A fiber modified adenovirus vector that targets to the EphrinA2 receptor reveals enhanced gene transfer to ex vivo pancreatic cancer.
Pancreatic cancer is an aggressive malignancy with a dismal prognosis. To improve treatment options new treatments, such as adenoviral (Ad) gene therapy are necessary. However, low expression of the coxsackie and adenovirus receptor (CAR) in pancreatic cancer cells (PC) limits the therapeutic efficacy of these vectors. The aim of this study was to improve transduction of PC by recombinant adenoviruses by inserting peptides into the HI loop that binds to receptors highly expressed on pancreatic cancer and were shown to target these carcinomas in vivo. We report the successful incorporation into the HI loop of peptide Tyr-Ser-Ala (YSA), a peptide ligand targeting the EphrinA2 (EphA2) receptor, and K237, a peptide targeting to the vascular endothelial growth factor receptor-II (VEGFRII). Subsequently, we showed that both peptides enhanced the transduction of a number of human PC lines that abundantly express the targeted receptor. Additional competition studies confirmed that the YSA peptide redirects Ad-YSA from CAR and specifically targets the EphA2 receptor. Due to this transduction efficiency of Ad-YSA is increased not only in human pancreatic cancer cell lines but more importantly also in pancreatic cancer resection specimens. Since the YSA peptide has been shown to specifically target pancreatic cancer in patients, it may be expected that Ad-YSA will also display increased tropism for this tumour.
Van Geer
Michael A
MA
AMC Liver Center, Academic Medical Center University of Amsterdam, Amsterdam, The Netherlands.
Brevoord
Daniel
D
Kuhlmann
Koert F D
KF
Bakker
Conny T
CT
Mizuguchi
Hiroyuki
H
Wesseling
John G
JG
Ten Kate
Fibo J
FJ
Gouma
Dirk J
DJ
Oude Elferink
Ronald P J
RP
Bosma
Piter J
PJ
D000256:Adenoviridae / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D045744:Cell Line, Tumor; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D036104:Receptor, EphA2 / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D010455:Peptides; D011994:Recombinant Proteins; D049452:Green Fluorescent Proteins; D036104:Receptor, EphA2; D040301:Vascular Endothelial Growth Factor Receptor-2