Imetelstat inhibits growth of megakaryocyte colony-forming units from patients with essential thrombocythemia

Baerlocher, Gabriela M.; Haubitz, Monika; Braschler, Thomas; Brunold, Claudio; Burington, Bart; Leibundgut, Elisabeth Oppliger; Go, Ning

doi:10.1182/bloodadvances.2019000167

Cited by 11 publications

(16 citation statements)

References 15 publications

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“…In conclusion, because imetelstat did not activate TLRs and had no impact on the expression of TLR signaling pathway target genes, the cytopenias, including anemia, neutropenia, and thrombocytopenia, observed in some patients treated with imetelstat are not mediated by off-target interactions with TLRs. These findings are supported by the structural differences between imetelstat and the minimal requirements to activate TLR9 [12], and by earlier results from our group and others demonstrating the effects of imetelstat on megakaryocytes through mechanisms other than TLRs [1,22,23]. We instead hypothesize that cytopenias and especially the thrombocytopenia associated with imetelstat treatment results from on-target effects on the stem and progenitor cell pool.…”

Section: -Tcgtttttttcgtttttttttttt-3 Criteria Not Metsupporting

confidence: 79%

“…The effects of imetelstat are also different in neoplastic cells compared with normal cells. Imetelstat treatment ex vivo inhibits megakaryocyte colony-forming units (CFU-MKs) in samples from patients with essential thrombocythemia but not CFU-MKs in samples from healthy individuals [ 23 ]. These results were supported by the inhibition of telomerase and clonal proliferation of megakaryocyte in samples from patients with essential thrombocythemia in a phase II study of imetelstat [ 1 ].…”

Section: Resultsmentioning

confidence: 99%

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Myelosuppression in Patients Treated with the Telomerase Inhibitor Imetelstat Is Not Mediated through Activation of Toll-Like Receptors

Baerlocher

Rusbuldt

Bussolari

et al. 2020

IJMS

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Imetelstat sodium (GRN163L; hereafter, imetelstat) is a first-in-class telomerase inhibitor that has demonstrated activity in patients with myeloproliferative neoplasms (MPNs). Treatment with imetelstat has been associated with thrombocytopenia and other hematologic adverse effects that were manageable and reversible. Toll-like receptors (TLRs) are proteins that recognize pathogen-associated molecular patterns and stimulate innate immune and pro-apoptotic responses. Because imetelstat is an oligonucleotide, and some oligonucleotides can activate TLRs, we conducted an in vitro study to rule out the possibility of imetelstat-associated thrombocytopenia by off-target effects through activation of TLRs. We used HEK293 cell lines stably co-expressing a human TLR gene and an NFκB-inducible reporter to investigate whether imetelstat can activate TLR signaling. We treated the cells with imetelstat or control oligonucleotides for 20 h, and used absorbance of the culture media to calculate the reporter activity. Treatment with imetelstat within or beyond the clinically relevant concentrations had no stimulatory effect on TLR2, TLR3, TLR4, TLR5, TLR7, or TLR9. This result was not surprising since the structure of imetelstat does not meet the reported minimal structural requirements for TLR9 activation. Furthermore, imetelstat treatment of the MPN cell line HEL did not impact the expression of TLR signaling pathway target genes that are commonly induced by activation of different TLRs, whereas it significantly reduced its target gene hTERT, human telomerase reverse transcriptase, in a dose- and time-dependent manner. Hence, cytopenias, especially thrombocytopenia observed in some patients treated with imetelstat, are not mediated by off-target interactions with TLRs.

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Section: -Tcgtttttttcgtttttttttttt-3 Criteria Not Metsupporting

confidence: 79%

Section: Resultsmentioning

confidence: 99%

Myelosuppression in Patients Treated with the Telomerase Inhibitor Imetelstat Is Not Mediated through Activation of Toll-Like Receptors

Baerlocher

Rusbuldt

Bussolari

et al. 2020

IJMS

Self Cite

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“…High telomerase activity is considered one of the six hallmarks of cancer proposed by Hanahan and Weinberg in 2000 [10]; therefore, targeting TERT/telomerase has long been considered to be a promising target for cancer drug development. To date, most drug development activities have focused on small molecule compounds [11,12] and oligonucleotides [13,14] as potential telomerase inhibitor drugs.…”

Section: Introductionmentioning

confidence: 99%

CRISPR/Cas9-Mediated TERT Disruption in Cancer Cells

Wen

Zhao

Song

et al. 2020

IJMS

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Mammalian telomere lengths are primarily regulated by telomerase, a ribonucleoprotein consisting of a reverse transcriptase (TERT) and an RNA subunit (TERC). TERC is constitutively expressed in all cells, whereas TERT expression is temporally and spatially regulated, such that in most adult somatic cells, TERT is inactivated and telomerase activity is undetectable. Most tumor cells activate TERT as a mechanism for preventing progressive telomere attrition to achieve proliferative immortality. Therefore, inactivating TERT has been considered to be a promising means of cancer therapy. Here we applied the CRISPR/Cas9 gene editing system to target the TERT gene in cancer cells. We report that disruption of TERT severely compromises cancer cell survival in vitro and in vivo. Haploinsufficiency of TERT in tumor cells is sufficient to result in telomere attrition and growth retardation in vitro. In vivo, TERT haploinsufficient tumor cells failed to form xenograft after transplantation to nude mice. Our work demonstrates that gene editing-mediated TERT knockout is a potential therapeutic option for treating cancer.

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“… 2 Previously, we demonstrated a dose-dependent inhibition of megakaryocytic colony-forming units from patients with ET but not from healthy individuals in vitro . 3 In a phase II study of ET patients who were refractory to or intolerant of prior treatment, imetelstat induced rapid and durable hematologic responses in all patients, and molecular responses were achieved in the majority of patients within 3-6 months. 4 …”

Section: Introductionmentioning

confidence: 94%

Dynamics of mutations in patients with essential thrombocythemia treated with imetelstat

et al. 2020

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In a phase-2 study, the telomerase inhibitor imetelstat induced rapid hematologic responses in all patients with essential thrombocythemia who were refractory or intolerant to prior therapies. Significant molecular responses were achieved within 3-6 months in 81% of patients with phenotypic driver mutations in JAK2, CALR and MPL. Here, we investigated the dynamics of additional somatic mutations in response to imetelstat. At study entry, 50% of patients carried 1-5 additional mutations in the genes ASXL1, CBL, DNMT3A, EZH2, IDH1, SF3B1, TET2, TP53 and U2AF1. Three patients with baseline mutations also had late-emerging mutations in TP53, IDH1 and TET2. Most clones with additional mutations were responsive to imetelstat and decreased with the driver mutation, including the poor prognostic ASXL1, EZH2 and U2AF1 mutations while SF3B1 and TP53 mutations were associated with poorer molecular response. Overall, phenotypic driver mutation response was significantly deeper in patients without additional mutations (P = 0.04) and correlated with longer duration of response. In conclusion, this detailed molecular analysis of highly pretreated and partly resistant patients with essential thrombocythemia reveals a high individual patient complexity. Moreover, imetelstat demonstrates potential to inhibit efficiently co-incident mutations occurring in neoplastic clones in patients with essential thrombocythemia. (ClinicalTrials.gov number,

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Imetelstat inhibits growth of megakaryocyte colony-forming units from patients with essential thrombocythemia

Abstract: Key Points Clinically relevant imetelstat concentrations significantly inhibit CFU-MEG formation from MNCs of ET patients and reduce hTERT expression. However, similar concentrations of imetelstat do not inhibit cytokine-induced CFU-MEG from MNCs of healthy donors.

Cited by 11 publications

References 15 publications

Myelosuppression in Patients Treated with the Telomerase Inhibitor Imetelstat Is Not Mediated through Activation of Toll-Like Receptors

Myelosuppression in Patients Treated with the Telomerase Inhibitor Imetelstat Is Not Mediated through Activation of Toll-Like Receptors

CRISPR/Cas9-Mediated TERT Disruption in Cancer Cells

Dynamics of mutations in patients with essential thrombocythemia treated with imetelstat

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