OSU-T315: a novel targeted therapeutic that antagonizes AKT membrane localization and activation of chronic lymphocytic leukemia cells

Abstract

• OSU-T315 impedes AKT localization in lipid rafts.• OSU-T315 shows in vitro and in vivo therapeutic effects.Aberrant regulation of endogenous survival pathways plays a major role in progression of chronic lymphocytic leukemia (CLL). Signaling via conjugation of surface receptors within the tumor environmental niche activates survival and proliferation pathways in CLL. Of these, the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway appears to be pivotal to support CLL pathogenesis, and pharmacologic inhibitors targeting this axis have shown clinical activity. Here we investigate OSU-T315, a compound that disrupts the PI3K/AKT pathway in a novel manner. Dose-dependent selective cytotoxicity by OSU-T315 is noted in both CLL-derived cell lines and primary CLL cells relative to normal lymphocytes. In contrast to the highly successful Bruton's tyrosine kinase and PI3K inhibitors that inhibit B-cell receptor (BCR) signaling pathway at proximal kinases, OSU-T315 directly abrogates AKT activation by preventing translocation of AKT into lipid rafts without altering the activation of receptor-associated kinases. Through this mechanism, the agent triggers caspase-dependent apoptosis in CLL by suppressing BCR, CD49d, CD40, and Toll-like receptor 9-mediated AKT activation in an integrin-linked kinase-independent manner. In vivo, OSU-T315 attains pharmacologically active drug levels and significantly prolongs survival in the TCL1 mouse model. Together, our findings indicate a novel mechanism of action of OSU-T315 with potential therapeutic application in CLL. (Blood. 2015;125(2):284-295)

ILK Induction in Lymphoid Organs by a TNFα–NF-κB–Regulated Pathway Promotes the Development of Chronic Lymphocytic Leukemia

“…In line with this perspective, OSU-T315, a compound formerly thought to function as a specific ILKinhibiting compound, has recently been suggested to target Akt localization instead of ILK activity (50). We observed similar off-target effects when using this inhibitor on ILK-null murine embryonic fibroblasts (data not shown) and therefore restricted our analysis to genetic manipulations only.…”

CD49d associates with nodal presentation and subsequent development of lymphadenopathy in patients with chronic lymphocytic leukaemia

“…Further investigation of these aspects is needed before any change in clinical practice can be recommended. Finally, CD49d may play a predictive role, particularly in patients with lymphadenopathy; at present, five drugs have shown the ability to decrease CD49d expression and/or inhibit CD49d function, namely Ibrutinib (Pepper et al, 2015), Fosamatinib (Buchner et al, 2010), Idelalisib (Fiorcari et al, 2013), Natalizumab (Walsby et al, 2014), and OSU-T315 (Liu et al, 2015). The effects of these drugs on the biology of nodal disease and their impact on CD49d expression should be explored.…”

CD49d (ITGA4) expression is a predictor of time to first treatment in patients with chronic lymphocytic leukaemia and mutated IGHV status

“…However, further studies are needed, particularly in relationship with novel BCR-targeted therapies that influence tumour cells homing and mobilization in which CD49d plays a critical role. It might well be that, in this new scenario, CD49d could be a predictive biomarker (Zucchetto et al, 2013;Liu et al, 2014;Mertens & Stilgenbauer, 2014;Walsby et al, 2014;Pepper et al, 2015).…”