title: Oncolytic adenovirus modified with somatostatin motifs for selective infection of neuroendocrine tumor cells.
abstract: 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. 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 systemic circulation time. We conclude that modification of adenovirus with the FWKT motif may be beneficial for NET therapy.
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Leja
authors.forename: D
authors.initials: D
authors.lastname: Yu
authors.forename: B
authors.initials: B
authors.lastname: Nilsson
authors.forename: L
authors.initials: L
authors.lastname: Gedda
authors.forename: A
authors.initials: A
authors.lastname: Zieba
authors.forename: T
authors.initials: T
authors.lastname: Hakkarainen
authors.forename: G
authors.initials: G
authors.lastname: Åkerström
authors.forename: K
authors.initials: K
authors.lastname: Öberg
authors.forename: V
authors.initials: V
authors.lastname: Giandomenico
authors.forename: M
authors.initials: M
authors.lastname: Essand
mesh_terms: D000260:Adenoviruses, Human / Q000235:genetics*; D001665:Binding Sites; D045744:Cell Line, Tumor; D006801:Humans; D007414:Intestinal Neoplasms / Q000628:therapy; D018358:Neuroendocrine Tumors / Q000235:genetics / Q000628:therapy*; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics*; D017481:Receptors, Somatostatin / Q000378:metabolism*; D014161:Transduction, Genetic
chemical_list: D017481:Receptors, Somatostatin