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Oncolytic Adenovirus Therapy of Neuroendocrine Tumors

Leja, Justyna, 1982- (författare)
Uppsala universitet, Institutionen för immunologi, genetik och patologi
Essand, Magnus, Prof, PhD (preses)
Uppsala universitet, Institutionen för immunologi, genetik och patologi
Giandomenico, Valeria, Assoc Prof, PhD (preses)
Uppsala universitet, Institutionen för medicinska vetenskaper
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Hemminki, Akseli, Prof, PhD, MD (opponent)
Cancer Gene Therapy Group, Finnish Institute for Molecular Medicine, University of Helsinki
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ISBN 978-91-554-8022-6
Uppsala : Acta Universitatis Upsaliensis, 2011
Engelska 60s.
Serie: Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, 1651-6206
  • Doktorsavhandling (övrigt vetenskapligt)
Abstract Ämnesord
Stäng  
  • <p>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 <em>ex vivo</em> 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.</p>

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska grundvetenskaper -- Mikrobiologi inom det medicinska området (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Microbiology in the medical area (hsv//eng)

Nyckelord

adenovirus
virotherapy
oncolytic virus
neuroendocrine tumors
chromogranin A
somatostatin receptors
microRNA
novel biomarkers
MEDICINE Dermatology and venerology,clinical genetics, internal medicine Clinical genetics Molecular biology
MEDICIN Dermatologi och venerologi, klinisk genetik, invärtesmedicin Klinisk genetik Molekylärbiologi
MEDICINE Surgery Oncology
MEDICIN Kirurgi Onkologi
MEDICINE Microbiology, immunology, infectious diseases Microbiology Virology
MEDICIN Mikrobiologi, immunologi, infektionssjukdomar Mikrobiologi Virologi
MEDICINE Morphology, cell biology, pathology Morphology Tumour biology
MEDICIN Morfologi, cellbiologi, patologi Morfologi Tumörbiologi
Medical Science
Medicinsk vetenskap
Oncology
Onkologi
Medical Virology
Medicinsk virologi
Molekylär cellbiologi
Molecular Cellbiology

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