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2. Tumor-targeting adenovirus OBP-401 inhibits primary and metastatic tumor growth of triple-negative breast cancer in orthotopic nude-mouse models

Author

Yano, Shuya, Takehara, Kiyoto, Kishimoto, Hiroyuki, Tazawa, Hiroshi, Urata, Yasuo, Kagawa, Shunsuke, Bouvet, Michael, Fujiwara, Toshiyoshi, and Hoffman, Robert M

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Breast Cancer, 2.1 Biological and endogenous factors, Aetiology, Adenoviridae, Animals, Cell Line, Tumor, Disease Models, Animal, Female, Humans, Mammary Glands, Animal, Mice, Mice, Nude, Neoplasm Metastasis, Oncolytic Virotherapy, Organ Specificity, Telomerase, Triple Negative Breast Neoplasms, Xenograft Model Antitumor Assays, GFP, green fluorescent protein, RFP, red fluorescent protein, OBP-401, TNBC, adenovirus, high-metastatic, nude mouse, triple-negative breast cancer, variants, Oncology and carcinogenesis
Abstract

Our laboratory previously developed a highly-invasive, triple-negative breast cancer (TNBC) variant using serial orthotopic implantation of the human MDA-MB-231 cell line in nude mice. The isolated variant was highly-invasive in the mammary gland and lymphatic channels and metastasized to lymph nodes in 10 of 12 mice compared to 2 of 12 of the parental cell line. In the present study, the tumor-selective telomerase dependent OBP-401 adenovirus was injected intratumorally (i.t.) (1 × 108 PFU) when the high-metastatic MDA-MB-231 primary tumor expressing red fluorescent protein (MDA-MB-231-RFP) reached approximately 500 mm3 (diameter; 10 mm). The mock-infected orthotopic primary tumor grew rapidly. After i.t. OBP-401 injection, the growth of the orthotopic tumors was arrested. Six weeks after implantation, the fluorescent area and fluorescence intensity showed no increase from the beginning of treatment. OBP-401 was then injected into high-metastatic MDA-MB-231-RFP primary orthotopic tumor growing in mice which already had developed metastasis within lymphatic ducts. All 7 of 7 control mice subsequently developed lymph node metastasis. In contrast, none of 7 mice which received OBP-401 had lymph node metastasis. Seven of 7 control mice also had gross lung metastasis. In contrast, none of the 7 mice which received OBP-401 had gross lung metastasis. Confocal laser microscopy imaging demonstrated that all control mice had diffuse lung metastases. In contrast, all 7 mice which received OBP-401 only had a few metastatic cells in the lung. OBP-401 treatment significantly extended survival of the treated mice.

Published
2016

3. Fluorescence-guided surgery of a highly-metastatic variant of human triple-negative breast cancer targeted with a cancer-specific GFP adenovirus prevents recurrence

Author

Yano, Shuya, Takehara, Kiyoto, Miwa, Shinji, Kishimoto, Hiroyuki, Tazawa, Hiroshi, Urata, Yasuo, Kagawa, Shunsuke, Bouvet, Michael, Fujiwara, Toshiyoshi, and Hoffman, Robert M

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Breast Cancer, Adenoviridae, Animals, Cell Line, Tumor, Cells, Cultured, Disease Models, Animal, Female, Gene Expression, Genetic Vectors, Green Fluorescent Proteins, Humans, Mice, Microscopy, Fluorescence, Optical Imaging, Recurrence, Surgery, Computer-Assisted, Transduction, Genetic, Triple Negative Breast Neoplasms, Xenograft Model Antitumor Assays, breast cancer, triple negative, nude mice, orthotopic, fluorescence-guided surgery, telomerase dependent, adenovirus, GFP/RFP, survival, Oncology and carcinogenesis
Abstract

We have previously developed a genetically-engineered GFP-expressing telomerase-dependent adenovirus, OBP-401, which can selectively illuminate cancer cells. In the present report, we demonstrate that targeting a triple-negative high-invasive human breast cancer, orthotopically-growing in nude mice, with OBP-401 enables curative fluorescence-guided surgery (FGS). OBP-401 enabled complete resection and prevented local recurrence and greatly inhibited lymph-node metastasis due to the ability of the virus to selectively label and subsequently kill cancer cells. In contrast, residual breast cancer cells become more aggressive after bright (white)-light surgery (BLS). OBP-401-based FGS also improved the overall survival compared with conventional BLS. Thus, metastasis from a highly-aggressive triple-negative breast cancer can be prevented by FGS in a clinically-relevant mouse model.

Published
2016

4. Tumor-specific cell-cycle decoy by Salmonella typhimurium A1-R combined with tumor-selective cell-cycle trap by methioninase overcome tumor intrinsic chemoresistance as visualized by FUCCI imaging

Author

Yano, Shuya, Takehara, Kiyoto, Zhao, Ming, Tan, Yuying, Han, Qinghong, Li, Shukuan, Bouvet, Michael, Fujiwara, Toshiyoshi, and Hoffman, Robert M

Subjects
Cancer, Digestive Diseases, Animals, Antineoplastic Agents, Carbon-Sulfur Lyases, Cell Cycle, Cisplatin, Drug Resistance, Neoplasm, Fluorescence, G2 Phase, HeLa Cells, Humans, Imaging, Three-Dimensional, Mice, Nude, Neoplasms, Paclitaxel, Recombinant Proteins, S Phase, Salmonella typhimurium, Ubiquitination, cancer, cell-cycle, cisplatinum, decoy, FUCCI, methioninase, nude mice, paclitaxel, Salmonella typhimurium A1-R, stomach cancer, trap, Hela Cells, Biochemistry and Cell Biology, Developmental Biology
Abstract

We previously reported real-time monitoring of cell cycle dynamics of cancer cells throughout a live tumor intravitally using a fluorescence ubiquitination cell cycle indicator (FUCCI). Approximately 90% of cancer cells in the center and 80% of total cells of an established tumor are in G0/G1 phase. Longitudinal real-time FUCCI imaging demonstrated that cytotoxic agents killed only proliferating cancer cells at the surface and, in contrast, and had little effect on the quiescent cancer cells. Resistant quiescent cancer cells restarted cycling after the cessation of chemotherapy. Thus cytotoxic chemotherapy which targets cells in S/G2/M, is mostly ineffective on solid tumors, but causes toxic side effects on tissues with high fractions of cycling cells, such as hair follicles, bone marrow and the intestinal lining. We have termed this phenomenon tumor intrinsic chemoresistance (TIC). We previously demonstrated that tumor-targeting Salmonella typhimurium A1-R (S. typhimurium A1-R) decoyed quiescent cancer cells in tumors to cycle from G0/G1 to S/G2/M demonstrated by FUCCI imaging. We have also previously shown that when cancer cells were treated with recombinant methioninase (rMETase), the cancer cells were selectively trapped in S/G2, shown by cell sorting as well as by FUCCI. In the present study, we show that sequential treatment of FUCCI-expressing stomach cancer MKN45 in vivo with S. typhimurium A1-R to decoy quiescent cancer cells to cycle, with subsequent rMETase to selectively trap the decoyed cancer cells in S/G2 phase, followed by cisplatinum (CDDP) or paclitaxel (PTX) chemotherapy to kill the decoyed and trapped cancer cells completely prevented or regressed tumor growth. These results demonstrate the effectiveness of the praradigm of "decoy, trap and shoot" chemotherapy.

Published
2016

5. Adenoviral targeting of malignant melanoma for fluorescence-guided surgery prevents recurrence in orthotopic nude-mouse models

Author

Yano, Shuya, Takehara, Kiyoto, Kishimoto, Hiroyuki, Urata, Yasuo, Kagawa, Shunsuke, Bouvet, Michael, Fujiwara, Toshiyoshi, and Hoffman, Robert M

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Rare Diseases, Adenoviridae, Animals, Cell Line, Tumor, Disease Models, Animal, Fluorescence, Humans, Melanoma, Experimental, Mice, Mice, Nude, Neoplasm Recurrence, Local, Optical Imaging, melanoma, nude mice, fluorescence-guided surgery, adenovirus, OBP-401, Oncology and carcinogenesis
Abstract

Malignant melanoma requires precise resection in order to avoid metastatic recurrence. We report here that the telomerase-dependent, green fluorescent protein (GFP)-containing adenovirus OBP-401 could label malignant melanoma with GFP in situ in orthotopic mouse models. OBP-401-based fluorescence-guided surgery (FGS) resulted in the complete resection of malignant melanoma in the orthotopic models, where conventional bright-light surgery (BLS) could not. High-dose administration of OBP-401 enabled FGS without residual cancer cells or recurrence, due to its dual effect of cancer-cell labeling with GFP and killing.

Published
2016

6. Improved Resection and Outcome of Colon-Cancer Liver Metastasis with Fluorescence-Guided Surgery Using In Situ GFP Labeling with a Telomerase-Dependent Adenovirus in an Orthotopic Mouse Model.

Author

Yano, Shuya, Takehara, Kiyoto, Miwa, Shinji, Kishimoto, Hiroyuki, Hiroshima, Yukihiko, Murakami, Takashi, Urata, Yasuo, Kagawa, Shunsuke, Bouvet, Michael, Fujiwara, Toshiyoshi, and Hoffman, Robert M

Subjects
Cell Line, Tumor, Animals, Humans, Mice, Nude, Adenoviridae, Colonic Neoplasms, Liver Neoplasms, Neoplasm Metastasis, Telomerase, Green Fluorescent Proteins, Cell Line, Tumor, Mice, Nude, General Science & Technology
Abstract

Fluorescence-guided surgery (FGS) of cancer is an area of intense development. In the present report, we demonstrate that the telomerase-dependent green fluorescent protein (GFP)-containing adenovirus OBP-401 could label colon-cancer liver metastasis in situ in an orthotopic mouse model enabling successful FGS. OBP-401-GFP-labeled liver metastasis resulted in complete resection with FGS, in contrast, conventional bright-light surgery (BLS) did not result in complete resection of the metastasis. OBP-401-FGS reduced the recurrence rate and prolonged over-all survival compared with BLS. In conclusion, adenovirus OBP-401 is a powerful tool to label liver metastasis in situ with GFP which enables its complete resection, not possible with conventional BLS.

Published
2016

10. Supplementary Figure S4: Evaluation of the treatment effects on luciferase activity in peritoneal dissemination xenografted mouse model bearing SKOV-3/Luc cells from Trastuzumab-Based Photoimmunotherapy Integrated with Viral HER2 Transduction Inhibits Peritoneally Disseminated HER2-Negative Cancer

Author

Ishida, Michihiro, primary, Kagawa, Shunsuke, primary, Shimoyama, Kyoko, primary, Takehara, Kiyoto, primary, Noma, Kazuhiro, primary, Tanabe, Shunsuke, primary, Shirakawa, Yasuhiro, primary, Tazawa, Hiroshi, primary, Kobayashi, Hisataka, primary, and Fujiwara, Toshiyoshi, primary

Published
2023
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11. Supplementary Figure S1: The sensitivity to trastuzumab in gastric cancer cell lines from Trastuzumab-Based Photoimmunotherapy Integrated with Viral HER2 Transduction Inhibits Peritoneally Disseminated HER2-Negative Cancer

Author

Ishida, Michihiro, primary, Kagawa, Shunsuke, primary, Shimoyama, Kyoko, primary, Takehara, Kiyoto, primary, Noma, Kazuhiro, primary, Tanabe, Shunsuke, primary, Shirakawa, Yasuhiro, primary, Tazawa, Hiroshi, primary, Kobayashi, Hisataka, primary, and Fujiwara, Toshiyoshi, primary

Published
2023
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12. Supplementary Figure S2: Transduction efficiency by Ad/HER2-ECD in organs and peritoneally disseminated tumor from Trastuzumab-Based Photoimmunotherapy Integrated with Viral HER2 Transduction Inhibits Peritoneally Disseminated HER2-Negative Cancer

Author

Ishida, Michihiro, primary, Kagawa, Shunsuke, primary, Shimoyama, Kyoko, primary, Takehara, Kiyoto, primary, Noma, Kazuhiro, primary, Tanabe, Shunsuke, primary, Shirakawa, Yasuhiro, primary, Tazawa, Hiroshi, primary, Kobayashi, Hisataka, primary, and Fujiwara, Toshiyoshi, primary

Published
2023
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14. Supplementary Figures S1-S2 from Targeted Photodynamic Virotherapy Armed with a Genetically Encoded Photosensitizer

Author

Takehara, Kiyoto, primary, Tazawa, Hiroshi, primary, Okada, Naohiro, primary, Hashimoto, Yuuri, primary, Kikuchi, Satoru, primary, Kuroda, Shinji, primary, Kishimoto, Hiroyuki, primary, Shirakawa, Yasuhiro, primary, Narii, Nobuhiro, primary, Mizuguchi, Hiroyuki, primary, Urata, Yasuo, primary, Kagawa, Shunsuke, primary, and Fujiwara, Toshiyoshi, primary

Published
2023
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15. Supplementary Movie from Targeted Photodynamic Virotherapy Armed with a Genetically Encoded Photosensitizer

Author

Takehara, Kiyoto, primary, Tazawa, Hiroshi, primary, Okada, Naohiro, primary, Hashimoto, Yuuri, primary, Kikuchi, Satoru, primary, Kuroda, Shinji, primary, Kishimoto, Hiroyuki, primary, Shirakawa, Yasuhiro, primary, Narii, Nobuhiro, primary, Mizuguchi, Hiroyuki, primary, Urata, Yasuo, primary, Kagawa, Shunsuke, primary, and Fujiwara, Toshiyoshi, primary

Published
2023
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16. Data from Targeted Photodynamic Virotherapy Armed with a Genetically Encoded Photosensitizer

Author

Takehara, Kiyoto, primary, Tazawa, Hiroshi, primary, Okada, Naohiro, primary, Hashimoto, Yuuri, primary, Kikuchi, Satoru, primary, Kuroda, Shinji, primary, Kishimoto, Hiroyuki, primary, Shirakawa, Yasuhiro, primary, Narii, Nobuhiro, primary, Mizuguchi, Hiroyuki, primary, Urata, Yasuo, primary, Kagawa, Shunsuke, primary, and Fujiwara, Toshiyoshi, primary

Published
2023
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17. Supplementary Figure S3: The characteristics of SKOV-3/Luc cells from Trastuzumab-Based Photoimmunotherapy Integrated with Viral HER2 Transduction Inhibits Peritoneally Disseminated HER2-Negative Cancer

Author

Ishida, Michihiro, primary, Kagawa, Shunsuke, primary, Shimoyama, Kyoko, primary, Takehara, Kiyoto, primary, Noma, Kazuhiro, primary, Tanabe, Shunsuke, primary, Shirakawa, Yasuhiro, primary, Tazawa, Hiroshi, primary, Kobayashi, Hisataka, primary, and Fujiwara, Toshiyoshi, primary

Published
2023
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18. Morphological changes induced immediately after Tra-IR700-mediated PIT from Trastuzumab-Based Photoimmunotherapy Integrated with Viral HER2 Transduction Inhibits Peritoneally Disseminated HER2-Negative Cancer

Author

Ishida, Michihiro, primary, Kagawa, Shunsuke, primary, Shimoyama, Kyoko, primary, Takehara, Kiyoto, primary, Noma, Kazuhiro, primary, Tanabe, Shunsuke, primary, Shirakawa, Yasuhiro, primary, Tazawa, Hiroshi, primary, Kobayashi, Hisataka, primary, and Fujiwara, Toshiyoshi, primary

Published
2023
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35. Targeted Photodynamic Virotherapy Armed with a Genetically Encoded Photosensitizer

Author

Takehara, Kiyoto, primary, Tazawa, Hiroshi, additional, Okada, Naohiro, additional, Hashimoto, Yuuri, additional, Kikuchi, Satoru, additional, Kuroda, Shinji, additional, Kishimoto, Hiroyuki, additional, Shirakawa, Yasuhiro, additional, Narii, Nobuhiro, additional, Mizuguchi, Hiroyuki, additional, Urata, Yasuo, additional, Kagawa, Shunsuke, additional, and Fujiwara, Toshiyoshi, additional

Published
2016
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37. Abstract CT123: Phase I/II trial of endoscopic intratumoral administration of OBP-301, a novel telomerase-specific oncolytic virus, with radiation in elderly esophageal cancer patients

Author

Tanabe, Shunsuke, primary, Tazawa, Hiroshi, additional, Kagawa, Shunsuke, additional, Noma, Kazuhiro, additional, Takehara, Kiyoto, additional, Koujima, Takeshi, additional, Kashima, Hajime, additional, Kato, Takuya, additional, Kuroda, Shinji, additional, Kikuchi, Satoru, additional, Shirakawa, Yasuhiro, additional, and Fujiwara, Toshiyoshi, additional

Published
2015
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38. Abstract 2615: Novel combination therapy of adenoviral gene transfer of HER2-extracellular domain and trastuzumab-based photoimmunotherapy for HER2 negative cancer cells

Author

Ishida, Michihiro, primary, Kagawa, Shunsuke, additional, Shimoyama, Kyoko, additional, Takehara, Kiyoto, additional, Noma, Kazuhiro, additional, Tanabe, Shunsuke, additional, Tazawa, Hiroshi, additional, Matsuoka, Junji, additional, Kobayashi, Hisataka, additional, and Fujiwara, Toshiyoshi, additional

Published
2014
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42. Mo2018 Cytokeratin 19 Staining Is a Novel, Predictive Biomarker for Extra-Hepatic Metastasis in Hepatocellular Carcinoma

Author

Yokomichi, Naosuke, primary, Nagasaka, Takeshi, additional, Nishida, Naoshi, additional, Umeda, Yuzo, additional, Mori, Yoshiko, additional, Morikawa, Tatsuya, additional, Kubota, Nobuhito, additional, Yoshida, Kazuhiro, additional, Takehara, Yuko, additional, Takehara, Kiyoto, additional, Shigeyasu, Kunitoshi, additional, Nyuya, Akihiro, additional, Shiwaku, Rikiya, additional, Suno, Manabu, additional, Fujiwara, Toshiyoshi, additional, and Goel, Ajay, additional

Published
2013
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43. 471 MGMT Methylation As a Novel Biomarker for the Identification of Stage III Colorectal Cancers At High-Risk of Disease Recurrence Following Curative Surgery

Author

Mori, Yoshiko, primary, Nagasaka, Takeshi, additional, Tazawa, Hiroshi, additional, Umeda, Yuzo, additional, Morikawa, Tatsuya, additional, Kubota, Nobuhito, additional, Yoshida, Kazuhiro, additional, Takehara, Yuko, additional, Yokomichi, Naosuke, additional, Takehara, Kiyoto, additional, Shigeyasu, Kunitoshi, additional, Nyuya, Akihiro, additional, Shiwaku, Rikiya, additional, Suno, Manabu, additional, Nishida, Naoshi, additional, Fujiwara, Toshiyoshi, additional, and Goel, Ajay, additional

Published
2013
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44. 540 Accumulation of Epigenetic Alteration Could Predict Malignant Formation in Intraductal Papillary Mucinous Neoplasm (IPMN)

Author

Yoshida, Kazuhiro, primary, Nagasaka, Takeshi, additional, Umeda, Yuzo, additional, Yokomichi, Naosuke, additional, Mori, Yoshiko, additional, Kubota, Nobuhito, additional, Morikawa, Tatsuya, additional, Takehara, Yuko, additional, Takehara, Kiyoto, additional, Shigeyasu, Kunitoshi, additional, Nyuya, Akihiro, additional, Shiwaku, Rikiya, additional, Suno, Manabu, additional, Nishida, Naoshi, additional, Fujiwara, Toshiyoshi, additional, and Goel, Ajay, additional

Published
2013
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45. Su1995 Genetic and Epigenetic Alterations in the Netrin-1 Receptors, UNC5c and DCC, Constitutes a Previously Unrecognized Pathway in Gastric Cancer Progression

Author

Kubota, Nobuhito, primary, Nagasaka, Takeshi, additional, Toda, Keisuke, additional, Mori, Yoshiko, additional, Morikawa, Tatsuya, additional, Umeda, Yuzo, additional, Yokomichi, Naosuke, additional, Yoshida, Kazuhiro, additional, Takehara, Yuko, additional, Takehara, Kiyoto, additional, Nyuya, Akihiro, additional, Shiwaku, Rikiya, additional, Shigeyasu, Kunitoshi, additional, Suno, Manabu, additional, Nishida, Naoshi, additional, Fujiwara, Toshiyoshi, additional, and Goel, Ajay, additional

Published
2013
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46. Mo1186 Fecal DNA Methylation Assay for the Identification of a Multiple Gastrointestinal Cancers Including Pancreatic Caner

Author

Morikawa, Tatsuya, primary, Nagasaka, Takeshi, additional, Yoshida, Kazuhiro, additional, Mori, Yoshiko, additional, Kubota, Nobuhito, additional, Takehara, Yuko, additional, Yokomichi, Naosuke, additional, Nishida, Naoshi, additional, Takehara, Kiyoto, additional, Shigeyasu, Kunitoshi, additional, Nyuya, Akihiro, additional, Shiwaku, Rikiya, additional, Suno, Manabu, additional, Fujiwara, Toshiyoshi, additional, and Goel, Ajay, additional

Published
2013
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48. A case of metastatic cecal cancer with mutation in the BRAF oncogene and poor survival

Author

Inada, Ryo, primary, Nagasaka, Takeshi, additional, Takehara, Kiyoto, additional, Sugihara, Masahiro, additional, Mori, Yoshiko, additional, Umeda, Yuzo, additional, Kubota, Nobuhito, additional, Morikawa, Tatsuya, additional, Kondo, Yoshitaka, additional, Uno, Futoshi, additional, Sadamori, Yu, additional, Yagi, Takahito, additional, and Fujiwara, Toshiyoshi, additional

Published
2013
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49. Efficacy of a Cell-Cycle Decoying Killer Adenovirus on 3-D Gelfoam®-Histoculture and Tumor-Sphere Models of Chemo-Resistant Stomach Carcinomatosis Visualized by FUCCI Imaging.

Author

Yano, Shuya, Takehara, Kiyoto, Tazawa, Hiroshi, Kishimoto, Hiroyuki, Urata, Yasuo, Kagawa, Shunsuke, Fujiwara, Toshiyoshi, and Hoffman, Robert M.

Subjects
*ADENOVIRUSES, *VIRAL cell cycle, *VIRUS cultures & culture media, *CANCER diagnosis, *STOMACH cancer, *CARCINOMA, *DRUG resistance in cancer cells
Abstract

Stomach cancer carcinomatosis peritonitis (SCCP) is a recalcitrant disease. The goal of the present study was to establish an in vitro-in vivo-like imageable model of SCCP to develop cell-cycle-based therapeutics of SCCP. We established 3-D Gelfoam® histoculture and tumor-sphere models of SCCP. FUCCI-expressing MKN-45 stomach cancer cells were transferred to express the fluorescence ubiquinized cell-cycle indicator (FUCCI). FUCCI-expressing MKN-45 cells formed spheres on agarose or on Gelfoam® grew into tumor-like structures with G0/G1 cancer cells in the center and S/G2 cancer cells located in the surface as indicated by FUCCI imaging when the cells fluoresced red or green, respectively. We treated FUCCI-expressing cancer cells forming SCCP tumors in Gelfoam® histoculture with OBP-301, cisplatinum (CDDP), or paclitaxel. CDDP or paclitaxel killed only cycling cancer cells and were ineffective against G1/G2 MKN-45 cells in tumors growing on Gelfoam®. In contrast, the telomerase-dependent adenovirus OBP-301 decoyed the MKN-45 cells in tumors on Gelfoam® to cycle from G0/G1 phase to S/G2 phase and reduced their viability. CDDP- or paclitaxel-treated MKN-45 tumors remained quiescent and did not change in size. In contrast, OB-301 reduced the size of the MKN-45 tumors on Gelfoam®. We examined the cell cycle-related proteins using Western blotting. CDDP increased the expression of p53 and p21 indicating cell cycle arrest. In contrast, OBP-301 decreased the expression of p53 and p21 Furthermore, OBP-301 increased the expression of E2F and pAkt as further indication of cell cycle decoy. This 3-D Gelfoam® histoculture and FUCCI imaging are powerful tools to discover effective therapy of SCCP such as OBP-301. [ABSTRACT FROM AUTHOR]

Published
2016
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