Pharmacological treatment with inhibitors of nuclear export enhances the antitumor activity of docetaxel in human prostate cancer

Gravina, Giovanni Luca; Mancini, Andrea; Colapietro, Alessandro; Marampon, Francesco; Sferra, Roberta; Pompili, Simona; Biordi, Leda; Iorio, Roberto; Flati, Vincenzo; Argueta, Christian; Landesman, Yosef; Kauffman, Michael; Shacham, Sharon; Festuccia, Claudio

doi:10.18632/oncotarget.22760

Cited by 19 publications

(23 citation statements)

References 70 publications

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“…SINE compounds, generally, cause nuclear accumulation of tumor suppressors and cell cycle inhibitors and sensitize resistant cancer cells to other drugs. The anti-cancer activity of SINE compounds in combination with standard therapies achieves high remission rates and has been highlighted by different studies [ 106 , 107 , 108 , 109 ]. For example, in multiple triple-negative breast cancer (TNBC) models, antitumor efficacy of Selinexor increased in combination with paclitaxel or eribulin [ 110 ].…”

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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“…Selinexor was administered twice per week at doses of 30 mg/m 2 , 50 mg/m 2 , or 60 mg flat dose. The most SINEs synergize with doxorubicin [159] In vitro /xenograft Selinexor, SINEs reduce bone metastasis [160] In vitro /xenograft Selinexor, KPT-251 Growth inhibition, apoptosis, increased DNA damage SINEs sensitize cells to docetaxel [161] Breast cancer…”

Section: Evaluation Of Selinexor In Clinical Trialsmentioning

confidence: 99%

Hitting a moving target: inhibition of the nuclear export receptor XPO1/CRM1 as a therapeutic approach in cancer

Sendino¹,

Omaetxebarria²,

Rodríguez³

2018

CDR

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Cellular homeostasis crucially relies on the correct nucleocytoplasmic distribution of a vast number of proteins and RNA molecules, which are shuttled in and out of the nucleus by specialized transport receptors. The nuclear export receptor XPO1, also called CRM1, mediates the translocation of hundreds of proteins and several classes of RNA to the cytoplasm, and thus regulates critical signaling pathways and cellular functions. The normal function of XPO1 appears to be often disrupted in malignant cells due to gene mutations or, most commonly, aberrant overexpression. Due to its important physiological roles and its frequent alteration in human tumors, XPO1 is a promising target for cancer therapy. XPO1 inhibitors have undergone extensive testing as therapeutic agents in preclinical models of cancer, with promising results. One of these inhibitors, Selinexor, is currently being evaluated in multiple clinical trials of different types of solid tumors and hematological malignancies. Here, we review several key aspects of XPO1 function, as well as the mechanisms that may lead to its alteration in cancer, and provide an update on the status of XPO1 inhibitors being developed as drugs for cancer therapy, including the definitive results of the first clinical trials with Selinexor that have been recently published. Figure 1. Receptor-mediated nucleocytoplasmic transport of proteins. A: Illustrative overview of the nuclear import of a cargo protein bearing a "classical" NLS mediated by the Importina/Importinb heterodimer (left) and the nuclear export of a cargo protein bearing a "leucine-rich" NES mediated by XPO1 (right); B: schematic depiction of the nuclear pore complex, illustrating its main structural features; C: examples of nucleocytoplasmic transport signals. The NLSs of SV40 large T antigen (monopartite) and nucleoplasmin (bipartite) are shown, with the basic residues that characterize "classical" NLSs highlighted in red. Below, the NES of PKI and a general consensus sequence of "leucine-rich" NESs are shown. The characteristic hydrophobic residues (represented by f in the consensus) are highlighted in colors and underlined. NLS: nuclear localization signal; NES: nuclear export signal Conception of the work, draft and revision of the work: Sendino M, Omaetxebarria MJ, Rodríguez JA

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“…Blockage of XPO1-mediated nuclear transport using SINEs like selinexor has been shown to be an effective anti-neoplastic approach in a variety of malignancies. [17,37,38] XPO1 inhibition forces nuclear localization of tumor suppressors and also interferes with additional signaling pathways, including NF-κB and BCR, which are crucial for survival of malignant B cells in general and for PCNSL cells in particular. The clinical use of selinexor in lymphoma has been studied in a phase I trial studying patients diagnosed with relapsed/refractory NHL and a phase IIb study in patients with DLBCL [17], which has led to a recent approval by the FDA in such an adverse setting.…”

Section: Discussionmentioning

confidence: 99%

Repolarization of tumor infiltrating macrophages and increased survival in mouse primary CNS lymphomas after XPO1 and BTK inhibition

et al. 2020

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Background Patients diagnosed with primary central nervous system lymphoma (PCNSL) often face dismal outcomes due to the limited availability of therapeutic options. PCNSL cells frequently have deregulated B-cell receptor (BCR) signaling, but clinical responses to its inhibition using ibrutinib have been brief. In this regard, blocking nuclear export by using selinexor, which covalently binds to XPO1, can also inhibit BCR signaling. Selinexor crosses the blood-brain barrier and was recently shown to have clinical activity in a patient with refractory diffuse large B-cell lymphoma in the CNS. We studied selinexor alone or in combination with ibrutinib in pre-clinical mouse models of PCNSL. Methods Orthotopic xenograft models were established by injecting lymphoma cells into the brain parenchyma of athymic mice. Tumor growth was monitored by bioluminescence. Malignant cells and macrophages were studied by immunohistochemistry and flow cytometry. Results Selinexor blocked tumor growth and prolonged survival in a bioluminescent mouse model, while its combination with ibrutinib further increased survival. CNS lymphoma in mice was infiltrated by tumor-promoting M2-like macrophages expressing PD-1 and SIRPα. Interestingly, treatment with selinexor and ibrutinib favored an anti-tumoral immune response by shifting polarization toward inflammatory M1-like and diminishing PD-1 and SIRPα expression in the remaining tumorpromoting M2-like macrophages. Conclusions These data highlight the pathogenic role of the innate immune microenvironment in PCNSL and provide preclinical evidence for the development of selinexor and ibrutinib as a new promising therapeutic option with cytotoxic and immunomodulatory potential.

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Pharmacological treatment with inhibitors of nuclear export enhances the antitumor activity of docetaxel in human prostate cancer

Cited by 19 publications

References 70 publications

Controlling the Gatekeeper: Therapeutic Targeting of Nuclear Transport

Controlling the Gatekeeper: Therapeutic Targeting of Nuclear Transport

Hitting a moving target: inhibition of the nuclear export receptor XPO1/CRM1 as a therapeutic approach in cancer

Repolarization of tumor infiltrating macrophages and increased survival in mouse primary CNS lymphomas after XPO1 and BTK inhibition

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