Identification of new therapeutic target in GIST focusing on KIT transcriptional activity.

• Project/Area Number: 18K15329
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Juntendo University
• Principal Investigator: Ohkubo Taketo 順天堂大学, 医学部, 非常勤助教 (90732884)
• Project Period (FY): 2018-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: CAGE / NTRK / GIST / pfetin / KIT / CAGE解析 / Pfetin / 遺伝子発現解析 / KCTD12 / PP2A / 脱リン酸化酵素

Outline of Final Research Achievements

Recently, the neurotrophic tyrosine receptor kinase (NTRK) fusion was reported in a small subset of wild-type gastrointestinal stromal tumors (GIST). We examined trk IHC and NTRK gene expressions in GIST. Pan-trk immunohistochemistry (IHC) was positive in 25 (all 16 duodenal and 9 out of 16 small intestinal GISTs) of 139 cases. All of these cases showed only trkB expression. Small intestinal GISTs with trkB expression showed adverse clinical outcomes compared with those without. Cap analysis of gene expression (CAGE) analysis showed that increased number of genes whose promoters were activated in trkB positive GISTs. The genetic analysis did not show amplification of NTRK2. Furthermore, imbalanced expression of NTRK2, which suggests the presence of NTRK2 fusion, was not observed in trkB positive GISTs. TrkB expression was found in and restricted to duodenal GISTs and more than half of small intestinal GISTs, and probably contributing to acquire aggressive phenotype in this subset.

Academic Significance and Societal Importance of the Research Achievements

十二指腸由来のGISTの全例および小腸由来のGISTの半数以上にpan-trk(trkB)タンパク質の過剰発現を認め、統計学的有意差を生じるまでには至らなかったが、trkB陽性の小腸GISTは陰性GISTと比べて予後不良となる傾向が示された。また、CAGE解析の結果からは、KCTD12とNTRK2の遺伝子発現の観点から３つに分類される可能性が示唆された。本研究からは予後不良とされる十二指腸由来のGISTの悪性度獲得にpan-trk(trkB)の発現が関与している可能性が示唆され、過剰発現を来しているtrkBタンパク質を標的とした新規治療法の可能性が示唆された。

Research Products

• [Journal Article] Protein Expression Profiles Corresponding to Histological Changes with Denosumab Treatment in Giant Cell Tumors of Bone. (2019)
  • Author(s): Suehara Y, Okubo T, Kurihara T, Hayashi T, Kohsaka S, Kazuno S, Sano K, Hasegawa N, Miura Y, Akaike K, Kim Y, Takamochi K, Takahashi F, Ueno T, Kaneko K, Saito T.
  • Journal Title: Proteomics Clin Appl Volume: 13 Issue: 5 Pages: 1800147-1800147
  • DOI: 10.1002/prca.201800147
  • Peer Reviewed
• [Journal Article] Detection of circulating sarcoma tumor cells using a microfluidic chip-type cell sorter. (2019)
  • Author(s): Hasegawa N, Takeda Nakamura I, Ueno T, Kojima S, Kawazu M, Akaike K, Okubo T, Takagi T, Suehara Y, Hayashi T, Saito T, Kaneko K, Mano H, Kohsaka S.
  • Journal Title: Sci Rep. Volume: 9 Issue: 1 Pages: 20047-20047
  • DOI: 10.1038/s41598-019-56377-z
  • Peer Reviewed / Open Access
• [Journal Article] Preoperative denosumab treatment with curettage maybe a risk factor for recurrence of giant cell tumor of bone (2019)
  • Author(s): Sano K, Suehara Y, Okubo T, Sasa K, Kurihara T, Akaike K, Kubota D, Torigoe T, Hasegawa N, Ishii M, Y Nakamura, Kim Y, Takagi T, Kaneko K, Hayashi T, Saito T
  • Journal Title: Journal of Orthopaedic Surgery Volume: -
  • Peer Reviewed
• [Journal Article] Assessment of Predictive Biomarkers of the Response to Pazopanib Based on an Integrative Analysis of High-grade Soft-tissue Sarcomas. (2019)
  • Author(s): Suehara Y, Kohsaka S, Yamaguchi S, Hayashi T, Kurihara T, Akaike K, Ueno T, Kojima S, Ikegami M, Mizuno S, Okubo T, Kim Y, Kaneko K, Saito T, Kato S, Mano H
  • Journal Title: Clin Orthop Relat Res. Volume: -
  • Peer Reviewed
• [Journal Article] Squamous cell carcinoma arising from chronic osteomyelitis massively expanding into the medullary cavity: A case report. (2019)
  • Author(s): Kurihara T, Suehara Y, Akaike K, Hayashi T, Okubo T, Kim Y, Takagi T, Kaneko K, Yao T, Saito T.
  • Journal Title: Human Pathology Case reports Volume: 16 Pages: 100289-100289
  • Peer Reviewed
• [Journal Article] Fibrocartilaginous mesenchymoma of the tibia with predominant microcystic features: A case report and literature review (2019)
  • Author(s): Saito T, Motoi T, Suehara Y, Takagi T, Okubo T, Kurihara T, Hayashi T, Kudo T, Maruyama Y, Kaneko K, YaoT.
  • Journal Title: Human Pathology Case reports Volume: 16 Pages: 100288-100288
  • Peer Reviewed
• [Journal Article] Squamous cell carcinoma arising from chronic osteomyelitis massively expanding into the medullary cavity: A case report. (2019)
  • Author(s): Kurihara T, Suehara Y, Akaike K, Hayashi T, Okubo T, Kim Y, Takagi T, Kaneko K, Yao T, Saito T
  • Journal Title: Pathology Case reports Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Proteomic signatures corresponding to the SS18/SSX fusion gene in synovial sarcoma. (2018)
  • Author(s): Ishii M, Suehara Y, Sano K, Kohsaka S, Hayashi T, Kazuno S, Akaike K, Mukaihara K, Kim Y, Okubo T, Takamochi K, Takahashi F, Kaneko K, Saito T.
  • Journal Title: Oncotarget Volume: 9(101) Issue: 101 Pages: 37509-37519
  • DOI: 10.18632/oncotarget.26493
  • Peer Reviewed / Open Access
• [Journal Article] The first study on locomotive syndrome in lower amputees. (2018)
  • Author(s): Sano K, Suehara Y*, Tanabe Y, Okubo T, Kim Y, Ishii M, Kawasaki T, Terakado A, Akaike K, Mukaihara K, Kubota D, Okubo N, Maruyama Y, Saito T, Kaneko K.
  • Journal Title: J Adv Med Med Res. Volume: 27 Pages: 1-10
  • Peer Reviewed
• [Journal Article] PPP2R1A regulated by PAX3/FOXO1 fusion contributes to the acquisition of aggressive behavior in PAX3/FOXO1-positive alveolar rhabdomyosarcoma. (2018)
  • Author(s): Akaike K, Suehara Y, Kohsaka S, Hayashi T, Tanabe Y, Kazuno S, Mukaihara K, Toda-Ishii M, Kurihara T, Kim Y, Okubo T, Hayashi Y, Takamochi K, Takahashi F, Kaneko K, Ladanyi M, Saito T.
  • Journal Title: Oncotarget Volume: 9(38) Issue: 38 Pages: 25206-25215
  • DOI: 10.18632/oncotarget.25392
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] KCTD12 is negatively regulated by Kit in gastrointestinal stromal tumors. (2018)
  • Author(s): Suehara Y, Akaike K, Mukaihara K, Kurisaki-Arakawa A, Kubota D, Okubo T, Mitomi H, Mitani K, Takahashi M, Toda-Ishii M1, Kim Y, Tanabe Y, Takagi T, Hayashi T, Mogushi K, Kaneko K, Yao T, Saito T.
  • Journal Title: Oncotarget Volume: 9(43) Issue: 43 Pages: 27016-27026
  • DOI: 10.18632/oncotarget.25469
  • Peer Reviewed / Open Access
• [Journal Article] An The development of the short-form “25-question Geriatric Locomotive Function Scale”. (2018)
  • Author(s): Tanabe Y, Suehara Y, Kim Y, Nojiri S, Okubo T, Ishii M, Kawasaki T, Matsuoka K, Akaike K, Mukaihara K, Okubo N, Saito T, Kaneko K
  • Journal Title: J Adv Med Med Res. Volume: 25 Pages: 1-13
  • Peer Reviewed
• [Journal Article] IRE1α-XBP1 inhibitors exerted anti-tumor activities in Ewing's sarcoma. (2018)
  • Author(s): Tanabe Y, Suehara Y, Kohsaka S, Hayashi T, Akaike K, Mukaihara K, Kurihara T, Kim Y, Okubo T, Ishii M, Kazuno S, Kaneko K, Saito T.
  • Journal Title: Oncotarget Volume: 9(18) Issue: 18 Pages: 14428-14443
  • DOI: 10.18632/oncotarget.24467
  • Peer Reviewed / Open Access
• [Presentation] Comparative analysis of protein profiles of prognosis-associated proteins and KIT-related proteins in gastrointestinal stromal tumor (2019)
  • Author(s): Suehara Y, Sasa K, Okubo T, Hayashi T, Sano K, Kurihara T, Akaike K, Ishii M, Kim Y, Kaneko K, Saito T.
  • Organizer: European Society For Medical Oncology – ASIA, Nov 22-24th 2019, Singapore, Singapore
  • Int'l Joint Research
• [Presentation] NanoString analyses of tyrosine kinase fusion genes in IMT / IPT (2019)
  • Author(s): Kurihara T, Suehara Y, Sano K, Akaike K, Hayashi T, Kohsaka S, Hasegawa N, Takagi T, Okubo T, Yao T, Kaneko K Saito T
  • Organizer: Connective Tissue Oncology Society, 24th Annual Meeting, November 13-16, 2019, Tokyo, Japan
  • Int'l Joint Research
• [Presentation] Protein expression analysis by regulating c-kit and KCTD12 expression in Gastrointestinal stromal tumor. (2019)
  • Author(s): Sasa K, Suehara Y, Okubo T, Hayashi T, Sano K, Kurihara T, Akaike K, Ishii M, Kim Y, Kaneko K, Saito T.
  • Organizer: Connective Tissue Oncology Society, 24th Annual Meeting, November 13-16, 2019, Tokyo, Japan
  • Int'l Joint Research
• [Presentation] High-throughput analysis of transcriptional starting point and identification of promoter usage in spindle cell sarcomas. (2019)
  • Author(s): Sano K, Suehara Y, Hayashi T, Kurihara T, Akaike K, Oguchi A, Takagi T, Kim Y, Okubo T, Murakawa Y, Kaneko K, Saito T.
  • Organizer: Connective Tissue Oncology Society, 24th Annual Meeting, November 13-16, 2019, Tokyo, Japan
  • Int'l Joint Research
• [Presentation] Relationship with adriamycin-resistant osteosarcomas and the pentose phosphate pathway using metabolomic approaches (2019)
  • Author(s): Sasa K, Suehara Y, Akaike K, Hayashi T, Taka H, Kim Y, Okubo T Kaneko K, Saito T.
  • Organizer: 20th International Symposium on Limb Salvage, 11-13, September 2019, Athens, Greek
  • Int'l Joint Research
• [Presentation] Metabolic fluctuations in adriamycin-resistant osteosarcomas using metabolomic approaches (2019)
  • Author(s): Sasa K, Suehara Y, Akaike K, Hayashi T, Taka H, Youngji K, Okubo T, Kaneko K, Saito T
  • Organizer: the 65th Annual Meeting of the Orthopaedic Research Society Feb 2 8211;5 2019, Austin, USA
  • Int'l Joint Research
• [Presentation] IRE1α-XBP1 Inhibitor exerts antiyumor activity in osteosarcoma. (2019)
  • Author(s): Kurihara T, Suehara Y, Hayashi T, Akaike K, Okubo T, Kim Y, Kaneko K, Saito T.
  • Organizer: the 65th Annual Meeting of the Orthopaedic Research Society Feb 2 8211;5 2019, Austin, USA
  • Int'l Joint Research
• [Presentation] Comprehensive mRNA-based screen for tyrosine kinase fusions and a de novo alternative transcription initiation site in soft tissue sarcomas. (2018)
  • Author(s): Suehara Y, Kohsaka S, Kurisaki A, Akaike K, Hayashi T, Mogushi K, Okubo T, Kim Y, Sato S, Kobayashi E, Kaneko K, Mano H, Saito T
  • Organizer: European Society For Medical Oncology 8211; ASIA, Nov 23-25th 2018, Singapore, Singapore
  • Int'l Joint Research
• [Presentation] IRE1α-XBP1 Inhibitor exerts antiyumor activity in osteosarcoma. (2018)
  • Author(s): Kurihara T, Suehara Y, Hayashi T, Akaike K, Okubo T, Kim Y, Kaneko K, Saito T.
  • Organizer: Connective Tissue Oncology Society, 23th Annual Meeting, November 14 - 17, 2018, Roma, Italy
  • Int'l Joint Research