Abstract 1871: Development of pelorol analogues to activate the SHIP1 lipid phosphatase; a novel paradigm to suppress B-cell receptor signaling in human B-cell cancers

Abstract

Abstract Signaling via the B-cell receptor (BCR) is a major driver of malignant B-cell proliferation and survival in B-cell malignancies including chronic lymphocytic leukemia (CLL). The role of kinases in BCR signalling is well understood and kinase inhibitors are effective therapies for B-cell cancers. However, resistance is increasingly common and new drugs are required. In this study we investigated an alternate strategy to block BCR signaling via small molecule activation of SHIP1, an inositol lipid phosphatase which suppresses PI3 kinase (PI3K)-mediated signaling by catalysing the conversion of the PI3K product PI(3,4,5)P3 (PIP3) to PI(3,4)P2. We focused on the exemplar compound, AQX-C5, which is structurally related to the natural product pelorol. AQX-C5 interfered with the ability of anti-IgM to activate PIP3-dependent signaling, including downstream phosphorylation of AKT, ERK1/2 and p70-S6K, and induction of MYC, in primary CLL cells. AQX-C5 also induced CLL cell apoptosis and overcame the survival-promoting effects of anti-IgM or CD40-ligand/interleukin-4. CLL cells were more sensitive to pro-apoptotic effects of AQX-C5 compared to non-malignant B cells. The AQX-C5-induced apoptosis in CLL cells was associated with down-modulation of the BCL2-related survival protein MCL1 in anti-IgM-stimulated cells, and induction of the pro-apoptotic protein NOXA. In addition to effects on PIP3-dependent signaling, AQX-C5 triggered down-modulation of CXCR4, a chemokine receptor important for homing of malignant cells to supportive tissue microenvironments. CXCR4 downmodulation was selective, since AQX-C5 did not alter surface expression of other receptors, including IgM and the transferrin receptor. In contrast to AQX-C5, the PI3Kδ inhibitor idelalisib failed to alter CXCR4 expression, indicating that these effects of AQX-C5 may be mediated via PI(3,4)P2 accumulation rather than PIP3 depletion. We evaluated the in vivo anti-lymphoma activity of AQX-C5 in a xenograft model using the TMD8 cell line, derived from a diffuse large B-cell lymphoma. Similar to the BTK inhibitor ibrutinib, AQX-C5 substantially reduced the rate of tumor growth and tumor mass at the end of the experiment, without evidence for gross toxicity. These findings suggest that SHIP1 activators, such as AQX-C5, may be interesting therapeutic agents for various B-cell cancers. Citation Format: Graham Packham, Elizabeth Lemm, Beatriz Valle-Argos, Lindsay Smith, Nichola Weston-Bell, Freda Stevenson, Matthew J. Carter, Mark S. Cragg, Francesco Forconi, Andrew J. Steele, Jennifer Cross, Curtis Harwig, Georg Lenz, Lloyd Mackenzie, Pavel Klener. Development of pelorol analogues to activate the SHIP1 lipid phosphatase; a novel paradigm to suppress B-cell receptor signaling in human B-cell cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1871.