Molecular mechanism of resistance to tyrosine kinase receptor in soft tissue sarcoma

• Project/Area Number: 17K08730
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Human pathology
• Research Institution: Juntendo University
• Principal Investigator: Saito Tsuyoshi 順天堂大学, 医学部, 准教授 (80439736)
• Co-Investigator(Kenkyū-buntansha): 末原 義之 順天堂大学, 医学部, 客員教授 (70509405)
• Project Period (FY): 2017-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: sarcoma / fusion gene / molecular target therapy / 肉腫 / 分子標的 / チロシンキナーゼ受容体 / 遺伝子増幅 / 治療抵抗性 / 遺伝子欠失 / 治療 / Nanostring / 骨軟部肉腫 / tyrosine kinase阻害剤 / 遺伝子異常 / 分子標的治療 / 軟部肉腫 / 阻害剤 / チロシンキナーゼ阻害剤

Outline of Final Research Achievements

We found a leiomyosarcoma of soft tissue with ROS1 fusion and a leiomyosarcoma of bone with NTRK3 fusion by the combination of immunohistochemistry and imbalanced gene expression assay using RNA.
Gene expression profiles were compared between sarcoma samples treated by multi-kinase inhibitor, pazopanib. Pazopanib targets including PDGFRA, PDGFRB, vascular endothelial growth factor receptor (VEGFR)1-3, and stem cell factor receptor (KIT). The mRNA expression of GLI1 and CDK4 was significantly higher in patient's sarcoma sample showing complete response (CR) to pazopanib. Furthermore, the amplification of receptor tyrosine kinase genes such as PDGFRA and VEGFRs was not observed in a patient with CR and the presence of amplification of these genes was closely associated with poor response.

Academic Significance and Societal Importance of the Research Achievements

骨軟部肉腫ではこれまでに融合遺伝子腫瘍が存在することはわかっていたが、肺腺癌のような直接の分子治療標的となるようなものはなく、それゆえこれまで治療に難渋していたが、今回の研究成果により骨軟部肉腫においても有効な治療標的となりうる新規の融合遺伝子が発見され、今後も探索の方法を工夫することにより、これまで思っていた以上の頻度で肉腫においても同様の遺伝子異常が発見される可能性があるという意味で大きな成果である。また、これらの治療には治療抵抗性・耐性の問題が切り離せないが、それらに影響を与える遺伝子異常を見つけられたことで、臨床的な治療戦略にも貢献すると考えらえる。

Research Products

• [Int'l Joint Research] MSKCC(米国)
• [Journal Article] Identification of a Novel MAN1A1-ROS1 Fusion Gene Through mRNA-based Screening for Tyrosine Kinase Gene Aberrations in a Patient with Leiomyosarcoma (2020)
  • Author(s): Suehara Y, Kohsaka S, Hayashi T, Akaike K, Kurisaki-Arakawa A, Sato S, Kobayashi E, Mizuno S, Ueno T, Morii T, Okuma T, Kurihara T, Hasegawa N, Sano K, Sasa K, Okubo T, Kim Y, Mano H, Saito T
  • Journal Title: Clin Orthop Relat Res Volume: － Issue: 4 Pages: 838-852
  • DOI: 10.1097/corr.0000000000001548
  • Peer Reviewed / Open Access
• [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] A Case of Pediatric Soft Tissue Sarcoma with LMNA-NTRK1 Gene Fusion Treated with Larotrectinib under Single Patient Expanded Access System (2019)
  • Author(s): Kato S, Fujimura J, Nozaki Y, Yamaguchi S, Takagi T, Hayashi T, Saito T, Henry D, Ku N, Suehara Y.
  • Journal Title: Gan To Kagaku Ryoho Volume: 46 Pages: 1595-1597
  • Peer Reviewed
• [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] Comprehensive assay for the molecular profiling of cancer by target enrichment from formalin‐fixed paraffin‐embedded specimens (2019)
  • Author(s): Kohsaka Shinji、Tatsuno Kenji、Ueno Toshihide、et al.
  • Journal Title: Cancer Science Volume: 110 Issue: 4 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, Hamanoue H, Yamanaka S, Ichikawa Y, Higurashi T, Ohashi K, Yamaguchi S, Nozaki Y, Terao Y, Saito T.
  • Journal Title: Jpn J Clin Oncol Volume: 49(2) Issue: 2 Pages: 174-182
  • DOI: 10.1093/jjco/hyy173
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] 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] 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] 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
• [Journal Article] Pediatric soft tissue tumor of the upper arm with LMNA-NTRK1 fusion (2018)
  • Author(s): Kohsaka Shinji、Saito Tsuyoshi、Akaike Keisuke、Suehara Yoshiyuki、Hayashi Takuo、Takagi Tatsuya、Kaneko Kazuo、Ueno Toshihide、Kojima Shinya、Kohashi Ken-ichi、Mano Hiroyuki、Oda Yoshinao、Yao Takashi
  • Journal Title: Human Pathology Volume: 72 Pages: 167-173
  • DOI: 10.1016/j.humpath.2017.08.017
  • Peer Reviewed / Open Access
• [Journal Article] Cabozantinib and dastinib exert anti-tumor activity in alveolar soft part sarcoma (2017)
  • 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.
  • Journal Title: PLoS One Volume: 12(9) Issue: 9 Pages: 0185321-0185321
  • DOI: 10.1371/journal.pone.0185321
  • Peer Reviewed / Open Access