Open Access Research

In vivo gene transfer targeting in pancreatic adenocarcinoma with cell surface antigens

Marie Lafitte12, Benoit Rousseau3, Isabelle Moranvillier12, Miguel Taillepierre12, Evelyne Peuchant12, Véronique Guyonnet-Dupérat24, Aurélie Bedel12, Pierre Dubus2, Hubert de Verneuil12, François Moreau-Gaudry1245* and Sandrine Dabernat12

Author Affiliations

1 INSERM U1035, Bordeaux, France

2 Université Bordeaux Segalen, Bordeaux, France

3 Animalerie A2, Université Victor Segalen, Bordeaux, France

4 Vectorology platform, Université Bordeaux Segalen, Bordeaux, France

5 Université Bordeaux Segalen INSERM U1035, 146, rue Léo Saignat, Bordeaux Cedex, 33076, France

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Molecular Cancer 2012, 11:81  doi:10.1186/1476-4598-11-81

Published: 22 October 2012

Abstract

Background

Pancreatic ductal adenocarcinoma is a deadly malignancy resistant to current therapies. It is critical to test new strategies, including tumor-targeted delivery of therapeutic agents. This study tested the possibility to target the transfer of a suicide gene in tumor cells using an oncotropic lentiviral vector.

Results

Three cell surface markers were evaluated to target the transduction of cells by lentiviruses pseudotyped with a modified glycoprotein from Sindbis virus. Only Mucin-4 and the Claudin-18 proteins were found efficient for targeted lentivirus transductions in vitro. In subcutaneous xenografts of human pancreatic cancer cells models, Claudin-18 failed to achieve efficient gene transfer but Mucin-4 was found very potent. Human pancreatic tumor cells were modified to express a fluorescent protein detectable in live animals by bioimaging, to perform a direct non invasive and costless follow up of the tumor growth. Targeted gene transfer of a bicistronic transgene bearing a luciferase gene and the herpes simplex virus thymidine kinase gene into orthotopic grafts was carried out with Mucin-4 oncotropic lentiviruses. By contrast to the broad tropism VSV-G carrying lentivirus, this oncotropic lentivirus was found to transduce specifically tumor cells, sparing normal pancreatic cells in vivo. Transduced cells disappeared after ganciclovir treatment while the orthotopic tumor growth was slowed down.

Conclusion

This work considered for the first time three aspect of pancreatic adenocarcinoma targeted therapy. First, lentiviral transduction of human pancreatic tumor cells was possible when cells were grafted orthotopically. Second, we used a system targeting the tumor cells with cell surface antigens and sparing the normal cells. Finally, the TK/GCV anticancer system showed promising results in vivo. Importantly, the approach presented here appeared to be a safer, much more specific and an as efficient way to perform gene delivery in pancreatic tumors, in comparison with a broad tropism lentivirus. This study will be useful in future designing of targeted therapies for pancreatic cancer.

Keywords:
Pancreatic adenocarcinoma; Targeted therapy; Surface marker