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Oncolytic adenovirus modified with somatostatin motifs for selective infection of neuroendocrine tumor cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
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2011 (English)In: Gene Therapy, ISSN 0969-7128, E-ISSN 1476-5462, Vol. 18, no 11, 1052-1062 p.Article in journal (Refereed) Published
Abstract [en]

We have previously described the oncolytic adenovirus, Ad(CgA-E1A-miR122), herein denoted Ad5(CgA-E1A-miR122) that selectively replicates in and kills neuroendocrine cells, including freshly isolated midgut carcinoid cells from liver metastases. Ad5(CgA-E1A-miR122) is based on human adenovirus serotype 5 (Ad5) and infects target cells by binding to the coxsackie-adenovirus receptor (CAR) and integrins on the cell surface. Some neuroendocrine tumor (NET) and neuroblastoma cells express low levels of CAR and are therefore poorly transduced by Ad5. However, they often express high levels of somatostatin receptors (SSTRs). Therefore, we introduced cyclic peptides, which contain four amino acids (FWKT) and mimic the binding site for SSTRs in the virus fiber knob. We show that FWKT-modified Ad5 binds to SSTR2 on NET cells and transduces midgut carcinoid cells from liver metastases about 3-4 times better than non-modified Ad5 while it transduces normal hepatocytes at about 50% of Ad5. Moreover, FWKT-modified Ad5 overcomes neutralization in an ex vivo human blood loop model to greater extent than Ad5, indicating that fiber knob modification may prolong the systematic circulation time. We conclude that modification of adenovirus with the FWKT motif may be beneficial for NET therapy.

Place, publisher, year, edition, pages
2011. Vol. 18, no 11, 1052-1062 p.
Keyword [en]
oncolytic adenovirus, somatostatin, neuroendocrine tumors, carcinoid, neuroblastoma, proximity ligation
National Category
Cell and Molecular Biology Cancer and Oncology Microbiology in the medical area
Research subject
Oncology; Molecular Medicine
Identifiers
URN: urn:nbn:se:uu:diva-146964DOI: 10.1038/gt.2011.54ISI: 000296889500004PubMedID: 21490682OAI: oai:DiVA.org:uu-146964DiVA: diva2:399465
Available from: 2011-02-22 Created: 2011-02-22 Last updated: 2017-12-11Bibliographically approved
In thesis
1. Oncolytic Adenovirus Therapy of Neuroendocrine Tumors
Open this publication in new window or tab >>Oncolytic Adenovirus Therapy of Neuroendocrine Tumors
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Neuroendocrine tumors (NETs), originally described as carcinoids, represent a rare and heterogeneous group of neoplasms associated with intensive secretion of hormones, bioactive peptides and amines. Most of the patients are diagnosed at a late stage of disease, often with liver metastases. Surgery remains the main treatment to control metastatic disease, but is not curative. Oncolytic virotherapy represents a promising approach to treat cancer and different strategies have been exploited to restrict viral replication to tumor cells. We developed an oncolytic adenovirus based on serotype 5, Ad5[CgA-E1A], where the chromogranin A (CgA) promoter controls expression of the E1A gene and thereby virus replication. We found that Ad5[CgA-E1A], selectively replicates in NET cells and it is able to suppress fast-growing human BON carcinoid tumors in nude mice. The activity of Ad5[CgA-E1A] was not completely blocked in liver cells. We further repressed virus replication in hepatocytes by targeting E1A with miR122, an miRNA specifically expressed in the liver. miRNAs bind to mRNA and induce its cleavage or translational blockage. By insertion of tandem repeats of miR122 target sequences in 3’UTR of E1A gene, we observed reduced E1A protein expression and replication arrest in miR122 expressing liver cells. The oncolytic potency of the miR122-targeted virus was not affected in NET cells. Since some NET and neuroblastoma cells express high levels of somatostatin receptors (SSTRs), we introduced in the virus fiber knob cyclic peptides, which contain four amino acids (FWKT) and mimic the binding site of somatostatin for SSTRs. The FWKT-modified Ad5 transduces midgut carcinoid cells from liver metastases about 3-4 times better than non-modified Ad5. Moreover, FWKT-modified Ad5 overcomes neutralization in an ex vivo human blood loop model to a greater extent than Ad5, indicating that the fiber knob modification may prolong the systemic circulation time. NETs represent a huge therapeutic challenge and novel diagnostic markers are needed for early detection and effective treatment of NETs. We have profiled primary tumors and liver metastases of ileocaceal NETs, using Affymetrix microarrays and advanced bioinformatics. We have identified six novel marker genes and show high similarity between primary lesions and liver metastases transcriptome by hierarchical clustering analysis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2011. 60 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 653
Keyword
adenovirus, virotherapy, oncolytic virus, neuroendocrine tumors, chromogranin A, somatostatin receptors, microRNA, novel biomarkers
National Category
Cell and Molecular Biology Cancer and Oncology Microbiology in the medical area Cell and Molecular Biology
Research subject
Medical Science; Oncology; Medical Virology; Molecular Cellbiology
Identifiers
urn:nbn:se:uu:diva-146966 (URN)978-91-554-8022-6 (ISBN)
Public defence
2011-04-15, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
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Available from: 2011-03-25 Created: 2011-02-22 Last updated: 2011-05-04Bibliographically approved

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Leja, JustynaYu, DiNilsson, BerithGedda, LarsZieba, AgataÅkerström, GöranÖberg, KjellGiandomenico, ValeriaEssand, Magnus

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Leja, JustynaYu, DiNilsson, BerithGedda, LarsZieba, AgataÅkerström, GöranÖberg, KjellGiandomenico, ValeriaEssand, Magnus
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Clinical ImmunologyScience for Life Laboratory, SciLifeLabBiomedical Radiation SciencesEndocrine SurgeryDepartment of Medical Sciences
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