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Oncolytic adenovirus modified with somatostatin motifs for selective infection of neuroendocrine tumor cells
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
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2011 (Engelska)Ingår i: Gene Therapy, ISSN 0969-7128, E-ISSN 1476-5462, Vol. 18, nr 11, s. 1052-1062Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
2011. Vol. 18, nr 11, s. 1052-1062
Nyckelord [en]
oncolytic adenovirus, somatostatin, neuroendocrine tumors, carcinoid, neuroblastoma, proximity ligation
Nationell ämneskategori
Cell- och molekylärbiologi Cancer och onkologi Mikrobiologi inom det medicinska området
Forskningsämne
Onkologi; Molekylär medicin
Identifikatorer
URN: urn:nbn:se:uu:diva-146964DOI: 10.1038/gt.2011.54ISI: 000296889500004PubMedID: 21490682OAI: oai:DiVA.org:uu-146964DiVA, id: diva2:399465
Tillgänglig från: 2011-02-22 Skapad: 2011-02-22 Senast uppdaterad: 2018-12-04
Ingår i avhandling
1. Oncolytic Adenovirus Therapy of Neuroendocrine Tumors
Öppna denna publikation i ny flik eller fönster >>Oncolytic Adenovirus Therapy of Neuroendocrine Tumors
2011 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2011. s. 60
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 653
Nyckelord
adenovirus, virotherapy, oncolytic virus, neuroendocrine tumors, chromogranin A, somatostatin receptors, microRNA, novel biomarkers
Nationell ämneskategori
Cell- och molekylärbiologi Cancer och onkologi Mikrobiologi inom det medicinska området Cell- och molekylärbiologi
Forskningsämne
Medicinsk vetenskap; Onkologi; Medicinsk virologi; Molekylär cellbiologi
Identifikatorer
urn:nbn:se:uu:diva-146966 (URN)978-91-554-8022-6 (ISBN)
Disputation
2011-04-15, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2011-03-25 Skapad: 2011-02-22 Senast uppdaterad: 2018-01-12Bibliografiskt granskad

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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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Klinisk immunologiScience for Life Laboratory, SciLifeLabEnheten för biomedicinsk strålningsvetenskapEndokrinkirurgiInstitutionen för medicinska vetenskaper
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