Combinin lenalidomide with CAL101

[Guest guest]

BlankThe role of phosphatidylinositol 3-kinase-{delta} in the immunomodulatory

effects of lenalidomide in chronic lymphocytic leukemia.

SE Herman, R Lapalombella, AL Gordon, A Ramanunni, KA Blum, J , X Zhang, BJ

Lannutti, KD Puri, N Muthusamy, JC Byrd, and AJ

Blood, March 4, 2011; .

Integrated Biomedical Science Graduate Program, The Ohio State University

Medical Center, Columbus, OH, United States;

In patients with chronic lymphocytic leukemia (CLL), lenalidomide can promote

humoral immune responses but also induces a distinct disease-specific toxicity

of tumor flare and cytokine release. These CLL-specific events result from

increased expression of co-stimulatory molecules on B cells. Here we demonstrate

that lenalidomide activation of CLL cells depends on the phosphatidylinositol

3-kinase p110-delta (PI3K-?) pathway. Inhibition of PI3K-? signaling by the

PI3K-?-inhibiting drug, CAL-101, or by siRNA knockdown of p110?, abrogates CLL

cell activation, co-stimulatory molecule expression, and VEGF and b-FGF gene

expression that are induced by lenalidomide. In addition, CAL-101 attenuates

lenalidomide-mediated increases in IgM production by normal B-cells.

Collectively, these data demonstrate the importance of PI3K-? signaling for

lenalidomide immune modulation. These findings may guide development of

strategies for the treatment of CLL that

In patients with chronic lymphocytic leukemia (CLL), lenalidomide can promote

humoral immune responses but also induces a distinct disease-specific toxicity

of tumor flare and cytokine release. These CLL-specific events result from

increased expression of co-stimulatory molecules on B cells. Here we demonstrate

that lenalidomide activation of CLL cells depends on the phosphatidylinositol

3-kinase p110-delta (PI3K-?) pathway. Inhibition of PI3K-? signaling by the

PI3K-?-inhibiting drug, CAL-101, or by siRNA knockdown of p110?, abrogates CLL

cell activation, co-stimulatory molecule expression, and VEGF and b-FGF gene

expression that are induced by lenalidomide. In addition, CAL-101 attenuates

lenalidomide-mediated increases in IgM production by normal B-cells.

Collectively, these data demonstrate the importance of PI3K-? signaling for

lenalidomide immune modulation. These findings may guide development of

strategies for the treatment of CLL that combine lenalidomide with CAL-101, with

other inhibitors of the PI3K-? pathway, or with other agents that target

downstream kinases of this signaling pathway.

PMID: 21378270 , with other inhibitors of the PI3K-? pathway, or with other

agents that target downstream kinases of this signaling pathway.

PMID: 21378270