Preclinical antitumor efficacy of MEK inhibitor against neuroblastoma

• Project/Area Number: 17K11517
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatric surgery
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: Higashi Mayumi 京都府立医科大学, 医学(系)研究科(研究院), 助教 (10380453)
• Co-Investigator(Kenkyū-buntansha): 文野 誠久 京都府立医科大学, 医学(系)研究科(研究院), 助教 (40405254) ; 田尻 達郎 京都府立医科大学, 医学(系)研究科(研究院), 教授 (80304806)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); 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: 神経芽腫 / MEK阻害剤 / 小児腫瘍学

Outline of Final Research Achievements

In short-term observation, MEK inhibitors (trametinib or CH5126766) showed significant anti-tumor effects on pERK-positive neuroblastomas in vivo model. Neither MEK inhibitors showed anti tumor effects on pERK-negative neuroblastomas. Tumors obtained tolerance to MEK inhibitors and showed regrowth in long-term administration of drugs. (Takeuchi J Pediatr Surg. 2018 Dec;53(12):2454-2459.).
In the analyses of clinical neuroblastoma cases, some tumors showed pERK positive after chemotherapy or recurrence by immunohistochemistry. This result indicates that immunohistological analysis of pERK is useful for determination of MEK inhibitor administration.

Academic Significance and Societal Importance of the Research Achievements

神経芽腫におけるRas-ERK経路阻害による抗腫瘍効果解析の報告はほとんど無く、新規の治療ターゲットとして期待される。MEK阻害剤は既に成人癌領域にて臨床で使用されており効果が認められているものであり、小児への応用が行いやすい。難治性神経芽腫において、再発症例は既存の治療薬のみでは予後の改善が望めず、新規治療薬が求められる。MEK阻害剤は、腫瘍において優位である特異的なシグナル伝達経路を標的とすることから、従来の治療に抵抗性である腫瘍にも効果を示す可能性がある。本研究の結果から、抗腫瘍効果が期待できる腫瘍の同定が可能であると考えられるが、長期投与時の治療抵抗性の獲得も課題として認められた。

Research Products

• [Journal Article] 【新生児外科疾患の精神・身体発育】仙尾部奇形腫術後の身体発育に関する長期予後 (2019)
  • Author(s): 文野誠久，宗崎良太，田口智章，田尻達郎
  • Journal Title: 小児外科 Volume: 51 Pages: 86-89
• [Journal Article] 小児がんに対する吸収性スペーサー留置を併用した粒子線治療 (2019)
  • Author(s): 佐々木良平，出水祐介，岩田宏満，亀井美智，文野誠久，赤坂浩亮，王 天延，妹尾悟史，犬伏祥子，宮脇大輔，吉田賢史，小松昇平，福本 巧
  • Journal Title: The Japanese Journal of Pediatric Hematology / Oncology Volume: 56 Issue: 2 Pages: 148-152
  • DOI: 10.11412/jspho.56.148
  • NAID: 130007705336
  • ISSN: 2187-011X, 2189-5384
  • Peer Reviewed
• [Journal Article] 低位鎖肛-外来フォローにおける診察の要点 (2019)
  • Author(s): 文野誠久，福永健治，青井重善，田尻達郎
  • Journal Title: 小児外科 Volume: 51 Pages: 688-691
• [Journal Article] 【そこが知りたいシリーズ：手術で必要な局所解剖（頭頸部・胸部編）】前縦隔腫瘍摘出（奇形腫・胸腺腫瘍） (2019)
  • Author(s): 文野誠久，田尻達郎
  • Journal Title: 小児外科 Volume: 51 Pages: 795-798
• [Journal Article] The roles played by the MYCN, Trk, and ALK genes in neuroblastoma and neural development (2019)
  • Author(s): Higashi M, Sakai K, Fumino S, Aoi S, Furukawa T, Tajiri T
  • Journal Title: Surgery Today Volume: 49 Issue: 9 Pages: 721-727
  • DOI: 10.1007/s00595-019-01790-0
  • Peer Reviewed
• [Journal Article] 【陽子線時代の小児がんに対するQOLを重視した放射線治療における工夫】小児がん放射線治療における外科的支持療法としての性腺移動術 (2019)
  • Author(s): 文野誠久
  • Journal Title: 京都府立医科大学雑誌 Volume: 128 Pages: 899-906
• [Journal Article] Mesenchymal hamartoma of the chest wall in a 10-year-old girl mimicking malignancy: a case report (2019)
  • Author(s): Tanaka T, Fumino S, Shirai T, Konishi E, Tajiri T
  • Journal Title: Skeletal Radiol Volume: 48 Issue: 4 Pages: 643-647
  • DOI: 10.1007/s00256-018-3106-2
  • Peer Reviewed
• [Journal Article] Mutations in the RAS pathway as potential precision medicine targets in treatment of rhabdomyosarcoma. (2019)
  • Author(s): Nakagawa N, Kikuchi K, Yagyu S, Miyachi M, Iehara T, Tajiri T, Sakai T, Hosoi H.
  • Journal Title: Biochem Biophys Res Commun Volume: 512 Issue: 3 Pages: 524-530
  • DOI: 10.1016/j.bbrc.2019.03.038
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Japanese Clinical Practice Guidelines for Sacrococcygeal Teratoma, 2017 (2019)
  • Author(s): Fumino S, Tajiri T, Usui N, Tamura M, Sago H, Ono S, Nosaka S, Yoneda A, Souzaki R, Higashi M, Sakai K, Takahashi K, Sugiura T, Taguchi T
  • Journal Title: Pediatrics International Volume: 61 Issue: 7 Pages: 672-678
  • DOI: 10.1111/ped.13844
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy and safety of sirolimus treatment for intractable lymphatic anomalies: A study protocol for an open-label, single-arm, multicenter, prospective study (SILA). (2019)
  • Author(s): Ozeki M, Asada R, Saito AM, Hashimoto H, Fujimura T, Kuroda T, Ueno S, Watanabe S, Nosaka S, Miyasaka M, Umezawa A, Matsuoka K, Maekawa T, Yamada Y, Fujino A, Hirakawa S, Furukawa T, Tajiri T, Kinoshita Y, Souzaki R, Fukao T
  • Journal Title: Regen Ther. Volume: 14 Pages: 84-91
  • DOI: 10.1016/j.reth.2018.12.001
  • Peer Reviewed / Open Access
• [Journal Article] Results of a prospective clinical trial JN-L-10 using image-defined risk factors to inform surgical decisions for children with low-risk neuroblastoma disease: A report from the Japan Children’s Cancer Group Neuroblastoma Committee (2019)
  • Author(s): Iehara T, Yoneda A, Yokota I, Takahashi H, Teramukai S, Kamijyo T, Nakazawa A, Takimoto T, Kikuta A, Yagyu S, Ikeda H, Nakagawara A, Tajiri T
  • Journal Title: Pediatr Blood Cancer Volume: 66 Issue: 11 Pages: 1-7
  • DOI: 10.1002/pbc.27914
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Novel mesenchymal stem cell delivery system as targeted therapy against neuroblastoma using the TH-MYCN mouse model (2019)
  • Author(s): Maniwa J, Fumino S, Kimura K, Tanaka T, Higashi M, Kishida T, Mazda O, Tajiri T
  • Journal Title: Journal of Pediatric Surgery Volume: 54 Issue: 12 Pages: 2600-2605
  • DOI: 10.1016/j.jpedsurg.2019.08.023
  • Peer Reviewed
• [Journal Article] An intra-amniotic injection of mesenchymal stem cells promotes lung maturity in a rat congenital diaphragmatic hernia model (2019)
  • Author(s): Takayama S, Sakai K, Fumino S, Furukawa T, Kishida T, Mazda O, Tajiri T
  • Journal Title: Pediatric Surgery International Volume: 35 Issue: 12 Pages: 1353-1361
  • DOI: 10.1007/s00383-019-04561-7
  • Peer Reviewed
• [Journal Article] Enhanced metastatic growth after local tumor resection in the presence of synchronous metastasis in a mouse allograft model of neuroblastoma (2019)
  • Author(s): Inoue M, Tsuchiya Y, Koike N, Umemura Y, Inokawa H, Togashi Y, Maniwa J, Higashi M, Fumino S, Tajiri T, Yagita K
  • Journal Title: Pediatric Surgery International Volume: 35 Issue: 12 Pages: 1403-1411
  • DOI: 10.1007/s00383-019-04568-0
  • Peer Reviewed / Open Access
• [Journal Article] Derivation of neural stem cells from human teratomas (2019)
  • Author(s): Kim K, Higashi M, Fumino S, Tajiri T
  • Journal Title: Stem Cell Research Volume: 41 Pages: 101633-101633
  • DOI: 10.1016/j.scr.2019.101633
  • Peer Reviewed / Open Access
• [Journal Article] Immunologic Effects of Sirolimus in Patients With Vascular Anomalies. (2019)
  • Author(s): Nozawa Akifumi、Ozeki Michio、Yasue Shiho、Endo Saori、Kawamoto Norio、Ohnishi Hidenori、Fumino Shigehisa、Furukawa Taizo、Tajiri Tatsuro、Maekawa Takanobu、Fujino Akihiro、Souzaki Ryota、Fukao Toshiyuki
  • Journal Title: Journal of Pediatric Hematology/Oncology Volume: e-pub Issue: 5 Pages: 1-1
  • DOI: 10.1097/mph.0000000000001650
  • Peer Reviewed / Open Access
• [Journal Article] Sequential actions of immune effector cells induced by viral activation of dendritic cells to eliminate murine neuroblastoma. (2018)
  • Author(s): Kawakubo N, Tanaka S, Kinoshita Y, Tajiri T, Yonemitsu Y, Taguchi T
  • Journal Title: J Pediatr Surg Case Rep Volume: 53 Issue: 8 Pages: 1615-1620
  • DOI: 10.1016/j.jpedsurg.2017.08.019
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Results of a phase II trial for high-risk neuroblastoma treatment protocol JN-H-07: a report from the Japan Childhood Cancer Group Neuroblastoma Committee (JNBSG) (2018)
  • Author(s): Hishiki T、For the Japan Childhood Cancer Group Neuroblastoma Committee (JNBSG)、Matsumoto K、Ohira M、Kamijo T、Shichino H、Kuroda T、Yoneda A、Soejima T、Nakazawa A、Takimoto T、Yokota I、Teramukai S、Takahashi H、Fukushima T、Kaneko T、Hara J、Kaneko M、Ikeda H、Tajiri T、Nakagawara A
  • Journal Title: International Journal of Clinical Oncology Volume: 23 Issue: 5 Pages: 965-973
  • DOI: 10.1007/s10147-018-1281-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Natural antibody against neuroblastoma of TH-MYCN transgenic mice does not correlate with spontaneous regression. (2018)
  • Author(s): Kawakubo N, Harada Y, Ishii M, Souzaki R, Kinoshita Y, Tajiri T, Taguchi T, Yonemitsu Y
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 503 Issue: 3 Pages: 1666-1673
  • DOI: 10.1016/j.bbrc.2018.07.097
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] In vivo effects of short-and long-term MAPK pathway inhibition against neuroblastoma. (2018)
  • Author(s): Takeuchi T, Tanaka T, Higashi M, Fumino S, Iehara T, Hosoi H, Sakai T, Tajiri T
  • Journal Title: J Pediatr Surg Volume: 53 Issue: 12 Pages: 2454-2459
  • DOI: 10.1016/j.jpedsurg.2018.08.026
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Advanced surgical strategy for giant mediastinal germ cell tumor in children. (2017)
  • Author(s): Fumino S, Sakai K, Higashi M, Aoi S, Furukawa T, Yamagishi M, Inoue M, Iehara T, Hosoi H, Tajiri T
  • Journal Title: J Pediatr Surg Case Rep Volume: 27 Pages: 51-55
  • DOI: 10.1016/j.epsc.2017.09.023
  • Peer Reviewed / Open Access
• [Journal Article] Laparoscopic intraperitoneal onlay mesh for pediatric incisional hernia - a case report. (2017)
  • Author(s): Inoue M, Aoi S, Taniguchi A, Sakai K, Higashi M, Fumino S, Furukawa T, Tajiri T
  • Journal Title: Surg Case Rep Volume: 3 Issue: 1 Pages: 122-122
  • DOI: 10.1186/s40792-017-0400-5
  • Peer Reviewed / Open Access
• [Presentation] Novel mesenchymal stem cell delivery system as targeted therapy against neuroblastoma using the TH-MYCN mouse model (2019)
  • Author(s): Maniwa J, Fumino S, Kimura K, Tanaka T, Higashi M, Kishida T, Mazda O, Tajiri T
  • Organizer: 52nd Pacific Association of Pediatric Surgeons (PAPS)
  • Int'l Joint Research
• [Presentation] Regeneration of mouse abdominal wall defects using engineered myoblasts with a biosheet (2019)
  • Author(s): Fumino S, Wakao J, Maniwa J, Sakai K, Higashi M, Aoi S, Furukawa T, Kishida T, Mazda O, Tajiri T
  • Organizer: 32nd International Symposium on Paediatric Surgical Research (ISPSR)
  • Int'l Joint Research
• [Presentation] Development of fetal cell therapy using the intra-amniotic injection of mesenchymal stem cells in rat nitrofen model of congenital diaphragmatic hernia (2019)
  • Author(s): Takayama S, Furukawa T, Sakai K, Higashi M, Fumino S, Aoi S, Kishida T, Mazda O, Tajiri T
  • Organizer: 32nd International Symposium on Paediatric Surgical Research (ISPSR)
  • Int'l Joint Research
• [Presentation] Enhanced metastatic growth after local tumor resection under residual metastasis in a neuroblastoma murine model (2019)
  • Author(s): Inoue M, Tsuchiya Y, Koike N, Umemura Y, Inokawa H, Togashi Y, Maniwa J, Higashi M, Fumino S, Yagita K & Tajiri T
  • Organizer: 32nd International Symposium on Paediatric Surgical Research (ISPSR)
  • Int'l Joint Research
• [Presentation] Post-chemotherapeutic phosphorylated-ERK immunohistochemical staining may predict the prognosis of neuroblastoma (2019)
  • Author(s): Tanaka T, Takeuchi Y, Higashi M, Fumino S, Iehara T, Hosoi H, Sakai T, Tajiri T
  • Organizer: 32nd International Symposium on Paediatric Surgical Research (ISPSR)
  • Int'l Joint Research
• [Presentation] Current Surgical Strategy of Neuroblastoma (2019)
  • Author(s): Tajiri T
  • Organizer: 32nd International Symposium on Paediatric Surgical Research (ISPSR)
  • Int'l Joint Research / Invited
• [Presentation] Regeneration of mouse abdominal wall defects using engineered myoblasts with a biosheet; a preliminary report (2019)
  • Author(s): Fumino H, Wakao J, aniwaJ, Sakai K, Higashi M, Aoi S, Furukawa F, Kishida T, Mazda O, Tajiri T
  • Organizer: 第119回日本外科学会定期学術集会
• [Presentation] 外科的oncologic emergencyにおける小児外科医の役割 (2019)
  • Author(s): 文野誠久，坂井宏平，東 真弓，青井重善，古川泰三，青井重善，家原知子，細井 創，田尻達郎
  • Organizer: 第56回日本小児外科学会学術集会
• [Presentation] AYA世代がん患者に対する外科的支持療法 (2019)
  • Author(s): 文野誠久，古川泰三，宮地 充，家原知子，細井 創，沖村浩之，森 泰輔，北脇 城，佐々木良平，田尻達郎
  • Organizer: 第57回日本癌治療学会学術集会
• [Presentation] 神経芽腫発症モデルマウスにおける悪性度に寄与する分子メカニズム解明にむけた研究 (2019)
  • Author(s): 井上真帆，土谷佳樹，池田亮介，小野龍太郎，笹脇ゆふ，坂井宏平，東 真弓，文野誠久，青井重善，古川泰三，梅村康浩，小池宣也，井之川仁，田尻達郎，八木田和弘
  • Organizer: 第14回環境生理プレコングレス
• [Presentation] 先天性横隔膜ヘルニアに対する間葉系幹細胞羊水腔投与による胎児治療開発 (2019)
  • Author(s): 高山勝平，坂井宏平，東 真弓，文野誠久，青井重善，古川泰三，岸田綱郎，松田 修，田尻達郎
  • Organizer: 第56回日本小児外科学会学術集会
• [Presentation] 神経芽腫治療における同種間葉系幹細胞による腫瘍選択的ドラッグデリバリーシステム (2019)
  • Author(s): 馬庭淳之介，木村幸積，文野誠久，東 真弓，坂井宏平，青井重善，古川泰三，岸田綱郎，松田 修，田尻達郎
  • Organizer: 第56回日本小児外科学会学術集会
• [Presentation] ラット胎仔横隔膜ヘルニアモデルにおける間葉系幹細胞子宮内投与による治療効果 (2019)
  • Author(s): 高山勝平，文野誠久，古川泰三，田尻達郎
  • Organizer: 第55回日本周産期・新生児医学会学術集会
• [Presentation] 神経芽腫マウスにおける神経芽腫選択的な新規間葉系幹細胞デリバリーシステム (2019)
  • Author(s): Maniwa J, Fimino S, Kimura K, Tanaka T, Higashi M, Sakai K, Aoi S, Furukawa T, Kishida T, Mazda O, Tajiri T
  • Organizer: 第57回日本癌治療学会学術集会
• [Presentation] 小児腫瘍性疾患に対するナビゲーション手術の経験 (2019)
  • Author(s): 文野誠久，古川泰三，青井重善，東 真弓，坂井宏平，田中智子，田尻達郎
  • Organizer: 第61回日本小児血液・がん学会学術集会
• [Presentation] 神経芽腫再発・転移（RM）マウスモデルを用いた MEK 阻害剤の治療効果の検討 (2019)
  • Author(s): Togashi Y, Takemoto M, Takeuchi Y, Tanaka T, Higashi M, Fumino S, Tajiri T
  • Organizer: 第61回日本小児血液・がん学会学術集会
• [Presentation] 神経芽腫転移マウスモデルにおける原発巣局所切除による残存遠隔転移巣への影響についての検討 (2019)
  • Author(s): 井上真帆，土谷佳樹，小池宣也，梅村康浩，井之川仁，富樫佑一，馬庭淳之介，文野誠久，東 真弓，田尻達郎，八木田和弘
  • Organizer: 第61回日本小児血液・がん学会学術集会
• [Presentation] 神経芽腫に対するMEK阻害剤臨床応用へ向けた臨床検体のリン酸化ERK免疫染色解析． (2018)
  • Author(s): 竹内雄毅，田中智子，東 真弓，文野誠久，家原知子，細井 創，酒井敏行，田尻達郎
  • Organizer: 第51回制癌剤適応研究会
• [Presentation] 臨床応用に向けた神経芽腫 xenograft に対する MEK 阻害剤前臨床試験． (2018)
  • Author(s): 竹内雄毅，田中智子，東 真弓，文野誠久，家原知子，細井 創，酒井敏行，田尻達郎
  • Organizer: 第55回日本小児外科学会学術集会
• [Presentation] MEK阻害剤感受性神経芽腫を予測するリン酸化ERK免疫組織化学の臨床応用へ向けた検討． (2018)
  • Author(s): 竹内雄毅，田中智子，東 真弓，文野誠久，家原知子，細井 創，酒井敏行，田尻達郎
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] MEK阻害剤の至適投与時期検討を目的とした神経芽腫MRDモデルの確立． (2018)
  • Author(s): Togashi Y, Takeuchi Y, Higashi M, Fumino S, Tajiri T
  • Organizer: 第60回日本小児血液・がん学会学術集会
• [Presentation] 神経芽腫モデルマウスに対するマウス由来間葉系幹細胞を用いたdrug delivery systemの開発． (2018)
  • Author(s): Maniwa J, Kimura K, Fumino S, Tanaka T, Higashi M, Sakai K, Aoi S, Furukawa T, Kishida T, Mazda O, Tajiri T
  • Organizer: 第60回日本小児血液・がん学会学術集会
• [Presentation] Advanced Surgical Strategy for Giant Mediastinal Germ Cell Tumor in Children. (2017)
  • Author(s): Fumino S, Sakai K, Higashi M, Aoi S, Furukawa T, Yamagishi M, Inoue M, Iehara T, Hosoi H, Tajiri T
  • Organizer: 50th Annual Meeting of the Pacific Association of Pediatric Surgeons
  • Int'l Joint Research
• [Presentation] The Direct Conversion of Human Fibroblasts Toward the Myogenic Cell Lineage: The implications of Diaphragmatic Regeneration. (2017)
  • Author(s): Wakao J，Kishida T，Fumino S，Kimura K，Higashi M，Aoi S，Furukawa T，Mazda O，Tajiri T
  • Organizer: 50th Annual Meeting of the Pacific Association of Pediatric Surgeons
  • Int'l Joint Research
• [Presentation] Immunohistochemical analysis of pre- and post-chemotherapeutic ERK phosphorylation in clinical neuroblastoma samples. (2017)
  • Author(s): Tanaka T,Takeuchi Y，Higashi M，Fumino S，Iehara T，Hosoi H，Sakai T，Tajiri T.
  • Organizer: 3rd Asia-Pacific International Symposium of Neuroblastoma,
  • Int'l Joint Research
• [Presentation] Preclinical study of novel MEK inhibitors on neuroblastoma and the biomarker for their therapeutic effects in neuroblastoma xenograft mice. (2017)
  • Author(s): Takeuchi Y, Tanaka T, Higashi M, Fumino S, Iehara T, Hosoi H, Sakai T, Tajiri T.
  • Organizer: 3rd Asia-Pacific International Symposium of Neuroblastoma
  • Int'l Joint Research
• [Presentation] Current surgical intervention for pediatric giant mediastinal germ cell tumors. (2017)
  • Author(s): Fumino S, Sakai K, Higashi M, Aoi S, Furukawa T, Yamagishi M, Inoue M, Iehara T, Hosoi H, Tajiri T
  • Organizer: 49th Congress of the International Society of Paediatric Oncology (SIOP)
  • Int'l Joint Research
• [Book] 標準小児外科学 第7版 第22章小児腫瘍 B神経芽腫 (2017)
  • Author(s): 髙松 英夫 田尻達郎
  • Total Pages: 432
  • Publisher: 医学書院
  • ISBN: 9784260027809
• [Book] 標準小児外科学 第7版 G悪性リンパ腫 (2017)
  • Author(s): 髙松 英夫 田尻達郎
  • Total Pages: 432
  • Publisher: 医学書院
  • ISBN: 9784260027809
• [Book] 標準小児外科学 第7版 Iその他の良性腫瘍 (2017)
  • Author(s): 髙松 英夫 田尻達郎
  • Total Pages: 432
  • Publisher: 医学書院
  • ISBN: 9784260027809
• [Book] スタンダード小児がん手術 : 臓器別アプローチと手技のポイント (2017)
  • Author(s): 田口 智章、黒田 達夫 田尻達郎
  • Total Pages: 313
  • Publisher: メジカルビュー社
  • ISBN: 9784758304658
• [Book] Ⅷ．血液，腫瘍 固形腫瘍（神経芽腫） (2017)
  • Author(s): 山岸 敬幸 田尻達郎
  • Total Pages: 407
  • Publisher: 診断と治療社