Phosphatidylinositol 3-kinase-δ inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals.

Abstract

Targeted therapy with imatinib in chronic myeloid leukemia (CML) prompted a new treatment paradigm. Unlike CML, chronic lymphocytic leukemia (CLL) lacks an aberrant fusion protein kinase but instead displays increased phosphatidylinositol 3-kinase (PI3K) activity. To date, PI3K inhibitor development has been limited because of the requirement of this pathway for many essential cellular functions. Identification of the hematopoietic-selective isoform PI3K-δ unlocks a new therapeutic potential for B-cell malignancies. Herein, we demonstrate that PI3K has increased enzymatic activity and that PI3K-δ is expressed in CLL cells. A PI3K-δ selective inhibitor CAL-101 promoted apoptosis in primary CLL cells ex vivo in a dose- and time-dependent fashion that was independent of common prognostic markers. CAL-101-mediated cytotoxicity was caspase dependent and was not diminished by coculture on stromal cells. In addition, CAL-101 abrogated protection from spontaneous apoptosis induced by B cell-activating factors CD40L, TNF-α, and fibronectin. In contrast to malignant cells, CAL-101 does not promote apoptosis in normal T cells or natural killer cells, nor does it diminish antibody-dependent cellular cytotoxicity. However, CAL-101 did decrease activated T-cell production of various inflammatory and antiapoptotic cytokines. Collectively, these studies provide rationale for the clinical development of CAL-101 as a first-in-class targeted therapy for CLL and related B-cell lymphoproliferative disorders.

• Authors: Sarah E M Herman, Amber L Gordon, Amy J Wagner, Nyla A Heerema, Weiqiang Zhao, Joseph M Flynn, Jeffrey Jones, Leslie Andritsos, Kamal D Puri, Brian J Lannutti, Neill A Giese, Xiaoli Zhang, Lai Wei, John C Byrd, Amy J Johnson
• Journal: Blood (Blood) Vol. 116 Issue 12 Pg. 2078-88 (Sep 23 2010) ISSN: 1528-0020 [Electronic] United States
• PMID: 20522708 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Phosphoinositide-3 Kinase Inhibitors
• Purines
• Quinazolinones
• Class I Phosphatidylinositol 3-Kinases
• PIK3CD protein, human
• idelalisib

Topics

• Antineoplastic Agents
• Apoptosis (drug effects)
• B-Lymphocytes (enzymology, pathology)
• Cell Survival (drug effects)
• Class I Phosphatidylinositol 3-Kinases
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Humans
• Leukemia, Lymphocytic, Chronic, B-Cell (drug therapy, pathology)
• Phosphoinositide-3 Kinase Inhibitors
• Purines (pharmacology)
• Quinazolinones (pharmacology)
• Signal Transduction (drug effects)
• Tumor Cells, Cultured