دورية أكاديمية
أعرض في EDS

Splicing modulation as novel therapeutic strategy against diffuse malignant peritoneal mesothelioma.

التفاصيل البيبلوغرافية
العنوان: Splicing modulation as novel therapeutic strategy against diffuse malignant peritoneal mesothelioma.
المؤلفون: Sciarrillo R; Department of Pediatric Oncology, Cancer Center Amsterdam, Amsterdam University Medical Center, location VUMC, Amsterdam, the Netherlands; Department of Hematology, Cancer Center Amsterdam, Amsterdam University Medical Center, location VUMC, Amsterdam, the Netherlands; Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Center, location VUMC, Amsterdam, the Netherlands., Wojtuszkiewicz A; Department of Pediatric Oncology, Cancer Center Amsterdam, Amsterdam University Medical Center, location VUMC, Amsterdam, the Netherlands; Department of Hematology, Cancer Center Amsterdam, Amsterdam University Medical Center, location VUMC, Amsterdam, the Netherlands., El Hassouni B; Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Center, location VUMC, Amsterdam, the Netherlands., Funel N; Cancer Pharmacology Lab, AIRC Start-Up Unit, University of Pisa, Italy; CNR-Nano, Institute of Nanoscience and Nanotechnology, Pisa, Italy., Gandellini P; Department of Applied Research and Technological Development, Molecular Pharmacology Unit, Fondazione IRCCS - National Cancer Institute, Milano, Italy., Lagerweij T; Department of Neurosurgery, Neuro-Oncology Research Group, Cancer Center Amsterdam, Amsterdam University Medical Center, location VUMC, Amsterdam, the Netherlands., Buonamici S; H3 Biomedicine, Inc., 300 Technology Square, FL 5, Cambridge, MA 02139, USA., Blijlevens M; Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Center, location VUMC, Amsterdam, the Netherlands., Zeeuw van der Laan EA; Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Center, location VUMC, Amsterdam, the Netherlands., Zaffaroni N; Department of Applied Research and Technological Development, Molecular Pharmacology Unit, Fondazione IRCCS - National Cancer Institute, Milano, Italy., Deraco M; Peritoneal Malignancy Program, National Cancer Institute, Milano, Italy., Kusamura S; Peritoneal Malignancy Program, National Cancer Institute, Milano, Italy., Würdinger T; Department of Neurosurgery, Neuro-Oncology Research Group, Cancer Center Amsterdam, Amsterdam University Medical Center, location VUMC, Amsterdam, the Netherlands., Peters GJ; Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Center, location VUMC, Amsterdam, the Netherlands., Molthoff CFM; Department of Radiology & Nuclear Medicine, Amsterdam University Medical Center, location VUMC, Amsterdam, the Netherlands., Jansen G; Amsterdam Rheumatology and Immunology Center, Amsterdam University Medical Center, location VUMC, Amsterdam, the Netherlands., Kaspers GJL; Princes Maxima Center for Pediatric Oncology, Utrecht, the Netherlands., Cloos J; Department of Pediatric Oncology, Cancer Center Amsterdam, Amsterdam University Medical Center, location VUMC, Amsterdam, the Netherlands; Department of Hematology, Cancer Center Amsterdam, Amsterdam University Medical Center, location VUMC, Amsterdam, the Netherlands., Giovannetti E; Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Center, location VUMC, Amsterdam, the Netherlands; Cancer Pharmacology Lab, AIRC Start-Up Unit, University of Pisa, Italy; CNR-Nano, Institute of Nanoscience and Nanotechnology, Pisa, Italy. Electronic address: elisa.giovannetti@gmail.com.
المصدر: EBioMedicine [EBioMedicine] 2019 Jan; Vol. 39, pp. 215-225. Date of Electronic Publication: 2018 Dec 20.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Elsevier B.V Country of Publication: Netherlands NLM ID: 101647039 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2352-3964 (Electronic) Linking ISSN: 23523964 NLM ISO Abbreviation: EBioMedicine Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [Amsterdam] : Elsevier B.V., [2014]-
مواضيع طبية MeSH: Antineoplastic Agents/*administration & dosage , Lung Neoplasms/*drug therapy , Mesothelioma/*drug therapy , Peritoneal Neoplasms/*drug therapy , Phosphoproteins/*metabolism , RNA Splicing/*drug effects , RNA Splicing Factors/*metabolism , Tissue Array Analysis/*methods, Aged ; Animals ; Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Epoxy Compounds/administration & dosage ; Epoxy Compounds/pharmacology ; Female ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Gene Regulatory Networks/drug effects ; Humans ; Lung Neoplasms/genetics ; Lung Neoplasms/metabolism ; Macrolides/administration & dosage ; Macrolides/pharmacology ; Male ; Mesothelioma/genetics ; Mesothelioma/metabolism ; Mesothelioma, Malignant ; Mice ; Middle Aged ; Morpholines/administration & dosage ; Morpholines/pharmacology ; Peritoneal Neoplasms/genetics ; Peritoneal Neoplasms/metabolism ; Phosphoproteins/genetics ; Pyrans/administration & dosage ; Pyrans/pharmacology ; RNA Splicing Factors/genetics ; Xenograft Model Antitumor Assays
مستخلص: Introduction: Therapeutic options for diffuse malignant peritoneal mesothelioma (DMPM) are limited to surgery and locoregional chemotherapy. Despite improvements in survival rates, patients eventually succumb to disease progression. We investigated splicing deregulation both as molecular prognostic factor and potential novel target in DMPM, while we tested modulators of SF3b complex for antitumor activity.
Methods: Tissue-microarrays of 64 DMPM specimens were subjected to immunohistochemical assessment of SF3B1 expression and correlation to clinical outcome. Two primary cell cultures were used for gene expression profiling and in vitro screening of SF3b modulators. Drug-induced splicing alterations affecting downstream cellular pathways were detected through RNA sequencing. Ultimately, we established bioluminescent orthotopic mouse models to test the efficacy of splicing modulation in vivo.
Results: Spliceosomal genes are differentially upregulated in DMPM cells compared to normal tissues and high expression of SF3B1 correlated with poor clinical outcome in univariate and multivariate analysis. SF3b modulators (Pladienolide-B, E7107, Meayamycin-B) showed potent cytotoxic activity in vitro with IC50 values in the low nanomolar range. Differential splicing analysis of Pladienolide-B-treated cells revealed abundant alterations of transcripts involved in cell cycle, apoptosis and other oncogenic pathways. This was validated by RT-PCR and functional assays. E7107 demonstrated remarkable in vivo antitumor efficacy, with significant improvement of survival rates compared to vehicle-treated controls.
Conclusions: SF3B1 emerged as a novel potential prognostic factor in DMPM. Splicing modulators markedly impair cancer cell viability, resulting also in potent antitumor activity in vivo. Our data designate splicing as a promising therapeutic target in DMPM.
(Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)
التعليقات: Comment in: EBioMedicine. 2019 Jan;39:7-8. (PMID: 30612942)
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فهرسة مساهمة: Keywords: Mesothelioma; RNA-sequencing; SF3b modulation; Splicing; Therapy
المشرفين على المادة: 0 (Antineoplastic Agents)
0 (E 7107)
0 (Epoxy Compounds)
0 (Macrolides)
0 (Morpholines)
0 (Phosphoproteins)
0 (Pyrans)
0 (RNA Splicing Factors)
0 (SF3B1 protein, human)
0 (meayamycin B)
0 (pladienolide B)
تواريخ الأحداث: Date Created: 20181225 Date Completed: 20190610 Latest Revision: 20201218
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC6355829
DOI: 10.1016/j.ebiom.2018.12.025
PMID: 30581150
قاعدة البيانات: MEDLINE
الوصف
تدمد:2352-3964
DOI:10.1016/j.ebiom.2018.12.025