Oncotarget

Research Papers:

Targeting tumors with a killer-reporter adenovirus for curative fluorescence-guided surgery of soft-tissue sarcoma

Shuya Yano, Shinji Miwa, Hiroyuki Kishimoto, Fuminari Uehara, Hiroshi Tazawa, Makoto Toneri, Yukihiko Hiroshima, Mako Yamamoto, Yasuo Urata, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara and Robert M. Hoffman _

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Oncotarget. 2015; 6:13133-13148. https://doi.org/10.18632/oncotarget.3811

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Abstract

Shuya Yano1,2,3, Shinji Miwa1,2, Hiroyuki Kishimoto3, Fuminari Uehara1,2, Hiroshi Tazawa4, Makoto Toneri1,2, Yukihiko Hiroshima1,2, Mako Yamamoto1,2, Yasuo Urata5, Shunsuke Kagawa3, Michael Bouvet2, Toshiyoshi Fujiwara3 and Robert M. Hoffman1,2

1 AntiCancer, Inc., San Diego, CA, USA

2 Department of Surgery, University of California San Diego, CA, USA

3 Department of Gastroenterological Surgery, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

4 Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan

5 Oncolys BioPharm Inc., Tokyo, Japan

Correspondence to:

Robert M. Hoffman, email:

Keywords: soft tissue sarcoma, nude mice, fluorescence-guided surgery (FGS), adenovirus, OBP-401

Received: January 07, 2015 Accepted: February 10, 2015 Published: April 14, 2015

Abbreviations: GFP- green fluorescent protein; RFP- red fluorescent protein; FGS-fluorescence-guided surgery; BLS-bright-light surgery

Abstract

Fluorescence-guided surgery (FGS) of cancer is an area of intense interest. However, FGS of cancer has not yet been shown to be curative due to residual microscopic disease. Human fibrosarcoma HT1080 expressing red fluorescent protein (RFP) was implanted orthotopically in the quadriceps femoris muscle of nude mice. The tumor-bearing mice were injected with high and low-dose telomerase-dependent, green fluorescent protein (GFP)-containing adenovirus OBP-401, which labeled the tumor with GFP. Fluorescence-guided surgery (FGS) or bright light surgery (BLS) was then performed. OBP-401 could label soft-tissue sarcoma (STS) with GFP in situ, concordant with RFP. OBP-401-based FGS resulted in superior resection of STS in the orthotopic model of soft-tissue sarcoma, compared to BLS. High-dose administration of OBP-401 enabled FGS without residual sarcoma cells or local or metastatic recurrence, due to its dual effect of cancer-cell labeling with GFP and killing. High-dose OBP-401 based-FGS improved disease free survival (p = 0.00049) as well as preserved muscle function compared with BLS. High-dose OBP-401-based FGS could cure STS, a presently incurable disease. Since the parent virus of OBP-401, OBP-301, has been previously proven safe in a Phase I clinical trial, it is expected the OBP-401-FGS technology described in the present report should be translatable to the clinic in the near future.


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