Therapeutic activity of retroviral replicating vector-mediated prodrug activator gene therapy for pancreatic cancer

Kazuho Inoko, Kei Hiraoka, Akihito Inagaki, Mizuna Takahashi, Toshihiro Kushibiki, Koji Hontani, Hironobu Takano, Shoki Sato, Shintaro Takeuchi, Toru Nakamura, Takahiro Tsuchikawa, Toshiaki Shichinohe, Harry E. Gruber, Douglas J. Jolly, Noriyuki Kasahara, Satoshi Hirano

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Toca 511, a retroviral replicating vector (RRV) encoding the yeast cytosine deaminase (yCD) prodrug activator gene, which mediates conversion of the prodrug 5-fluorocytosine (5-FC) to the anticancer drug 5-fluorouracil (5-FU), is currently being evaluated in Phase II/III clinical trials for glioma, and showing highly promising evidence of therapeutic activity. Here we evaluated RRV-mediated prodrug activator gene therapy as a new therapeutic approach for pancreatic ductal adenocarcinoma (PDAC). RRV spread rapidly and conferred significant cytotoxicity with prodrug in a panel of PDAC cells. Efficient intratumoral replication and complete inhibition of tumor growth upon 5-FC administration were observed in both immunodeficient and immunocompetent subcutaneous PDAC models. Biodistribution of RRV was highly restricted in normal tissues, especially in immunocompetent hosts. Tumor growth inhibition by Toca 511 followed by 5-FC was also confirmed in the orthotopic PDAC model. This study provides the first proof-of-concept for application of Toca 511 and Toca FC (extended release 5-FC) to the treatment of human PDAC, and provided support for inclusion of PDAC in a Phase I study evaluating Toca 511 in various systemic malignancies, (NCT02576665), which has recently been initiated.

Original languageEnglish (US)
Pages (from-to)184-195
Number of pages12
JournalCancer gene therapy
Volume25
Issue number7-8
DOIs
StatePublished - Aug 1 2018

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ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Cancer Research

Cite this

Inoko, K., Hiraoka, K., Inagaki, A., Takahashi, M., Kushibiki, T., Hontani, K., Takano, H., Sato, S., Takeuchi, S., Nakamura, T., Tsuchikawa, T., Shichinohe, T., Gruber, H. E., Jolly, D. J., Kasahara, N., & Hirano, S. (2018). Therapeutic activity of retroviral replicating vector-mediated prodrug activator gene therapy for pancreatic cancer. Cancer gene therapy, 25(7-8), 184-195. https://doi.org/10.1038/s41417-018-0020-7