Oncolytic Adenovirus Therapy of Neuroendocrine Tumors

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Fältnamn	Indikatorer	Metadata
000		05447nam a2200661 4500
001		oai:DiVA.org:uu-146966
003		SwePub
008		110222s2011 \| \|\|\|\|\|\|\|\|\|\|\|000 \|\|eng\|
020		a 9789155480226q print
024	7	a https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-1469662 URI
040		a (SwePub)uu
041		a engb eng
042		9 SwePub
072	7	a vet2 swepub-contenttype
072	7	a dok2 swepub-publicationtype
100	1	a Leja, Justyna,d 1982-u Uppsala universitet,Institutionen för immunologi, genetik och patologi4 aut0 (Swepub:uu)jusle909
245	1 0	a Oncolytic Adenovirus Therapy of Neuroendocrine Tumors
264	1	a Uppsala :b Acta Universitatis Upsaliensis,c 2011
300		a 60 s.
338		a electronic2 rdacarrier
490	0	a Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine,x 1651-6206 ;v 653
520		a 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.
650	7	a MEDICIN OCH HÄLSOVETENSKAPx Medicinska och farmaceutiska grundvetenskaperx Cell- och molekylärbiologi0 (SwePub)301082 hsv//swe
650	7	a MEDICAL AND HEALTH SCIENCESx Basic Medicinex Cell and Molecular Biology0 (SwePub)301082 hsv//eng
650	7	a MEDICIN OCH HÄLSOVETENSKAPx Klinisk medicinx Cancer och onkologi0 (SwePub)302032 hsv//swe
650	7	a MEDICAL AND HEALTH SCIENCESx Clinical Medicinex Cancer and Oncology0 (SwePub)302032 hsv//eng
650	7	a MEDICIN OCH HÄLSOVETENSKAPx Medicinska och farmaceutiska grundvetenskaperx Mikrobiologi inom det medicinska området0 (SwePub)301092 hsv//swe
650	7	a MEDICAL AND HEALTH SCIENCESx Basic Medicinex Microbiology in the medical area0 (SwePub)301092 hsv//eng
653		a adenovirus
653		a virotherapy
653		a oncolytic virus
653		a neuroendocrine tumors
653		a chromogranin A
653		a somatostatin receptors
653		a microRNA
653		a novel biomarkers
653		a Molecular biology
653		a Molekylärbiologi
653		a Oncology
653		a Onkologi
653		a Virology
653		a Virologi
653		a Tumour biology
653		a Tumörbiologi
653		a Medical Science
653		a Medicinsk vetenskap
653		a Oncology
653		a Onkologi
653		a Medical Virology
653		a Medicinsk virologi
653		a Molekylär cellbiologi
653		a Molecular Cellbiology
700	1	a Essand, Magnus,c Prof, PhDu Uppsala universitet,Institutionen för immunologi, genetik och patologi4 ths
700	1	a Giandomenico, Valeria,c Assoc Prof, PhDu Uppsala universitet,Institutionen för medicinska vetenskaper4 ths
700	1	a Hemminki, Akseli,c Prof, PhD, MDu Cancer Gene Therapy Group, Finnish Institute for Molecular Medicine, University of Helsinki4 opn
710	2	a Uppsala universitetb Institutionen för immunologi, genetik och patologi4 org
856	4	u https://uu.diva-portal.org/smash/get/diva2:399527/FULLTEXT01.pdfx primaryx Raw objecty fulltext
856	4 8	u https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-146966

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