2. Academic Validation
  3. Preclinical Evaluation of a Novel SHIP1 Phosphatase Activator for Inhibition of PI3K Signaling in Malignant B Cells

Preclinical Evaluation of a Novel SHIP1 Phosphatase Activator for Inhibition of PI3K Signaling in Malignant B Cells

  • Clin Cancer Res. 2020 Apr 1;26(7):1700-1711. doi: 10.1158/1078-0432.CCR-19-2202.
Elizabeth A Lemm  # 1,  Beatriz Valle-Argos  # 1,  Lindsay D Smith 1,  Johanna Richter 1,  Yohannes Gebreselassie 1,  Matthew J Carter 2,  Jana Karolova 3 4,  Michael Svaton 3 4,  Karel Helman 5,  Nicola J Weston-Bell 1,  Laura Karydis 1,  Chris T Williamson 6,  Georg Lenz 7,  Jeremy Pettigrew 6,  Curtis Harwig 6,  Freda K Stevenson 1,  Mark Cragg 2,  Francesco Forconi 1,  Andrew J Steele 1,  Jennifer Cross 6,  Lloyd Mackenzie 6,  Pavel Klener 3 4,  Graham Packham 8
Affiliations

Affiliations

  • 1 Cancer Research UK Centre, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
  • 2 Centre for Cancer Immunology, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
  • 3 Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic.
  • 4 CLIP - Childhood Leukaemia Investigation Prague, Second Faculty of Medicine and Charles University Hospital in Motol, Prague, Czech Republic.
  • 5 Faculty of Informatics and Statistics, University of Economics, Prague, Czech Republic.
  • 6 Aquinox Pharmaceuticals (Canada) Inc., Vancouver, British Columbia, Canada.
  • 7 Department of Medicine A for Hematology, Oncology, and Pneumology, University Hospital Münster, Münster, Germany.
  • 8 Cancer Research UK Centre, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom. gpackham@soton.ac.uk.
  • # Contributed equally.
PMID: 31831562 DOI: 10.1158/1078-0432.CCR-19-2202
Abstract

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.

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