Analyses of anti-tumor activities regarding pazopanib in soft tissue sarcoma

• Project/Area Number: 17K10987
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: Juntendo University
• Principal Investigator: Kaneko Kazuo 順天堂大学, 医学部, 教授 (50311981)
• Co-Investigator(Kenkyū-buntansha): 末原 義之 順天堂大学, 医学部, 准教授 (70509405) ; 齋藤 剛 順天堂大学, 医学部, 准教授 (80439736)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); 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: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 軟部肉腫 / pazopanib / GLI1 / 12q13 / 著効例 / Pazopanib / 骨軟部腫瘍 / キナーゼ阻害剤 / 遺伝子変異 / リン酸化

Outline of Final Research Achievements

In this study, we performed integrate analyses using tumor/normal samples of a advanced STS that achieved a CR to pazopanib to elucidate molecular pathological background of pazopanib response in STSs. The integrate analyses was consisting of a next-generation sequencer (DNA / RNA sequence) and phosphorylation kinase membrane antibody array. As validation study, we verified identified gene alterations and phosphorylated protein expression using the comparative verification cohorts. As the results, we found both characteristic elevated PDGFRB phosphorylation protein of PDGFRB which is the target of pazopanib and specific gene amplification (12q13-14 locus: GLI1, CDK4) in cases that had highly sensitive response to pazopanib. Furthermore, functional analysis also confirmed that characteristic gene amplifications induced the expression of PDGFRB. Based on subsequent validation studies, it was considered that it would contribute to the development of personalized medicine for STSs.

Academic Significance and Societal Importance of the Research Achievements

本研究は、難治性かつ「希少がん」である高悪性軟部肉腫における生命予後の改善に貢献する新規治療法の開発を目的とした。具体的には我々のグループが、Tyrosine kinase (TK)阻害剤であるpazopanib 著効例の高悪性軟部肉腫手術検体より新規発見したキナーゼ遺伝子変異、及びそれらに一致したリン酸化タンパク質の高発現に注目し、大規模コホートによる変異・発現検証及びin vitro, in vivoの機能解析を行った。それら成果は現在まで未知であった難治性軟部肉腫におけるpazopanibの治療奏効・抵抗因子の解明に寄与し、新規個別化治療法の開発に貢献した。

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] 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: 100288-100288
  • DOI: 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: 100288-100288
  • DOI: 10.1016/j.ehpc.2019.01.007
  • Peer Reviewed / Open Access
• [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] 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] 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] 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
• [Presentation] Integrative analysis including whole genome sequencing, transcriptome sequencing, and phospho-protein expression profiling of super responder to pazopanib in 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, Kaneko K , Kato S, Mano H, Saito T.
  • Organizer: 20th International Symposium on Limb Salvage
  • Int'l Joint Research
• [Presentation] 軟部肉腫pazopanib著効例の12q13-14遺伝子増幅変化. (2019)
  • Author(s): 末原義之, 高阪真路, 山口茂夫, 林大久生, 栗原大聖, 赤池慶祐, 金子和夫, 齋藤 剛, 間野博行, 加藤俊介.
  • Organizer: 第34回日本整形外科学会基礎学術集会
• [Presentation] 軟部肉腫pazopanib著効例の特徴的遺伝子増幅変化. (2019)
  • Author(s): 末原義之, 高阪真路, 山口茂夫, 林大久生, 栗原大聖, 赤池慶祐, 金子和夫, 齋藤 剛, 間野博行, 加藤俊介.
  • Organizer: 第92回日本整形外科学会学術総会
• [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] Anti-tumor activity of tyrosine kinase inhibitors and gene expression profiles in alveolar soft part sarcoma. (2018)
  • Author(s): Suehara Y, Tanabe Y, Mukaihara K, Kurihara K, Akaike K, Hayashi T, Mogushi K, Kaneko K, Saito T.
  • Organizer: the 64th Annual Meeting of the Orthopaedic Research Society March 10-13 2018, New Orleans, USA
  • Int'l Joint Research
• [Presentation] Anti-tumor activity of tyrosine kinase inhibitors in alveolar soft part sarcoma. (2017)
  • Author(s): Suehara Y, Tanabe Y, Akaike K, Mogushi K, Hayashi T, Kurihara T, Kaneko K, Saito T.
  • Organizer: European Society For Medical Oncology ASIA, Nov 17-19th 2017, Singapore, Singapore
  • Int'l Joint Research
• [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, November 8 - 11, 2017 , Hawaii, USA
  • Int'l Joint Research
• [Presentation] Diagnostic strategy for skeletal metastasis of unknown primary origin at the initial visit/ Up-to-date treatment of skeletal metastasis (2017)
  • Author(s): Kim Y, Suehara Y, Kaneko K.
  • Organizer: 27th Korean-Japanese Combined Orthopedic Symposium May 25-26 2017, Incheon, Korea
  • Int'l Joint Research / Invited
• [Presentation] 軟部肉腫Pazopanib著効例における分子病理学的探索 (2017)
  • Author(s): 末原義之、高阪真路、赤池慶祐、加藤俊介、林大久生、山口茂夫、田邊雄、窪田大介、高木辰哉、金子和夫、間野博行、齋藤剛
  • Organizer: 第32回日本整形外科学会基礎学術集会 2017年10月26-27日 沖縄コンベンションセンター 那覇市 沖縄県
  • Invited
• [Presentation] 軟部肉腫Pazopanib著効例 “super-responder”に基づいた分子病理学的探索 (2017)
  • Author(s): 末原義之、高阪真路、赤池慶祐、加藤俊介、林大久生、山口茂夫、田邊雄、窪田大介、高木辰哉、金子和夫、間野博行、齋藤剛
  • Organizer: 第50回日本整形外科学会骨軟部腫瘍学術集会 2017年7月13-14日 京王プラザホテル 新宿 東京