Journal
CURRENT HEMATOLOGIC MALIGNANCY REPORTS
Volume 8, Issue 1, Pages 22-27Publisher
CURRENT MEDICINE GROUP
DOI: 10.1007/s11899-012-0142-1
Keywords
Signaling pathways; B-cell receptor; BCR; Chronic lymphocytic leukemia; CLL; New targets; PI3-Kinase; CAL-101; GS-1101; PI3K delta; PI3K; Microenvironment
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Chronic lymphocytic leukemia (CLL) remains an incurable B-cell malignancy with many unanswered questions. While the cell of origin and etiology are still unknown, significant scientific progress has revealed numerous molecular targets for novel therapeutic interventions. Phosphatidylinositol 3-kinases (PI3K) regulate key cellular functions, including growth, survival and migration, by integrating and transmitting signals from diverse surface molecules including the B-cell receptor (BCR). In lymphocytes, the PI3K delta isoform plays a critical role in B-cell homeostasis and function. In CLL, the PI3K pathway is constitutively active and dependent on PI3K delta. GS-1101 is a highly selective PI3K delta inhibitor that in CLL patients causes a rapid and sustained reduction in lymphadenopathy, accompanied by transient lymphocytosis. This article will review new insights into the pathophysiology of CLL, the preclinical rationale of a PI3K delta inhibitor in CLL, and the clinical evidence supporting this first-in-class therapeutic target for CLL patients.
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