دورية أكاديمية
Splicing modulation as novel therapeutic strategy against diffuse malignant peritoneal mesothelioma.
العنوان: | Splicing modulation as novel therapeutic strategy against diffuse malignant peritoneal mesothelioma. |
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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) |
References: | Clin Cancer Res. 2003 Aug 1;9(8):3080-97. (PMID: 12912960) Oncogene. 2003 Dec 8;22(56):9041-7. (PMID: 14663482) Mol Cell. 2005 Dec 22;20(6):881-90. (PMID: 16364913) Stat Appl Genet Mol Biol. 2004;3:Article3. (PMID: 16646809) Nat Chem Biol. 2007 Sep;3(9):570-5. (PMID: 17643112) Cell Oncol. 2007;29(6):453-66. (PMID: 18032822) Nat Methods. 2008 Feb;5(2):171-3. (PMID: 18204457) Bioinformatics. 2008 Jul 1;24(13):1547-8. (PMID: 18467348) Lung Cancer. 2010 Jan;67(1):57-68. (PMID: 19380173) N Engl J Med. 2011 Oct 13;365(15):1384-95. (PMID: 21995386) Cell Mol Life Sci. 2012 Aug;69(15):2515-26. (PMID: 22349259) Nat Rev Drug Discov. 2012 Nov;11(11):847-59. (PMID: 23123942) BMC Bioinformatics. 2012;13 Suppl 16:S12. (PMID: 23176165) Sci Rep. 2013;3:1046. (PMID: 23308339) Arthritis Res Ther. 2013 Mar 01;15(2):R37. (PMID: 23452511) Clin Cancer Res. 2013 Nov 15;19(22):6296-304. (PMID: 23983259) Cancer Res. 2013 Nov 15;73(22):6745-56. (PMID: 24085787) Invest New Drugs. 2014 Jun;32(3):436-44. (PMID: 24258465) J Biol Chem. 2014 Jan 24;289(4):1938-47. (PMID: 24302718) Biochim Biophys Acta. 2014 Apr;1845(2):232-47. (PMID: 24491449) J Thorac Oncol. 2014 Jul;9(7):998-1007. (PMID: 24926545) Sci Rep. 2014 Aug 20;4:6098. (PMID: 25139387) J Clin Pathol. 2014 Dec;67(12):1038-43. (PMID: 25217709) Proc Natl Acad Sci U S A. 2014 Dec 23;111(51):E5593-601. (PMID: 25480548) Expert Opin Drug Metab Toxicol. 2015 May;11(5):673-89. (PMID: 25495223) Ann Surg Oncol. 2015 Dec;22(13):4344-51. (PMID: 25777091) Oncotarget. 2015 May 30;6(15):13119-32. (PMID: 25948791) Oncogene. 2016 May 12;35(19):2413-27. (PMID: 26300000) Nature. 2015 Sep 17;525(7569):384-8. (PMID: 26331541) Cell Rep. 2015 Nov 3;13(5):1033-45. (PMID: 26565915) Trends Mol Med. 2016 Jan;22(1):28-37. (PMID: 26700537) J Cell Biol. 2016 Jan 4;212(1):13-27. (PMID: 26728853) Nat Genet. 2016 Apr;48(4):407-16. (PMID: 26928227) Nucleic Acids Res. 2016 Jul 8;44(W1):W83-9. (PMID: 27098042) Hum Pathol. 2016 Sep;55:72-82. (PMID: 27184482) Nat Rev Cancer. 2016 Jul;16(7):413-30. (PMID: 27282250) Oncotarget. 2016 Nov 15;7(46):75503-75517. (PMID: 27705913) Mod Pathol. 2017 Feb;30(2):246-254. (PMID: 27813512) Clin Cancer Res. 2017 Jan 15;23(2):336-341. (PMID: 27836865) J Vis Exp. 2016 Dec 9;(118):. (PMID: 28060337) PLoS One. 2017 Feb 13;12(2):e0172209. (PMID: 28192473) Int J Biochem Cell Biol. 2017 Oct;91(Pt B):84-97. (PMID: 28433505) Cancer Cell. 2017 Aug 14;32(2):204-220.e15. (PMID: 28810145) Curr Opin Genet Dev. 2018 Feb;48:67-74. (PMID: 29136527) J Gastrointest Oncol. 2017 Oct;8(5):915-924. (PMID: 29184697) Expert Opin Ther Targets. 2018 Feb;22(2):107-121. (PMID: 29235382) Ann Surg Oncol. 2018 Aug;25(8):2159-2164. (PMID: 29423664) Int J Hyperthermia. 2018 Aug;34(5):578-584. (PMID: 29431036) Nat Med. 2018 May;24(4):497-504. (PMID: 29457796) Genes Dev. 2018 Feb 1;32(3-4):309-320. (PMID: 29491137) Mol Cell. 2018 Apr 19;70(2):265-273.e8. (PMID: 29656923) Mol Cell Biol. 1996 Oct;16(10):5518-26. (PMID: 8816464) |
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 |
تدمد: | 2352-3964 |
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DOI: | 10.1016/j.ebiom.2018.12.025 |