Preclinical antitumor efficacy of selective exportin 1 inhibitors in glioblastoma

Green, Adam L.; Ramkissoon, Shakti; McCauley, Dilara; Jones, Kristen L.; Perry, Jennifer A.; Hsu, Jessie Hao-Ru; Ramkissoon, Lori; Maire, Cécile L.; Hubbell-Engler, Benjamin; Knoff, David; Shacham, Sharon; Ligon, Keith L.; Kung, Andrew L.

doi:10.1093/neuonc/nou303

Cited by 61 publications

(70 citation statements)

References 29 publications

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“…8 In addition, selinexor has demonstrated excellent brain penetration and promising results in both pre-clinical and clinical models of glioblastoma. 9,10 Recently, a phase 2 study in patients with recurrent glioblastoma showed 17% of PR and 33% of stable disease in 12 patients, which confirms its activity in brain tumors. 9 Finally, our group studied the effect of selinexor in a pre-clinical model of PCNSL using an intracerebral xenograft murine model.…”

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confidence: 86%

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Promising activity of selinexor in the treatment of a patient with refractory diffuse large B-cell lymphoma and central nervous system involvement

et al. 2017

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confidence: 86%

“…7,8 Moreover, selinexor has shown excellent brain penetration and encouraging efficacy in patients with recurrent glioblastoma. 9,10 Promising results in pre-clinical models of primary CNS lymphoma (PCNSL) have been reported as well. 11 The efficacy of selinexor in patients with SCNSL or PCNSL has not yet been demonstrated.…”

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confidence: 99%

Promising activity of selinexor in the treatment of a patient with refractory diffuse large B-cell lymphoma and central nervous system involvement

et al. 2017

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“…These data were indicative of synergistic regulatory effects between the two lncRNAs. Within this module, XPO1 was associated with GBM prognosis [38]. To evaluate the association between the 5-ceRNA module and GBM survival, we integrated the expression profiles of the nodes into a risk model (Materials and Methods).…”

Section: Resultsmentioning

confidence: 99%

“…MCM3AP-AS, which is involved in RNA processing and cell cycle-related functions, was significantly associated with survival. By exploring the highly competitive sub-network of the LMCN, we determined that MCM3AP-AS and MIR17HG comprised a ceRNA regulating module that competed with MATR3, ZCCHC14, and XPO1, which was associated with GBM prognosis [38]. By integrating the expression profile of this module into a risk model, we could stratify GBM patients from both the TCGA and the GSE7696 datasets into different risk groups.…”

Section: Discussionmentioning

confidence: 99%

Identification of prognostic biomarkers in glioblastoma using a long non-coding RNA-mediated, competitive endogenous RNA network

et al. 2016

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Glioblastoma multiforme (GBM) is a highly malignant brain tumor associated with a poor prognosis. Cross-talk between competitive endogenous RNAs (ceRNAs) plays a critical role in tumor development and physiology. In this study, we present a multi-step computational approach to construct a functional GBM long non-coding RNA (lncRNA)-mediated ceRNA network (LMCN) by integrating genome-wide lncRNA and mRNA expression profiles, miRNA-target interactions, functional analyses, and clinical survival analyses. LncRNAs in the LMCN exhibited specific topological features consistent with a regulatory association with coding mRNAs across GBM pathology. We determined that the lncRNA MCM3AP-AS was involved in RNA processing and cell cycle-related functions, and was correlated with patient survival. MCM3AP-AS and MIR17HG acted synergistically to regulate mRNAs in a network module of the competitive LMCN. By integrating the expression profile of this module into a risk model, we stratified GBM patients in both the The Cancer Genome Atlas and an independent GBM dataset into distinct risk groups. Finally, survival analyses demonstrated that the lncRNAs and network module are potential prognostic biomarkers for GBM. Thus, ceRNAs could accelerate biomarker discovery and therapeutic development in GBM.

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“…Different from research exploring the mechanism of tumor transplantation and blood metastases as the object of study, this study primarily compared the efficacy of EGFR-TKIs in the treatment of intracranial tumors, for which the direct intracranial transplant method created a more consistent model. Furthermore, whether in drug efficacy studies of metastatic brain tumors or intracranial primary tumors, this type of animal model is widely applied [20, 42, 43]. Secondly, in this study, we did not investigate the potential effect of WBRT on the penetration of EGFR-TKIs into the CSF.…”

Section: Discussionmentioning

confidence: 99%

Tyrosine kinase inhibitors show different anti-brain metastases efficacy in NSCLC: A direct comparative analysis of icotinib, gefitinib, and erlotinib in a nude mouse model

Tan

Zhong

et al. 2017

Oncotarget

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Brain metastasis is an increasing problem in non-small cell lung cancer (NSCLC) patients. Tyrosine kinase inhibitors (TKIs), including gefitinib, erlotinib, and icotinib, are reported to be effective in patients with brain metastases. However, direct comparative studies of the pharmacokinetics and efficacy of these three drugs in treating brain metastases are lacking. In the present investigation, we found that gefitinib penetrated the blood-tumor barrier and was distributed to brain metastases more effectively than erlotinib or icotinib in a nude mouse model. The 1-h ratio of brain metastases to plasma concentration for gefitinib, erlotinib, and icotinib was 9.82±1.03%, 4.83±0.25%, and 2.62±0.21%, respectively. The 2-h ratio of brain metastases to plasma concentration for gefitinib, erlotinib, and icotinib was 15.11±2.00%, 5.73±1.31%, and 2.69±0.31%, respectively. Gefitinib exhibited the strongest antitumor activity (pgefitinib vs. erlotinib=0.005; pgefitinib vs. icotinib=0.002). Notably, erlotinib exhibited a better treatment efficacy than icotinib (p=0.037). Consistently, immunohistochemical data showed that TKIs differentially inhibit the proliferation of metastatical tumor cells. Gefitinib and erlotinib markedly inhibited the proliferation of tumor cells, while there were more ki-67-positive tumor cells in the icotinib group. Additionally, gefitinib inhibited the phosphorylation of EGFR better than the other drugs, whereas pEGFR expression levels in erlotinib groups were lower than levels in the icotinib group (pgefitinib vs. erlotinib=0.995; pgefitinib vs. icotinib=0.028; perlotinib vs. icotinib=0.042).Altogether, our findings suggest that gefitinib and erlotinib can inhibit the growth of PC-9-luc brain tumors. Gefitinib demonstrated better antitumor activity and penetration rate in brain metastases than erlotinib or icotinib.

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Preclinical antitumor efficacy of selective exportin 1 inhibitors in glioblastoma

Cited by 61 publications

References 29 publications

Promising activity of selinexor in the treatment of a patient with refractory diffuse large B-cell lymphoma and central nervous system involvement

Promising activity of selinexor in the treatment of a patient with refractory diffuse large B-cell lymphoma and central nervous system involvement

Identification of prognostic biomarkers in glioblastoma using a long non-coding RNA-mediated, competitive endogenous RNA network

Tyrosine kinase inhibitors show different anti-brain metastases efficacy in NSCLC: A direct comparative analysis of icotinib, gefitinib, and erlotinib in a nude mouse model

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