Screening for alternative transcription initiation of tyrosine kinase genes in bone and soft tissue tumors
Project/Area Number |
16K15670
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Research Category |
Grant-in-Aid for Challenging Exploratory Research
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Allocation Type | Multi-year Fund |
Research Field |
Orthopaedic surgery
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Research Institution | Juntendo University |
Principal Investigator |
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Co-Investigator(Kenkyū-buntansha) |
高阪 真路 国立研究開発法人国立がん研究センター, 研究所, 主任研究員 (00627119)
小林 英介 国立研究開発法人国立がん研究センター, 中央病院, 医長 (40365292)
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Research Collaborator |
ENDO Makoto
SAITO Tsuyoshi
HAYASHI Takuo
KUBOTA Daisuke
MUKAIHARA Kenta
AKAIKE Keisuke
TANABE Yu
ISHII Midori
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Project Period (FY) |
2016-04-01 – 2019-03-31
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Project Status |
Completed (Fiscal Year 2018)
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Budget Amount *help |
¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2016: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
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Keywords | 骨軟部腫瘍 / 軟部肉腫 / 融合遺伝子 / 遺伝子転写変異体 / 遺伝子変異体 / tyrosine Kinase / TK遺伝子転写変異体 / TK遺伝子変異 / 転写変異体 / チロシンキナーゼ |
Outline of Final Research Achievements |
Soft tissue sarcomas (STSs) are a heterogeneous group of rare malignant tumors. Systemic chemotherapy consisting cytotoxic anticancer agents for STS contributes on improving prognosis of STS treatment. However, advanced STSs have still poor prognosis and effective systemic therapies have not yet been established. Therefore, the identification of novel therapeutic targets and novel effective therapies are required. Receptor tyrosine kinases (RTKs) are being increasingly used as therapeutic targets for a variety of cancers, especially RTK fusion genes. A recent report found that the novel TK transcript initiates from a de novo alternative transcription initiation (ATI) site, especially in ALK. In addition, the TK-ATI has a novel mechanism of oncogene activation in cancer and TK inhibitors could suppress the kinase activity of TK-ATI. Based on these background, we conducted TK screening using NanoString to identify rational therapeutic TK targets including TK-fusions and TK-ATIs in STSs.
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Academic Significance and Societal Importance of the Research Achievements |
本研究は、難治性かつ「希少がん」である骨軟部腫瘍の生命予後改善の要となる新規分子治療標的の開発を行った。具体的には、他癌種において発見されているdriver-oncogeneである転写変異体について、骨軟部腫瘍の手術検体を用いて全TK遺伝子の探索を進めた。その方法として独自のNanostringの手法に基づいたTK遺伝子転写変異体・融合遺伝子探索システムを用い、それら同定TK遺伝子転写変異体・融合遺伝子については、骨軟部腫瘍における癌化機能の解明とそのターゲットとなるTK阻害剤奏功性の検証を進め、TK阻害剤の適応拡大を含めた新規分子治療標的の開発を行い、骨軟部腫瘍の予後改善へ貢献を目的とした。
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Report
(4 results)
Research Products
(51 results)
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[Journal Article] Multicenter experience with large panel next-generation sequencing in patients with advanced solid cancers in Japan.2019
Author(s)
Kato S, Hayashi T, Suehara Y, Hamanoue H, Yamanaka S, Ichikawa Y, Higurashi T, Ohashi K, Yamaguchi S, Nozaki Y, Terao Y, Saito T.
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Journal Title
Jpn J Clin Oncol
Volume: 49(2)
Issue: 2
Pages: 174-182
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Fibrocartilaginous mesenchymoma of the tibia with predominant microcystic features: A case report and literature review2019
Author(s)
Saito T, Motoi T, Suehara Y, Takagi T, Okubo T, Kurihara T, Hayashi T, Kudo T, Maruyama Y, Kaneko K, YaoT.
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Journal Title
Human Pathology Case reports
Volume: 16
Pages: 100288-100288
DOI
Related Report
Peer Reviewed / Open Access
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[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.
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Journal Title
Oncotarget
Volume: 9(101)
Issue: 101
Pages: 37509-37519
DOI
Related Report
Peer Reviewed / Open Access
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[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.
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Journal Title
Oncotarget
Volume: 9(38)
Issue: 38
Pages: 25206-25215
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Next-generation sequencing analysis for gastric adenocarcinoma with enteroblastic differentiation: emphasis on the relationship with hepatoid adenocarcinoma.2018
Author(s)
1.Akazawa Y, Saito T, Hayashi T, Yanai Y, Tsuyama S, Akaike K, Suehara Y, Takahashi F, Takamochi K, Ueyama H, Murakami T, Watanabe S, Nagahara A, Yao T.
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Journal Title
Hum Pathol
Volume: 78
Pages: 79-88
DOI
Related Report
Peer Reviewed / Open Access
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[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.
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Journal Title
Oncotarget
Volume: 9(43)
Issue: 43
Pages: 27016-27026
DOI
Related Report
Peer Reviewed / Open Access
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[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.
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Journal Title
Oncotarget
Volume: 9(18)
Issue: 18
Pages: 14428-14443
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Cabozantinib and dastinib exert anti-tumor activity in alveolar soft part sarcoma2017
Author(s)
Mukaihara K, Tanabe Y, Kubota D, Akaike K, Hayashi T, Mogushi K, Hosoya M, Sato S,Kobayashi E, Okubo T, Kohsaka S, Saito T, Kaneko K, Suehara Y.
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Journal Title
PLoS One
Volume: 12(9)
Issue: 9
Pages: 0185321-0185321
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Protein Expression Profiling of Giant Cell Tumors of Bone Treated with Denosumab.2016
Author(s)
Mukaihara K, Suehara Y, Kohsaka S, Akaike K, Tanabe Y, Kubota D, Ishii M, Fujimura T, Kazuno S, Okubo T, Takagi T, Yao T, Kaneko K, Saito T.
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Journal Title
PLoS One
Volume: 10
Issue: 2
Pages: e0148401-e0148401
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
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[Journal Article] Expression of F-actin-capping protein subunit beta is associated with cell growth and motility in epithelioid sarcoma.2016
Author(s)
Mukaihara K, Suehara Y*, Kohsaka S, Kubota D, Toda-Ishii M, Akaike K, Fujimura T, Kobayashi E, Yao T, Ladanyi, M, Kaneko K, Saito T.
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Journal Title
BMC cancer.
Volume: 16(1)
Issue: 1
Pages: 206-206
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] An Outpatient-based Survey on the Recognition of Locomotive Syndrome in Japan: The Results of three Years of Surveys.2016
Author(s)
Tanabe Y, Suehara Y, Okubo T, Kim Y, Ishii M,Kawasaki T, Matsuoka K, Akaike K, Mukaihara K, Kubota D, Okubo N, Maruyama Y, Saito T, Kaneko K.
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Journal Title
British Journal of Medicine & Medical Research.
Volume: 15(9)
Issue: 9
Pages: 1-9
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Clinicopathological effects of protein phosphatase 2, regulatory subunit A, alpha mutations in gastrointestinal stromal tumors2016
Author(s)
Ishii M, Akaike K, Suehara Y, Mukaihara K, Kubota K , Kohsaka S, Okubo T, Mitani K, Mogushi K, Takagi T, Kaneko K, Yao T, Saito T.
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Journal Title
Modern Pathology.
Volume: 29
Issue: 11
Pages: 1424-1432
DOI
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Journal Article] Reduced argininosuccinate synthetase expression in refractory sarcomas.2016
Author(s)
Kim Y, Kobayashi E, Kubota D, Suehara Y, Mukaihara K, Akaike K, Ito A, Kaneko K, Chuman H, Kawai A, Kitano S.
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Journal Title
Oncotarget.
Volume: 7(43)
Issue: 43
Pages: 70832-70844
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] A comparative study of 2 screening tools for locomotive syndrome (the “Loco-check” and the “GLFS-25”): An orthopedic outpatient-based survey.2016
Author(s)
Kim Y, Suehara Y, Ishii M, Kawasaki T, Matsuoka K, Okubo T, Okubo N, Tanabe Y, Akaike K, Mukaihara K, Kubota D, Maruyama Y, Saito T, Kaneko K.
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Journal Title
British Journal of Medicine & Medical Research
Volume: 17(5)
Issue: 5
Pages: 1-13
DOI
Related Report
Peer Reviewed / Open Access
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[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 ASIA,
Related Report
Int'l Joint Research
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[Presentation] Expanded access of larotrectenib to manage pediatric TRK fusion sarcomas.2018
Author(s)
Suehara Y, Trahair T, Kirby M, Saito S, Capra M, Ghosh T, Henry D, Ku NC, Cox MC, Kato S, Ziegler DS.
Organizer
50th Congress of International Society of Paediatric Oncology,
Related Report
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[Presentation] Clinical genomic sequencing of 72 pediatric and adult osteosarcomas reveals distinct molecular subsets with potentially targetable alterations.2018
Author(s)
Alex D, Suehara Y, Bowman A, Middha S, Zehir A, Wang L, Jour G, Nafa K, Meyers P, Healey J, Hameed M, Ladanyi M.
Organizer
USCAP, the 2018 Annual Meeting,
Related Report
Int'l Joint Research
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[Presentation] Proteomics analysis of characteristic histological changes with Denosumab treatment in giant cell tumors of bone.2017
Author(s)
SueharaY, Mukaihara K, TanabeY, Kohsaka S, Kazuno S, Ishii M, Akaike K, Kubota D, Kaneko K, Saito T.
Organizer
the 63th Annual Meeting of the Orthopaedic Research Society
Place of Presentation
San Diego, USA
Year and Date
2017-03-19
Related Report
Int'l Joint Research
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[Presentation] Proteomic approaches reveal that inhibition of the IRE1/XBP1 pathway reduces tumor growth in Ewing's sarcoma.2017
Author(s)
Tanabe Y, Suehara Y, Kohsaka S, Mukaihara K, Kubota D, Akaike K, Ishii M, Kazuno S, Mineki R, Kaneko K, Ladanyi M, Saito T.
Organizer
the 63th Annual Meeting of the Orthopaedic Research Society
Place of Presentation
San Diego, USA
Year and Date
2017-03-19
Related Report
Int'l Joint Research
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[Presentation] A complete responder to pazopanib in high-grade soft tissue sarcomas.2017
Author(s)
Suehara Y, Kohsaka S, Yamaguchi S, Akaike K, Hayashi T, Tanabe Y, Ueno T, Kojima S, Takeda I, Hayashi R, Saito T, Mano H, Kato S.
Organizer
Connective Tissue Oncology Society, 22th Annual Meeting
Related Report
Int'l Joint Research
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[Presentation] The Regulation of Malignant Transformation by PPP2R1A in Alveolar Rhabdomyosarcoma Based On A Proteomic Approach Corresponding To The PAX3/FOXO1 Fusion Gene.2016
Author(s)
Akaike K, Suehara Y, Kohsaka S, Mukaihara K, Ishii M, Kubota D, Tanabe Y, Kazuno S, Mineki R, Fujimura T, Kaneko K, Ladanyi M, Saito T.
Organizer
Connective Tissue Oncology Society, 21th Annual Meeting,
Place of Presentation
Lisbon, Portugal
Year and Date
2016-09-09
Related Report
Int'l Joint Research
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[Presentation] Protein Expression Profiles Corresponding To Histological Changes With Denosumab Treatment in Giant Cell Tumors of Bone.2016
Author(s)
Suehara Y, Mukaihara K, Tanabe Y, Kohsaka S, Kazuno S, Ishii M, Akaike K, Kubota D, Kaneko K, Saito T.
Organizer
Connective Tissue Oncology Society, 21th Annual Meeting,
Place of Presentation
Lisbon, Portugal
Year and Date
2016-09-09
Related Report
Int'l Joint Research
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[Presentation] Proteomic approaches revealed inhibition of IRE1/XBP1 pathway reduces tumor growths in Ewing's sarcomas.2016
Author(s)
Tanabe Y, Suehara Y, Kohsaka S, Mukaihara K, Kubota D, Akaike K, Ishii M, Kazuno S, Mineki R, Kaneko K, Ladanyi M, Saito T.
Organizer
Connective Tissue Oncology Society, 21th Annual Meeting,
Place of Presentation
Lisbon, Portugal
Year and Date
2016-09-09
Related Report
Int'l Joint Research
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