Abstract 1938: Exportin-1 (XPO1) is a novel therapeutic biomarker for patients with neuroblastoma
| Autor: | Marcus Luxemburg, Basia Galinski, Yosef Landesman, Daniel A. Weiser, Michelle Ewart |
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| Rok vydání: | 2017 |
| Předmět: | |
| Zdroj: | Cancer Research. 77:1938-1938 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | Background: Half of patients with high-risk neuroblastoma succumb to disease, yet these patients with inferior outcome cannot be identified at diagnosis despite contemporary risk stratification that integrates MYCN copy number status, tumor histology, and patient age. We have shown that overexpression of Exportin-1 (XPO1) is associated with poor survival in neuroblastoma, affirming what has been identified across a range of malignancies. Selinexor (KPT-330, Karyopharm Therapeutics), an XPO1 inhibitor in early phase clinical trials, inhibits the nuclear to cytoplasmic translocation of tumor suppressor and growth regulatory proteins implicated in oncogenesis. We hypothesized that protein expression level of XPO1 in neuroblastoma cell lines predict the effective response of treatment with selinexor. Methods: We used a panel of early passage patient derived neuroblastoma cell lines including IMR5, NLF, KELLY, NB-EBC1, and SKNSH that are representative of the spectrum and genetic diversity of human disease. Cell lines were treated with varying concentrations of selinexor. RNA and whole cell protein extract as well as nuclear and cytoplasmic fractionated protein was obtained from untreated and treated conditions. Treated and untreated cells were also pelleted, and, along with patient tumor samples, formalin-fixed and paraffin-embedded for microscopic and immunohistochemical (IHC) evaluation. Results: Compared to noncancerous cell lines, neuroblastoma cell lines have high protein and mRNA expression of XPO1; higher expression correlates with greater sensitivity to selinexor. Selinexor treatment reduced XPO1 protein and increased XPO1 mRNA expression, and it lead to nuclear retention of XPO1 cargo such as p53 and survivin. Comparison of microscopic features and protein staining intensity of patient samples with known XPO1 expression is ongoing. Conclusions: This study provides rationale for XPO1 protein abundance as a potential biomarker of therapeutic response to the drug selinexor. By using patient derived neuroblastoma cell lines, we are able to evaluate the response of selinexor and XPO1 expression in the context of this enigmatic disease. These data suggest that initial drug response to selinexor can be predicted early in the course of disease and more investigation of the high expression of XPO1 seen in patients with poor outcome will provide strategies for combinatorial treatment approaches. Citation Format: Basia Galinski, Marcus Luxemburg, Michelle Ewart, Yosef Landesman, Daniel Weiser. Exportin-1 (XPO1) is a novel therapeutic biomarker for patients with neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1938. doi:10.1158/1538-7445.AM2017-1938 |
| Databáze: | OpenAIRE |
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