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

Cancer Gene Therapy volume 25, pages 184–195 (2018)Cite this article

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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.

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Acknowledgements

The authors thank Drs. Woong-Ryeon Park (Department of Gastroenterological Surgery II, Hokkaido University), Sara Collins and Katrin Hacke (Department of Cell Biology, University of Miami) for technical and logistical assistance. We also thank Drs. Asha Das and Nicholas A. Boyle (Tocagen) for regulatory support.

Funding: This research was supported by the JSPS KAKENHI grant number 26461936.

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Authors and Affiliations

  1. Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Hokkaido, Japan

    Kazuho Inoko, Kei Hiraoka, Mizuna Takahashi, Toshihiro Kushibiki, Koji Hontani, Hironobu Takano, Shoki Sato, Shintaro Takeuchi, Toru Nakamura, Takahiro Tsuchikawa, Toshiaki Shichinohe & Satoshi Hirano

  2. Department of Cell Biology, University of Miami, Miami, FL, USA

    Akihito Inagaki & Noriyuki Kasahara

  3. Tocagen Inc., San Diego, CA, USA

    Harry E Gruber & Douglas J Jolly

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Correspondence to Kei Hiraoka.

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D.J.J., and H.E.G. are employees of Tocagen. N.K. is a consultant. All three have an ownership interest in Tocagen. All other authors declare that they have no conflict of interest.

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Inoko, K., Hiraoka, K., Inagaki, A. et al. Therapeutic activity of retroviral replicating vector-mediated prodrug activator gene therapy for pancreatic cancer. Cancer Gene Ther 25, 184–195 (2018). https://doi.org/10.1038/s41417-018-0020-7

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