A novel cancer therapeutics with gene medicine and molecular targeted agents directing the p53 pathways in esophageal carcinoma

• Project/Area Number: 26462000
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Chiba Cancer Center (Research Institute)
• Principal Investigator: Tagawa Masatoshi 千葉県がんセンター(研究所), がん治療開発グループ, 部長 (20171572)
• Co-Investigator(Kenkyū-buntansha): 島田 英昭 東邦大学, 医学部, 教授 (20292691)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 食道がん / p53経路 / 細胞障害活性 / アデノウイルス / 遺伝子医薬 / 分子標的薬 / p21分子 / CP-31398 / pRb蛋白質 / 脱リン酸化 / p53

Outline of Final Research Achievements

Esophageal carcinoma remains intractable despite therapeutic multi-modality when it develops into an advanced case or became chemotherapy-resistant. A next-generation sequencing technique revealed that a majority of the patients in East Asia had aberration of p53 gene and the down-stream pathways, which consequently indicated that the p53 pathways was the major therapeutic target. We then investigated a novel therapeutic approach to augment the p53 pathways with gene medicine and a molecular targeted agent. Recombinant replicative adenoviruses (Ad) induced up-regulated p53 expression and produced cytotoxic effects on esophageal carcinoma cells. Transduction of the cells with the wild-type p53 gene increased the cytotoxicity but the replicative Ad numbers decreased. In contrast, molecular targeted agents which stabilize the wild-type p53 in the terms of ubiquitination or functionally convert mutated p53 into the wild-type were not effectively cytotoxic to esophageal carcinoma.

Research Products

• [Journal Article] A panel of autoantibodies against multiple tumor-associated antigens for detecting gastric cancer (2017)
  • Author(s): Hoshino, I., Nagata, M., Takiguchi, N., Nabeya, Y., Ikeda, A., Yokoi, S., Kuwajima, A., Tagawa, M., Matsushita, K., Yajima, S., Shimada, H.
  • Journal Title: Cancer Sci Volume: 108 Issue: 3 Pages: 308-315
  • DOI: 10.1111/cas.13158
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Combination of a third generation bisphosphonate and replication-competent adenoviruses augments the cytotoxicity on mesothelioma (2016)
  • Author(s): Jiang, Y., Zhong, B., Kawamura, K., Morinaga, T., Shingyoji, M., Sekine, I., Tada, Y., Tatsumi, K., Shimada, H., Hiroshima, K. and Tagawa, M.
  • Journal Title: BMC Cancer Volume: 16 Issue: 1 Pages: 455-455
  • DOI: 10.1186/s12885-016-2483-y
  • NAID: 120007129538
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Clinical significance of serum autoantibodies against Ras-like GTPases, RalA, in patients with esophageal squamous cell carcinoma. (2016)
  • Author(s): Nanami, T., Shimada, H., Yajima, S., Oshima, Y., Matsushita, K., Nomura, F., Nagata, M., Tagawa, M., Otsuka, S., Kuwajima, A. and Kaneko, H
  • Journal Title: Esophagus Volume: 13 Issue: 2 Pages: 167-172
  • DOI: 10.1007/s10388-015-0510-8
  • NAID: 40020807867
  • Peer Reviewed / Open Access
• [Journal Article] NY-ESO-1 autoantibody as a tumor-specific biomarker for esophageal cancer: screening in 1969 patients with various cancers (2015)
  • Author(s): Oshima Y, Shimada H, Yajima S, Nanami T, Matsushita K, Nomura F, Kainuma O, Takiguchi N, Soda H, Ueda T, Iizasa T, Yamamoto N, Yamamoto H, Nagata M, Yokoi S, Tagawa M, Ohtsuka S, Kuwajima A, Murakami A, Kaneko H
  • Journal Title: J Gastroenterol Volume: Epub ahead of print Issue: 1 Pages: 30-34
  • DOI: 10.1007/s00535-015-1078-8
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Cytotoxic effects of replication-competent adenoviruses on human esophageal carcinoma are enhanced by forced p53 expression. (2015)
  • Author(s): Yang, S., Kawamura, K., Okamoto, S., Yamauchi, S., Shingyoji, M., Sekine, I., Kobayashi, H., Tada, Y., Tatsumi, K., Hiroshima, K., Shimada, H. and Tagawa, M.
  • Journal Title: BMC Cancer Volume: 15 Issue: 1 Pages: 464-464
  • DOI: 10.1186/s12885-015-1482-8
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Combination of adenoviruses expressing melanoma differentiation-associated gene-7 and chemotherapeutic agents produces enhanced cytotoxicity on esophageal carcinoma. (2014)
  • Author(s): Ma, G., Kawamura, K., Yang, S., Okamoto, S., Li, Q., Namba, M., Shingyoji, M., Tada, Y., Tatsumi, K., Hiroshima, K., Shimada, H. and Tagawa, M.
  • Journal Title: Cancer Gene Ther. Volume: 21 Issue: 1 Pages: 31-37
  • DOI: 10.1038/cgt.2013.79
  • Peer Reviewed
• [Journal Article] Mesenchymal stem cells are efficiently transduced with adenoviruses bearing type 35-derived fibers and the transduced cells with the IL-28A gene produces cytotoxicity to lung carcinoma cells co-cultured. (2014)
  • Author(s): Suzuki, T., Kawamura, K., Li, Q, Okamoto, S., Tada, Y., Tatsumi, K., Shimada, H., Hiroshima, K., Yamaguchi, N. and Tagawa, M.
  • Journal Title: BMC Cancer Volume: 14 Pages: 713-713
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 細胞周期促進は増殖性アデノウイルスによるアポトーシスを増強する (2016)
  • Author(s): 盛永敬郎, グエンタオ, チョンボウヤア, 久保秀司, 関根郁夫, 多田裕司, 巽浩一郎, 島田英昭, 廣島健三, 田川雅敏
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（横浜）
  • Year and Date: 2016-10-06
• [Presentation] MDM2 and MDM4 inhibitors in combination with adenoviruses up-regulating p53 produce synergistic anti-tumor effects on mesothelioma through augmenting apoptotic processes (2016)
  • Author(s): Masatoshi Tagawa, Taka-aki Kozono, Yiyang Qin, Xue Rao Ning, Takao Morinaga, Shuji Kubo, Masato Shingyoji, Ikuo Sekine, Yuji Tada, Koichiro Tatsumi, Hideaki Shimada, Kenzo Hiroshima
  • Organizer: 22th annual meeting of Japan Society of Gene Therapy
  • Place of Presentation: 虎ノ門ヒルズフォーラム（東京）
  • Year and Date: 2016-07-28
• [Presentation] Heat shock protein 90 inhibitors augment endogenous p53 in p53 wild-type tumors but suppress Ad-mediated over-expressed exogenous p53 levels. (2015)
  • Author(s): Masatoshi Tagawa, Shinya Okamoto, Takao Morinaga, Taka-Aki Kozono, Shuji Kubo, Masato Shingyoji, Ikuo Sekine, Yuji Tada, Koichiro Tatsumi, Hideaki Shimada, Kenzo Hiroshima
  • Organizer: 21th annual meeting of Japan Society of Gene Therapy
  • Place of Presentation: 大阪市
  • Year and Date: 2015-07-24
• [Presentation] Cytotoxicity by Adenovirus Replications is Associated with DNA Damages and the Activated P53 Pathways and is Dependent on Reactive Oxygen Species. (2015)
  • Author(s): Masatoshi Tagawa, Kiyoko Kawamura, Shinya Okamoto, Yuanyuan Jiang, Zhihan Li, Takao Morinaga, Shuji Kubo, Masato Shingyoji, Ikuo Sekine, Yuji Tada, Koichiro Tatsumi, Hideaki Shimada, Kenzo Hiroshima
  • Organizer: 18th annual meeting of American Society of Gene and Cell Therapy
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2015-05-13
  • Int'l Joint Research
• [Presentation] Transduced p53 enhances cytotoxic effects achieved withoncolytic adenoviruses on pancreatic carcinoma cells. (2014)
  • Author(s): 江媛媛、岡本慎也、李知瀚、久保秀司、関根郁夫、滝口裕一、多田祐司、巽浩一郎、島田英昭、廣島健三、田川雅敏
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜市
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Immune response to tumor antigen, RalA, in patients with gastrointestinal cancers. (2014)
  • Author(s): 島田英昭、谷島聡、小池淳一、松下一之、野村文夫、日和佐隆樹、田川雅敏
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜市
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] A new therapeutic strategy for cancer with replication-competent adenoviruses powered by the midkine promoter. (2014)
  • Author(s): Masatoshi Tagawa, Kiyoko Kawamura, Shinya Okamoto, Yuji Tada, Koichiro Tatsumi, Kenzo Hiroshima, Hideaki Shimada.
  • Organizer: Third Midkine Symposium
  • Place of Presentation: 京都市
  • Year and Date: 2014-04-21 – 2014-04-23