI3K-delta and promotes apoptosis in primary CLL cells while disrupting multiple external survival pathways; CAL-101 cell killing is caspase-dependent and not diminished by stromal cells; and CAL-101 does not kill normal T cells or natural killer (NK) cells or reduce antibody-dependent cellular cytotoxicity, but it does lower production of inflammatory and antiapoptotic cytokines by activated T cells.

A phase I clinical trial of CAL-101 is under way in select relapsed or refractory hematologic malignancies at Ohio State and other centers.

Published in the journal Blood.

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