Development of diagnostic method and its application to treatment in GIST with particular mutations through creating monoclonal antibodies

• Project/Area Number: 16H05166
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Human pathology
• Research Institution: Hyogo Medical University
• Principal Investigator: Hirota Seiichi 兵庫医科大学, 医学部, 教授 (50218856)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2018: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2017: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000); Fiscal Year 2016: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: GIST / c-kit / PDGFRA / mutation / antibody / Mutation / 病理学 / ＧＩＳＴ / c-kit遺伝子変異 / 特異抗体 / 診断と治療

Outline of Final Research Achievements

Among the gene mutations observed in GISTs, Dup-502&503 of the c-kit gene, Asp842Val of the PDGFRA gene and Del-557&558 of the c-kit gene were targeted to make specific antibodies to use for image diagnosis and therapy. High titer fraction on ELISA was obtained, but the final products of specific antibodies for them were not gained. We also investigated the clinicopathological characteristics of GISTs in NF1 patients, effective neoadjuvant imatinib therapy for giant gastric GISTs and condition of management of high-risk GIST patients in the real world.

Academic Significance and Societal Importance of the Research Achievements

GISTの治療はその病態解明に伴って劇的に進歩したが、分子標的治療に対する二次耐性の問題は患者のさらなる予後改善の足かせとなっている。GISTに特徴的なc-kit遺伝子やPDGFRA遺伝子の変異に対する特異的なモノクローナル抗体の作製が可能となれば、これまでの分子標的薬とは異なった機序で病気を制御できる可能性があり、画像診断にも応用できると考えたが、思いのほか抗体作製に難渋し、達成できなかった。補助金による研究終了後もさらなる工夫を行って継続したい。並行する研究では、各種GISTの病態の解明や実臨床での再発高リスクGIST症例の実態等が明らかにでき、今後のGIST診療に役立つものと考えられた。

Research Products

• [Journal Article] Adherence to the guidelines and the pathological diagnosis of high-risk gastrointestinal stromal tumors in the real world (2019)
  • Author(s): Nishida T, Sakai Y, Takagi M, Ozaka M, Kitagawa Y, Kurokawa Y, Masuzawa T, Naito Y, Kagimura T, Hirota S, and the members of the STAR ReGISTry Study Group
  • Journal Title: Gastric Cancer Volume: 印刷中 Issue: 1 Pages: 118-125
  • DOI: 10.1007/s10120-019-00966-4
  • NAID: 120006786938
  • Peer Reviewed / Open Access
• [Journal Article] An unusual case of duodenal gastrointestinal stromal tumour combined with the neuronal elements (2019)
  • Author(s): Iemura Y, Katsushima H, Kataoka TR, Hirota S, Shimada T
  • Journal Title: Pathol Int. Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Clinicopathological features and prognosis of primary GISTs with tumor rupture in the real world. (2018)
  • Author(s): Nishida T, Cho H, Hirota S, Masuzawa T, Chiguchi G, Tsujinaka T, Kinki GIST Study Group
  • Journal Title: Ann Surg Oncol. Volume: 25 Issue: 7 Pages: 1961-1969
  • DOI: 10.1245/s10434-018-6505-7
  • Peer Reviewed / Open Access
• [Journal Article] SOCS1 gene therapy has antitumor effects in imatinib-resistant gastrointestinal stromal tumor cells through FAK/PI3K signaling. (2018)
  • Author(s): Sugase T, Takahashi T, Serada S, Fujimoto M, Ohkawara T, Hiramatsu K, Nishida T, Hirota S, Saito Y, Tanaka K, Miyazaki Y, Makino T, Kurokawa Y, Yamasaki M, Nakajima K, Hanasaki K, Kishimoto T, Mori M, Doki Y, Naka T.
  • Journal Title: Gastric Cancer. Volume: epub Issue: 6 Pages: 968-976
  • DOI: 10.1007/s10120-018-0822-1
  • NAID: 40021694606
  • Peer Reviewed / Open Access
• [Journal Article] Coexistence of gastrointestinal stromal tumor and leiomyosarcoma of the stomach presenting as a collision tumor: a case report and review of literature. (2018)
  • Author(s): Kitagawa H, Kaneko M, Kano M, Ibuki Y, Amatya VJ, Takeshima Y, Hirota S, Hirabayashi N.
  • Journal Title: Pathol Int. Volume: 68 Issue: 5 Pages: 313-317
  • DOI: 10.1111/pin.12662
  • Peer Reviewed
• [Journal Article] Genomic and transcriptomic analysis of imatinib resistance in gastrointestinal stromal tumors. (2017)
  • Author(s): Takahashi T, Elzawahry A, Mimaki S, Furukawa E, Nakatsuka R, Nakamura H, Nishigaki T, Serada S, Naka T, Hirota S, Shibata T, Tsuchihara K, Nishida T, Kato M.
  • Journal Title: Genes Chromosomes Cancer. Volume: 56 Issue: 4 Pages: 303-313
  • DOI: 10.1002/gcc.22438
  • Peer Reviewed / Open Access
• [Journal Article] Familial gastrointestinal stromal tumor with germline KIT mutations accompanying hereditary breast and ovarian cancer syndrome. (2017)
  • Author(s): Sekido Y, Ohigashi S, Takahashi T, Hayashi N, Suzuki K, Hirota S.
  • Journal Title: Anticancer Res Volume: 37 Issue: 3 Pages: 1425-1431
  • DOI: 10.21873/anticanres.11466
  • Peer Reviewed
• [Journal Article] Phase II study of neoadjuvant imatinib in large gastrointestinal stromal tumours of the stomach (2017)
  • Author(s): Kurokawa Yukinori、Yang Han-Kwang、Cho Haruhiko、Ryu Min-Hee、Masuzawa Toru、Park Sook Ryun、Matsumoto Sohei、Lee Hyuk-Joon、Honda Hiroshi、Kwon Oh Kyoung、Ishikawa Takashi、Lee Kyung Hee、Nabeshima Kazuhito、Kong Seong-Ho、Shimokawa Toshio、et al.
  • Journal Title: British Journal of Cancer Volume: 117 Issue: 1 Pages: 25-32
  • DOI: 10.1038/bjc.2017.144
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prognostic factors after imatinib secondary resistance: survival analysis in patients with unresectable and metastatic gastrointestinal stromal tumors. (2016)
  • Author(s): Kanda T, Ishikawa T, Kosugi S-I, Ueki K, Naito T, Wakai T, Hirota S.
  • Journal Title: Int J Clin Oncol. Volume: 21 Issue: 2 Pages: 295-301
  • DOI: 10.1007/s10147-015-0903-7
  • Peer Reviewed
• [Journal Article] Detecting secondary c-KIT mutations in the peripheral blood of patients with imatinib-resistant gastrointestinal stromal tumor. (2016)
  • Author(s): Wada N, Kurokawa Y, Takahashi T, Hamakawa T, Hirota S, Naka T, Miyazaki Y, Makino T, Yamasaki M, Nakajima K, Takiguchi S, Mori M, Doki Y.
  • Journal Title: Oncology Volume: 90 Issue: 2 Pages: 112-117
  • DOI: 10.1159/000442948
  • Peer Reviewed
• [Journal Article] Clinicopathological characteristics, surgery and survival outcomes of patients with duodenal gastrointestinal stromal tumors. (2016)
  • Author(s): Sugase T, Takahashi T, Nakajima K, Hirota S, Masuzawa T, Nishida T, Kimura Y, Miyazaki Y, Makino T, Kurokawa Y, Yamasaki M, Takiguchi S, Mori M, Doki Y.
  • Journal Title: Digestion. Volume: 94 Issue: 1 Pages: 30-36
  • DOI: 10.1159/000447665
  • Peer Reviewed
• [Journal Article] Gastrointestinal stromal tumors in Japanese patients with neurofibromatosis type I. (2015)
  • Author(s): Nishida T, Tsujimoto M, Takahashi T, Hirota S, Blay J-V, Wataya-Kaneda M.
  • Journal Title: J Gastroenterol Volume: s00535 Issue: 6 Pages: 1132-6
  • DOI: 10.1007/s00535-015-1132-6
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Pathology of Gastrointestinal stromal tumor. (2017)
  • Author(s): Seiichi Hirota
  • Organizer: 第89回日本胃癌学会総会
  • Invited
• [Presentation] gastrointestinal stromal tumor の病理学的研究から分子標的治療へ, (2016)
  • Author(s): 廣田誠一
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-10-07
  • Invited
• [Presentation] Gastrointestinal stromal tumor (GIST) の病態解析と診断 (2016)
  • Author(s): 廣田誠一
  • Organizer: 第105回日本病理学会総会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2016-05-14
  • Invited