Nuclear Transport Inhibition in Acute Myeloid Leukemia: Recent Advances and Future Perspectives

Talati, Chetasi; Sweet, Kendra

doi:10.2217/ijh-2018-0001

Cited by 22 publications

(16 citation statements)

References 35 publications

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“…A selection of these clinical trials is presented in Table 2 . Detalied information is available from other excellent reviews covering data available from a high number of clinical trials [ 112 , 113 , 114 , 115 , 116 ]. To sum up, the results of these trials are encouraging, as they have shown that SINE compounds in general, and Selinexor in particular, are active in heavily pretreated cancer conditions [ 72 , 86 ].…”

Section: Targeting Nucleocytoplasmic Transportmentioning

confidence: 99%

Controlling the Gatekeeper: Therapeutic Targeting of Nuclear Transport

Kosyna

Depping

2018

Cells

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Nuclear transport receptors of the karyopherin superfamily of proteins transport macromolecules from one compartment to the other and are critical for both cell physiology and pathophysiology. The nuclear transport machinery is tightly regulated and essential to a number of key cellular processes since the spatiotemporally expression of many proteins and the nuclear transporters themselves is crucial for cellular activities. Dysregulation of the nuclear transport machinery results in localization shifts of specific cargo proteins and associates with the pathogenesis of disease states such as cancer, inflammation, viral illness and neurodegenerative diseases. Therefore, inhibition of the nuclear transport system has future potential for therapeutic intervention and could contribute to the elucidation of disease mechanisms. In this review, we recapitulate clue findings in the pathophysiological significance of nuclear transport processes and describe the development of nuclear transport inhibitors. Finally, clinical implications and results of the first clinical trials are discussed for the most promising nuclear transport inhibitors.

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Section: Targeting Nucleocytoplasmic Transportmentioning

confidence: 99%

Controlling the Gatekeeper: Therapeutic Targeting of Nuclear Transport

Kosyna

Depping

2018

Cells

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“…Kojima et al have demonstrated that increased expression of XPO1 have been independently associated with a worse prognosis in adults with AML. Overexpressed levels of XPO1 lead to enhanced transport of TSP/GRP to the cytoplasm thus, forcing nuclear retention of these proteins is a rational therapeutic strategy of selinexor use in AML [17, 18].…”

Section: Introductionmentioning

confidence: 99%

Gal9/Tim-3 expression level is higher in AML patients who fail chemotherapy

Dama

Tang

Fulton

et al. 2019

j. immunotherapy cancer

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Immune checkpoint pathways active in Acute Myeloid Leukemia (AML) patients, especially during the course of remission induction chemotherapy, have not been well studied. Although dominant in mediating T cell dysfunction in cancer, it is now well-accepted that interruption of PD-1/PD-L1 axes alone does not always completely restore T cell function, indicating the involvement of additional negative regulatory pathways, such as TIM-3/Gal-9, in promoting T cell exhaustion. Here, we characterized these pathways in AML patients enrolled in a phase I dose escalation trial that combined Selinexor, a Selective Inhibitor of Nuclear Export (SINE), with high-dose cytarabine (HiDAC) and mitoxantrone (Mito) (NCT02573363) as induction therapy. To monitor changes in expression of immune checkpoint receptors, multi-parameter flow cytometry was performed on peripheral blood and bone marrow biopsy specimens at diagnosis and following induction therapy in 26 AML patients. Expression of CD47, PD-L1, PD-L2 and Gal9 was assessed on CD34 + AML blasts, as well as on CD34 − cell populations. In parallel, we evaluated expression of inhibitory (PD1, CTLA4, LAG3, TIM-3) and stimulatory (CD28, ICOS, CD137, OX40, CD40L, HLA-DR) co-receptors on CD4 + and CD8 + T cell subsets. Compared to baseline, the frequency of Gal9 + CD34 − cells was significantly higher in patients with treatment failure (TF) than in those in complete remission (CR), and this finding correlated with increased TIM-3 expression on marrow-resident T cells in TF patients. Moreover, when we measured the expression level of PD-1 and TIM-3 in bone marrow samples compared to peripheral blood, TIM-3 was significantly higher in BM specimens. Our results suggest that targeting the Gal9/Tim-3 axis could be effective in combination with induction chemotherapy to increase the likelihood of complete remission in AML patients. Electronic supplementary material The online version of this article (10.1186/s40425-019-0611-3) contains supplementary material, which is available to authorized users.

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“…Thereby, promising antitumor activity in both solid and hematological cancer types was demonstrated. [26][27][28] In July 2019, the U.S. Food and Drug Administration (FDA) has approved selinexor (XPOVIO TM ) in combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma (NCT02336815).…”

Section: Introductionmentioning

confidence: 99%

<p>The Nuclear Export Inhibitor Selinexor Inhibits Hypoxia Signaling Pathways And 3D Spheroid Growth Of Cancer Cells</p>

Depping

Fallois

Landesman

et al. 2019

OTT

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Purpose: The nucleocytoplasmic transport of macromolecules is critical for both cell physiology and pathophysiology. Exportin 1 (XPO1), the major nuclear export receptor, is involved in the cellular adaptation to reduced oxygen availability by controlling the nuclear activity of the hypoxia-inducible factors (HIFs). Recently, a specific inhibitor of XPO1, selinexor (KPT-330), has been identified that inhibits nuclear export of cargo proteins by binding to the XPO1 cargo-binding pocket. Patients and methods: We used different cancer cell lines from human tissues and evaluated the physiological activity of selinexor on the hypoxia response pathway in twodimensional (2D) monolayer cell cultures in quantitative real-time (qRT)-PCR experiments and luciferase reporter gene assays. A three-dimensional (3D) tumor spheroid culture model of MCF-7 breast cancer cells was established to analyze the effect of selinexor on 3D tumor spheroid structure, formation and viability. Results: Selinexor treatment reduces HIF-transcriptional activity and expression of the HIF-1 target gene solute carrier family 2 member 1 (SLC2A1). Moreover, 3D tumor spheroid structure, formation and viability are inhibited in response to selinexor-induced nuclear export inhibition. Conclusion: Here, we demonstrate the effect of specific XPO1-inhibition on the hypoxic response on the molecular level in 2D and 3D culture models of MCF-7 cells.

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Nuclear Transport Inhibition in Acute Myeloid Leukemia: Recent Advances and Future Perspectives

Cited by 22 publications

References 35 publications

Controlling the Gatekeeper: Therapeutic Targeting of Nuclear Transport

Controlling the Gatekeeper: Therapeutic Targeting of Nuclear Transport

Gal9/Tim-3 expression level is higher in AML patients who fail chemotherapy

<p>The Nuclear Export Inhibitor Selinexor Inhibits Hypoxia Signaling Pathways And 3D Spheroid Growth Of Cancer Cells</p>

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