Development of novel therapeutic strategies for bone and soft tissue tumors

2018 Fiscal Year Annual Research Report

• Project/Area Number: 15H04964
• Research Institution: Juntendo University
• Principal Investigator: 末原 義之 順天堂大学, 医学部, 准教授 (70509405)
• Co-Investigator(Kenkyū-buntansha): 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) ; 北野 滋久 国立研究開発法人国立がん研究センター, 中央病院, 医員 (60402682) ; 齋藤 剛 順天堂大学, 医学部, 准教授 (80439736)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Keywords: 骨軟部腫瘍 / プロテオミクス / タンパク質発現解析 / 小胞体ストレス / 免疫応答 / 遺伝子変異 / 融合遺伝子

Outline of Annual 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の改善を目的として、腫瘍発生・悪性化・ 治療抵抗の原因因子を特定し、個別化医療や治療標的の開発を進めた。特徴として、下記３つの探索を実施し、TK阻害剤の適応拡大による新規分子標的治療法開発を進めた。以上を進め、早期骨軟部腫瘍の予後改善に向けた臨床医学の基盤構築を進めた。
(1)組織型特 異的融合遺伝子のタンパク質発現プロファイリングによる腫瘍発生・悪性化の鍵因子の解明：前年度に引き続き、手術検体及び組織型特異的融合遺伝子の発現解析データベースを構築し、ネットワーク解析及び阻害剤効果を含めた機能解析を進め、腫瘍の悪性化・抵抗性因子を明らかにした。特にユーング肉腫のXBP1タンパク質（小胞体ストレス）、横紋筋肉腫のPP2A（セリンスレオニン）が予後因子及び治療標的になることを同定した。
(2)骨軟部腫瘍検体を用いた免疫応 答解析による免疫担当細胞プロファイリングならびに免疫応答の側面より発癌・悪性化・抵抗性の因子の同定：前年度に引き続き、骨軟部腫瘍検体に対して免疫応答解析を行い、免疫担当細胞のプロファイリングを構築し、腫瘍の悪性化・抵抗性因子を明らかにした。同定された免疫担当細胞について発現検証を行いデータベース化を行った。
(3)阻害剤(特にチ ロシンキナーゼ)が奏効するチロシンキナーゼ遺伝子変異の探索：前年度に引き続き、骨軟部腫瘍の遺伝子変異プロファイリングを進め、その同定されたTK遺伝子変異に対して、阻害剤奏効性を含めた機能解析及びその発見に基づいた臨床応用(臨床試験)を前年度 に引き続き進めた。特にNTRK、ROS1の新規融合遺伝子を軟部肉腫に同定しプレシジョンメディシンに基づいた新規治療法開発、承認薬TK阻害剤(pazopanib)の著効因子の同定にて個別化医療促進に成功した。

Research Progress Status

平成30年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

平成30年度が最終年度であるため、記入しない。

Research Products

• [Int'l Joint Research] Memorial Sloan Kettering Cancer Center/Department of Pathology/Marc Ladanyi(米国)
  • Country Name: U.S.A.
  • Counterpart Institution: Memorial Sloan Kettering Cancer Center/Department of Pathology/Marc Ladanyi
  • # of Other Institutions: 1
• [Journal Article] Comprehensive assay for the molecular profiling of cancer by using DNA and RNA hybridization capture-based target enrichment from formalin- fixed paraffin-embedded specimens. (2019)
  • Author(s): Kohsaka S, Suehara Y, Mano H et al.
  • Journal Title: Cancer Science Volume: 110 Pages: 1464-1479
  • DOI: 10.1111/cas.13968.
  • Peer Reviewed / Open Access
• [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, Hananoue H, Yamanaka S, Ichikawa Y, Higurashi T, Ohashi K, Yamaguchi S, Nozaki Y, Terao Y, Saito T, Yao T, Nakajima A, Syed A, Zehir A, Ladanyi M, Kato S.
  • Journal Title: Japanese Journal of Clinical Oncology Volume: 49 Pages: 174-182
  • DOI: 10.1093/jjco/hyy173.
  • Peer Reviewed / Int'l Joint Research
• [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
  • DOI: https://doi.org/10.1016/j.ehpc.2019.01.008
  • Peer Reviewed / Open Access
• [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
  • DOI: https://doi.org/10.1016/j.ehpc.2019.01.007
  • Peer Reviewed / Open Access
• [Journal Article] Proteomic signatures corresponding to the SS18/SSX fusion gene. (2018)
  • Author(s): Ishii M, Suehara Y, Kohsaka S, Tanabe Y, Hayashi T, Kazuno S, Tanabe Y, Akaike K, Mukaihara K, Kim Y, Okubo T, Takamochi K, Takahashi F, Kaneko K, Saito T.
  • Journal Title: Oncotarget Volume: 9 Pages: 37509-37519
  • DOI: 10.18632/oncotarget.26493
  • Peer Reviewed / Open Access
• [Journal Article] PPP2R1A regulated by PAX3/FOXO3 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, Ishii M, Kurihara T, Youngji K, Okubo T, Hayashi Y, Takamochi K, Takahashi F, Kaneko K, Ladanyi M, Saito T.
  • Journal Title: Oncotarget Volume: 9 Pages: 25206-25215
  • DOI: 10.18632/oncotarget.25392
  • Peer Reviewed / Open Access
• [Journal Article] A comprehensive clinicopathological analysis of gastric adenocarcinoma with enteroblastic differentiation using next generation sequencing with emphasis on the distinction from socalled hepatoid adenocarcinoma. (2018)
  • Author(s): Akazawa Y, Saito T, Hayashi T, Yanai Y, Tsuyama S, Akaike K,Suehara Y, Takahashi F, Takamochi K, Murakami T, Watanabe S, Yao T.
  • Journal Title: Human Pathology Volume: 78 Pages: 79-88
  • DOI: 10.1016/j.humpath.2018.04.022.
  • Peer Reviewed / Open Access
• [Journal Article] KCTD12 may be 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 M, Taguchi T, Takagi T, Kaneko K, Yao T, Saito T.
  • Journal Title: Oncotarget Volume: 9 Pages: 27016-27026
  • DOI: 10.18632/oncotarget.25469
  • Peer Reviewed / Open Access
• [Journal Article] IRE1α-XBP1 inhibitors exerted anti-tumor activities in Ewing's sarcomas. (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 Pages: 14428-14443
  • DOI: 10.18632/oncotarget.24467.
  • Peer Reviewed / Open Access
• [Presentation] Clinicopathological characteristics of lung adenocarcinoma with EGFR compound mutations. (2019)
  • Author(s): Hayashi T, Kohsaka S, Takamochi K, Takahashi F, Suehara Y, SaitoT, Suzuki K, Mano H, Yao T.
  • Organizer: USCAP, the 2019 Annual Meeting
  • 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
  • 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
  • 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 ASIA
  • 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
  • Int'l Joint Research
• [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,
  • Int'l Joint Research