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Medientyp:
E-Artikel
Titel:
Abstract 2732: Myelosuppression in patients treated with the telomerase inhibitor imetelstat is not mediated through activation of toll-like receptors
Beteiligte:
Baerlocher, Gabriela M.;
Rusbuldt, Joshua;
Huang, Fei;
Bussolari, Jacqueline
Erschienen:
American Association for Cancer Research (AACR), 2016
Beschreibung:
<jats:title>Abstract</jats:title>
<jats:p>Imetelstat is a covalently lipidated 13-mer N3′-P5′ thio-phosphoramidate (NPS) oligonucleotide (5′-TAGGGTTAGACAA-3′) that is complementary to the RNA template region (hTR; 3′-AUCCCAACCUGUU-5′) of telomerase. Imetelstat is believed to act as a direct competitive inhibitor of telomerase enzyme activity and to not have an antisense mechanism of action (MOA) typical of other oligonucleotides. The purpose of this study was to assess whether the thrombocytopenia observed in some patients with myeloproliferative neoplasm treated with imetelstat can be attributed to activation of toll-like receptors (TLRs) by imetelstat. Imetelstat and related control oligonucleotides (Mis-match and Sense) were tested using 7 different HEK-Blue™ TLR cell lines, each stably coexpressing a human TLR gene (TLR2, 3, 4, 5, 7, 8, and 9) and a NF-κB-inducible secreted embryonic alkaline phosphatase (SEAP) reporter gene. After 20 hours’ incubation, the cells were measured for absorbance at 650 nm for SEAP activity. Each TLR experiment was performed twice, with 3 replicates per experiment. The results showed that the positive control for each individual TLR was recognized by the corresponding TLR, leading to a strong SEAP activity, whereas imetelstat at a clinically relevant concentration range (10 μM-60 μM) and the control oligonucleotides related to imetelstat yielded no induction of SEAP activity (similar level to untreated). These data demonstrate that imetelstat has no stimulatory effect on the majority of the tested TLRs. Imetelstat yielded slightly higher induction on TLR8 than the untreated control, but significantly lower than the positive control. Although thrombocytopenia has been observed in patients with myeloproliferative neoplasms treated with imetelstat, these data show that it cannot result from imetelstat acting as a ligand for TLRs. TLR9, associated with thrombocytopenia, was not activated by imetelstat and the slight activity of imetelstat on TLR8 is likely irrelevant as no link between TLR8 activation and thrombocytopenia has been reported. These findings are consistent with 13-mer sequence of imetelstat, differing from oligonucleotides known to stimulate TLR9, which comprise 2 CpG islands separated by 6-10 nucleotides and are longer than 21 nucleotides. Ex vivo studies have provided evidence that imetelstat may induce thrombocytopenia in patients with myeloproliferative neoplasms by blocking the terminal maturation of normal megakaryocyte precursors: megakaryocytic differentiation requires upregulation of telomerase activity which is inhibited by imetelstat. Correct understanding of the MOA of imetelstat is vital to guide its clinical use and strategies to mitigate thrombocytopenia in patients with myeloproliferative neoplasms.</jats:p>
<jats:p>Citation Format: Gabriela M. Baerlocher, Joshua Rusbuldt, Fei Huang, Jacqueline Bussolari. Myelosuppression in patients treated with the telomerase inhibitor imetelstat is not mediated through activation of toll-like receptors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2732.</jats:p>