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Preclinical Evaluation of a Novel SHIP1 Phosphatase Activator for Inhibition of PI3K Signaling in Malignant B Cells
EA. Lemm, B. Valle-Argos, LD. Smith, J. Richter, Y. Gebreselassie, MJ. Carter, J. Karolova, M. Svaton, K. Helman, NJ. Weston-Bell, L. Karydis, CT. Williamson, G. Lenz, J. Pettigrew, C. Harwig, FK. Stevenson, M. Cragg, F. Forconi, AJ. Steele, J....
Language English Country United States
Document type Journal Article, Research Support, Non-U.S. Gov't
Grant support
A23669
Cancer Research UK - United Kingdom
14045
Blood Cancer UK - United Kingdom
A18087
Cancer Research UK - United Kingdom
13-0267
Worldwide Cancer Research - United Kingdom
A15581
Cancer Research UK - United Kingdom
16004
Blood Cancer UK - United Kingdom
16003
Blood Cancer UK - United Kingdom
NLK
Free Medical Journals
from 1995 to 1 year ago
Freely Accessible Science Journals
from 1995
Open Access Digital Library
from 1995-01-01
Open Access Digital Library
from 1995-01-01
- MeSH
- Enzyme Activators pharmacology MeSH
- Apoptosis drug effects MeSH
- Leukemia, Lymphocytic, Chronic, B-Cell drug therapy metabolism pathology MeSH
- Lymphoma, Large B-Cell, Diffuse drug therapy metabolism pathology MeSH
- Phosphatidylinositol 3-Kinases chemistry metabolism MeSH
- Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases genetics metabolism MeSH
- Humans MeSH
- Mice, Inbred NOD MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Antineoplastic Agents pharmacology MeSH
- Sesquiterpenes pharmacology MeSH
- Signal Transduction MeSH
- Xenograft Model Antitumor Assays MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
PURPOSE: PI3K signaling is a common feature of B-cell neoplasms, including chronic lymphocytic leukemia (CLL) and diffuse large B-cell lymphoma (DLBCL), and PI3K inhibitors have been introduced into the clinic. However, there remains a clear need to develop new strategies to target PI3K signaling. PI3K activity is countered by Src homology domain 2-containing inositol-5'-phosphatase 1 (SHIP1) and, here, we have characterized the activity of a novel SHIP1 activator, AQX-435, in preclinical models of B-cell malignancies. EXPERIMENTAL DESIGN: In vitro activity of AQX-435 was evaluated using primary CLL cells and DLBCL-derived cell lines. In vivo activity of AQX-435, alone or in combination with the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, was assessed using DLBCL cell line and patient-derived xenograft models. RESULTS: Pharmacologic activation of SHIP1 using AQX-435 was sufficient to inhibit anti-IgM-induced PI3K-mediated signaling, including induction of AKT phosphorylation and MYC expression, without effects on upstream SYK phosphorylation. AQX-435 also cooperated with the BTK inhibitor ibrutinib to enhance inhibition of anti-IgM-induced AKT phosphorylation. AQX-435 induced caspase-dependent apoptosis of CLL cells preferentially as compared with normal B cells, and overcame in vitro survival-promoting effects of microenvironmental stimuli. Finally, AQX-435 reduced AKT phosphorylation and growth of DLBCL in vivo and cooperated with ibrutinib for tumor growth inhibition. CONCLUSIONS: Our results using AQX-435 demonstrate that SHIP1 activation may be an effective novel therapeutic strategy for treatment of B-cell neoplasms, alone or in combination with ibrutinib.
Aquinox Pharmaceuticals Inc Vancouver British Columbia Canada
Faculty of Informatics and Statistics University of Economics Prague Czech Republic
References provided by Crossref.org
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