Adenoviruses with an αvβ integrin targeting moiety in the fiber shaft or the HI-loop increase tumor specificity without compromising antitumor efficacy in magnetic resonance imaging of colorectal cancer metastases.
BACKGROUND
Colorectal cancer is often a deadly disease and cannot be cured at metastatic stage. Oncolytic adenoviruses have been considered as a new therapeutic option for treatment of refractory disseminated cancers, including colorectal cancer. The safety data has been excellent but tumor transduction and antitumor efficacy especially in systemic administration needs to be improved.


METHODS
Here, the utility of αvβ integrin targeting moiety Arg-Gly-Asp (RGD) in the Lys-Lys-Thr-Lys (KKTK) domain of the fiber shaft or in the HI-loop of adenovirus serotype 5 for increased tumor targeting and antitumor efficacy was evaluated. To this end, novel spleen-to-liver metastatic colorectal cancer mouse model was used and the antitumor efficacy was evaluated with magnetic resonance imaging (MRI).


RESULTS
Both modifications (RGD in the HI-loop or in the fiber shaft) increased gene transfer efficacy in colorectal cancer cell lines and improved tumor-to-normal ratio in systemic administration of the vector.


CONCLUSIONS
Antitumor potency was not compromised with RGD modified viruses suggesting increased safety profile and tumor specificity.
Lavilla-Alonso
Sergio
S
Transplantation Laboratory, Haartman Institute and Finnish Institute of Molecular Medicine, University of Helsinki, Finland.
Bauerschmitz
Gerd
G
Abo-Ramadan
Usama
U
Halavaara
Juha
J
Escutenaire
Sophie
S
Diaconu
Iulia
I
Tatlisumak
Turgut
T
Kanerva
Anna
A
Hemminki
Akseli
A
Pesonen
Sari
S
D000256:Adenoviridae / Q000737:chemistry* / Q000235:genetics* / Q000502:physiology; D000818:Animals; D002213:Capsid / Q000378:metabolism; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000473:pathology / Q000628:therapy*; D003602:Cytotoxicity, Immunologic; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000493:pharmacokinetics; D006801:Humans; D008113:Liver Neoplasms / Q000556:secondary; D008279:Magnetic Resonance Imaging; D051379:Mice; D009362:Neoplasm Metastasis; D009842:Oligopeptides / Q000378:metabolism*; D009928:Organ Specificity; D019030:Receptors, Vitronectin / Q000378:metabolism*; D013160:Splenic Neoplasms / Q000556:secondary; D014018:Tissue Distribution; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
D009842:Oligopeptides; D019030:Receptors, Vitronectin; C094340:integrin alphavbeta1; C047981:arginyl-glycyl-aspartic acid