Development of novel anti-leukemic therapy targeting clathrin-dependent endocytosis

• Project/Area Number: 15K09461
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Kindai University
• Principal Investigator: MATSUMURA Itaru 近畿大学, 医学部, 教授 (00294083)
• Co-Investigator(Kenkyū-buntansha): 平瀬 主税 近畿大学, 医学部, 講師 (30548590) ; 田中 宏和 近畿大学, 医学部, 講師 (40360846) ; 森田 泰慶 近畿大学, 医学部, 講師 (80411594)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 白血病 / 阻害薬 / 分子標的

Outline of Final Research Achievements

We here show that pharmacologic inhibition of clathrin-dependent trafficking of mutated receptor tyrosine kinases (mtRTK such as FLT3-ITS and KIT D814V mutation) with chlorpromazine (CPZ) disrupts their cellular localization and inhibits their activities. CPZ suppressed the growth of primary AML cells with mtRTK, including CD34+38- AML stem cells in vitro. In mice transplanted with primary AML cells, administration of CPZ at a clinically relevant concentration inhibited the growth of AML cells with mtRTK while it showed a marginal effect on the growth of AML cells with wild-type RTK. Also, CPZ treatment eliminated AML stem cells at the periosteal region in the bone marrow of the recipient mice. These results demonstrate that the intracellular trafficking of mtRTKs would be a good therapeutic target and CPZ would be new therapeutic agent against AML with mtRTK.

Research Products

• [Journal Article] Management of cardiovascular complications in CML patients treated with tyrosine kinase inhibitors (2018)
  • Author(s): 松村 到
  • Journal Title: Rinsho Ketsueki Volume: 59 Issue: 1 Pages: 13-26
  • DOI: 10.11406/rinketsu.59.13
  • NAID: 130006337957
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed / Open Access
• [Journal Article] Gastric microbiota: An emerging player in Helicobacter pylori -induced gastric malignancies (2018)
  • Author(s): Espinoza JL, Matsumoto A, Tanaka H, Matsumura I.
  • Journal Title: Cancer Lett. Volume: 414 Pages: 147-152
  • DOI: 10.1016/j.canlet.2017.11.009
  • Peer Reviewed / Open Access
• [Journal Article] Deeper molecular response is a predictive factor for treatment-free remission after imatinib discontinuation in patients with chronic phase chronic myeloid leukemia: the JALSG-STIM213 study (2017)
  • Author(s): Takahashi Naoto、Miyata Yasuhiko、Kobayashi Shinichi、Usuki Kensuke、Matsumura Itaru、Minami Yosuke、Usui Noriko、Fukuda Tetsuya、Kobayashi Yukio、Kiyoi Hitoshi、et al.
  • Journal Title: Int J Hematol Volume: 107 Issue: 2 Pages: 185-193
  • DOI: 10.1007/s12185-017-2334-x
  • Peer Reviewed / Open Access
• [Journal Article] Ponatinib in Japanese patients with Philadelphia chromosome-positive leukemia, a phase 1/2 study (2017)
  • Author(s): Tojo A, Kyo T, Yamamoto K, Nakamae H, Takahashi N, Kobayashi Y, Tauchi T, Okamoto S, Miyamura K, Hatake K, Iwasaki H, Matsumura I, Usui N, Naoe T, Tugnait M, Narasimhan NI, Lustgarten S, Farin H, Haluska F, Ohyashiki K.
  • Journal Title: Int J Hematol. Volume: 106 Issue: 3 Pages: 385-397
  • DOI: 10.1007/s12185-017-2238-9
  • Peer Reviewed / Open Access
• [Journal Article] Elevated plasma levels of procoagulant microparticles are a novel risk factor for thrombosis in patients with myeloproliferative neoplasms (2017)
  • Author(s): Taniguchi Yasuhiro、Tanaka Hirokazu、Luis Espinoza J.、Sakai Kazuko、Kumode Takahiro、Sano Keigo、Serizawa Kentarou、Rai Shinya、Morita Yasuyoshi、Hanamoto Hitoshi、Tsubaki Kazuo、Nishio Kazuto、Matsumura Itaru
  • Journal Title: Int J Hematol. Volume: 106 Issue: 5 Pages: 691-703
  • DOI: 10.1007/s12185-017-2302-5
  • Peer Reviewed / Open Access
• [Journal Article] Nilotinib vs. imatinib in Japanese patients with newly diagnosed chronic myeloid leukemia in chronic phase: long-term follow-up of the Japanese subgroup of the randomized ENESTnd trial (2017)
  • Author(s): Nakamae H, Fukuda T, Nakaseko C, Kanda Y, Ohmine K, Ono T, Matsumura I,Matsuda A, Aoki M, Ito K, Shibayama H.
  • Journal Title: Int J Hematol. Volume: 107 Issue: 3 Pages: 327-336
  • DOI: 10.1007/s12185-017-2353-7
  • Peer Reviewed / Open Access
• [Journal Article] Langerhans Cell Histiocytosis and Langerhans Cell Sarcoma: Current Understanding and Differential Diagnosis. (2016)
  • Author(s): Nakamine H, Yamakawa M, Yoshino T, Fukumoto T, Enomoto Y, Matsumura I.
  • Journal Title: J Clin Exp Hematop. Volume: 56 Pages: 109-118
  • NAID: 130005433864
  • Peer Reviewed / Open Access
• [Journal Article] Switching to nilotinib in patients with chronic myeloid leukemia in chronic phase with molecular suboptimal response to frontline imatinib: SENSOR final results and BIM polymorphism substudy (2016)
  • Author(s): Miyamura K, Miyamoto T, Tanimoto M, Yamamoto K, Kimura S, Kawaguchi T, Matsumura I, Hata T, Tsurumi H, Saito S, Hino M, Tadokoro S, Meguro K, Hyodo H, Yamamoto M, Kubo K, Tsukada J, Kondo M, Aoki M, Okada H, Yanada M, Ohyashiki K, Taniwaki M
  • Journal Title: Leuk Res Volume: 51 Pages: 11-18
  • DOI: 10.1016/j.leukres.2016.09.009
  • Peer Reviewed / Open Access
• [Journal Article] Interim analysis of post-marketing surveillance of eculizumab for paroxysmal nocturnal hemoglobinuria in Japan. (2016)
  • Author(s): Ninomiya H, Obara N, Chiba S, Usuki K, Nishiwaki K, Matsumura I, Shichishima T, Okamoto S, Nishimura JI, Ohyashiki K, Nakao S, Ando K, Kanda Y, Kawaguchi T, Nakakuma H, Harada D, Akiyama H, Kinoshita T, Ozawa K, Omine M, Kanakura Y.
  • Journal Title: Int J Hematol. Volume: 104 Pages: 548-558
  • Peer Reviewed / Open Access
• [Journal Article] Second primary malignancies among patients with myeloma-related-diseases in the KMF database (2016)
  • Author(s): Kosugi S, Shibayama H, Nakatani E, Kida T, Ohta K, Kaneko H, Yagi H, Tanaka H, Fuchida S, Nakaya A, Kobayashi M, Kuroda J, Kamitsuji Y, Uoshima N, Adachi Y, Tsudo M, Shimazaki C, Nomura S, Hino M, Matsumura I, Taniwaki M, Kanakura Y, Takaori-Kondo A.
  • Journal Title: Rinsho Ketsueki Volume: 57 Issue: 7 Pages: 839-847
  • DOI: 10.11406/rinketsu.57.839
  • NAID: 130005254870
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed / Open Access
• [Journal Article] Validation of a rapid one-step high sensitivity real-time quantitative PCR system for detecting major BCR-ABL1 mRNA on an International Scale. (2016)
  • Author(s): Yoshida C, Nakamae H, Fletcher L, Koga D, Sogabe T, Matsumura I, Kanakura Y, Branford S, Naoe T.
  • Journal Title: Springerplus. Volume: 5 Issue: 1 Pages: 569-569
  • DOI: 10.1186/s40064-016-2258-6
  • Peer Reviewed / Open Access
• [Journal Article] Lenalidomide and low-dose dexamethasone in Japanese patients with newly diagnosed multiple myeloma:A phase II study． (2016)
  • Author(s): Suzuki K，Shinagawa A，Uchida T，taniwaki M，Hirata H，Ishizawa K，Matsue K，Ogawa Y，Shimizu T，Otsuka M，Matsumoto M，Iida S，Terui Y，Matsumura I，Ikeda T，Takezako N，Ogaki Y，Midorikawa S，Houck V，Ervin-Haynes A，Chou T
  • Journal Title: Cancer Sci． Volume: 107 Issue: 5 Pages: 653-658
  • DOI: 10.1111/cas.12916
  • Peer Reviewed / Open Access
• [Journal Article] Cryoglobulinaemia (IgG-κ-type and IgM-γ-type) with Occluding Leukocytoclastic Vasculitis in a Patient with Vitiligo and Demyelinating Polyneuropathy. (2016)
  • Author(s): Sato M, Oiso N, Shiga T, Morita R, Kimura M, Funauchi M, Matsumura I, Kawada A.
  • Journal Title: Acta Derm Venereol. Volume: 107 Pages: 653-658
  • Peer Reviewed / Open Access
• [Journal Article] Estimation of the symptoms for GERD by GerdQ in the patients with rheumatic diseases. (2016)
  • Author(s): Nozaki Y, Kinoshita K, Ri J, Sakai K, Shiga T, Hino S, Hirooka Y, Sugiyama M, Funauchi M, Matsumura I.
  • Journal Title: Mod Rheumatol. Volume: 26 Issue: 2 Pages: 265-270
  • DOI: 10.3109/14397595.2015.1077556
  • Peer Reviewed / Open Access
• [Journal Article] ESAM is a novel human hematopoietic stem cell marker associated with a subset of human leukemias. (2016)
  • Author(s): Ishibashi T, Yokota T, Tanaka H, Ichii M, Sudo T, Satoh Y, Doi Y, Ueda T, Tanimura A, Hamanaka Y, Ezoe S, Shibayama H, Oritani K, Kanakura Y.
  • Journal Title: Experimental Hematology Volume: 44 Issue: 4 Pages: 269-281
  • DOI: 10.1016/j.exphem.2015.12.010
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Two consecutive pregnancies in a patient with paroxysmal nocturnal haemoglobinuria treated with anticoagulant therapy at different doses. (2016)
  • Author(s): Sasano T, Matsumura I, Kimura T ,et al.
  • Journal Title: Blood Coagul Fibrinolysis. Volume: 27 Issue: 1 Pages: 109-112
  • DOI: 10.1097/mbc.0000000000000386
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mice doubly-deficient in the Arf GAPs SMAP1 and SMAP2 exhibit embryonic lethality (2015)
  • Author(s): Sumiyoshi M, Rai S, Tanaka H, Matsumura I, et al.
  • Journal Title: FEBS Lett. Volume: 589 Issue: 19PartB Pages: 2754-2762
  • DOI: 10.1016/j.febslet.2015.07.050
  • Peer Reviewed / Open Access
• [Journal Article] A new diagnostic kit, ODK-1201, for the quantitation of low major BCR-ABL mRNA level in chronic myeloid leukemia: correlation of quantitation with major BCR-ABL mRNA kits. (2015)
  • Author(s): Nakamae H, Matsumura I, Naoe T,et al.
  • Journal Title: Int J Hematol. Volume: 102 Issue: 3 Pages: 301-311
  • DOI: 10.1007/s12185-015-1826-9
  • Peer Reviewed / Open Access
• [Journal Article] HIV-negative Primary Bone Marrow Hodgkin Lymphoma Manifesting with a High Fever Associated with Hemophagocytosis as the Initial Symptom: A Case Report and Review of the Previous Literature (2015)
  • Author(s): Morita Y, Matsumura I,et al.
  • Journal Title: Internal Medicine Volume: 54 Issue: 11 Pages: 1393-1396
  • DOI: 10.2169/internalmedicine.54.3770
  • NAID: 130005072946
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed / Open Access
• [Journal Article] Mosaicism of an ELANE mutation in an asymptomatic mother in a familial case of cyclic neutropenia. (2015)
  • Author(s): Hirata O, Okada S, Ttsumura M, Karakawa S, Matsumura I, Kimura Y, Mihara T, Yasunaga S, Takihara Y, Ohara O, Kobayashi M
  • Journal Title: Journal of Clinical Immunology Volume: 2015 Issue: 5 Pages: 1-5
  • DOI: 10.1007/s10875-015-0165-1
  • Peer Reviewed / Open Access
• [Journal Article] The preventative effects of recombinant thrombomodulin on transplantation- associated coagulopathy after allogeneic hematopoietic stem cell transplantation (2014)
  • Author(s): Nomura S, Ishii K, Maeda Y, Katayama Y, Yagi H, Fujishima N, Ota S, Seki M, Okada M, Ikezoe T, Hayashi K, Fujita S, Satake A, Ito T, Kyo T, Ishida Y, Chiba S, Ogawa H, Tanimoto M, Sawada K
  • Journal Title: Journal of Stem Cell Research & Therapy Volume: 4 Issue: 1 Pages: 247-247
  • DOI: 10.1007/s12185-014-1696-6
  • Peer Reviewed / Open Access
• [Presentation] In vitro safety and efficacy of S888711, a novel thrombopoietin receptor agonist, in Myelodysplastic syndrome (2018)
  • Author(s): Keigo Sano, Hirokazu Tanaka, Itaru Matsumura
  • Organizer: 第1回国際がん研究シンポジウム
• [Presentation] アザシチジンをつなぎ治療として非血縁造血幹細胞移植を行い、2回目の再発時にアザシチジン併用ドナーリンパ球輸注を行い良好な経過を辿ったモノソミー７を有する骨髄異形成症候群 (2017)
  • Author(s): 小森舞子、井上宏昭、角谷宏明、大山泰世、森田泰慶、芦田隆司、松村到
  • Organizer: 第39回 日本造血細胞移植学会総会
  • Place of Presentation: 島根 くにびきメッセ
  • Year and Date: 2017-03-02
• [Presentation] FLU+MELは強度減弱移植前処置として適切でない ～D-indexを用いた解析～ (2017)
  • Author(s): 芦田隆司、齋藤花往里、藤本昂、末田早苗、角谷宏明、大山泰世、井上宏昭、谷口康博、賴晋也、森田泰慶、岩本ちづる、中野勝彦、福島靖幸、川野亜美、山田枝里佳、井出大輔、前田岳宏、椿本祐子、金光靖、松村到
  • Organizer: 第39回 日本造血細胞移植学会総会
  • Place of Presentation: 島根 くにびきメッセ
  • Year and Date: 2017-03-02
• [Presentation] Identification of a patients-derived cd34+ myeloma cell population with tumor-propagating capacity and resistance to anticancer drugs (2017)
  • Author(s): Kentaro Serizawa, Hirokazu Tanaka, Ayano Fukui, Ryosuke Fujiwara, Keigo Sano, Hiroaki Inoue, Takahiro Kumode, Yasuhiro Taniguchi, Yasuyoshi Morita, Luis Espinoza, Itaru Matsumura
  • Organizer: 59th ASH Annual Meeting and Exposition
  • Int'l Joint Research
• [Presentation] C-type lectin-like peceptor 2 specifies a finctionally distinct subpopulation of megakaryocyte-biased long-term hematopoietic stem cells. (2017)
  • Author(s): Takahiro Kumode, Hirokazu Tanaka, Ryosuke Fujiwara, Keigo Sano, Kentaro Serizawa, Yasuhiro Taniguchi, Sinya Rai, Itaru Matsumura
  • Organizer: 22th 欧州血液学会(EHA)
  • Int'l Joint Research
• [Presentation] A 5-day regimen of azacitidine for untreated patients with low-risk MDS: A prospective phase 2 trial (2017)
  • Author(s): 森田 泰慶、前田 裕弘、山口 晃史、浦瀬 文明、川田 修平、花本 仁、椿 和央、石川 淳、柴山 浩彦、松村 到、松田 光弘
  • Organizer: 第79回日本血液学会学術集会
• [Presentation] Successful treatment of Hodgkin lymphoma variant of Richter syndrome with Bendamustine -Rituximab (2017)
  • Author(s): 藤本 昂、頼 晋也 、齋藤 花往里、口分田 貴裕、井上 宏昭、森田 泰慶、田中 宏和、嶋田 高広、辰巳 陽一、芦田 隆司、松村 到
  • Organizer: 第79回日本血液学会学術集会
• [Presentation] Azacitidine for patients with low-risk MDS after organ transplantation: a report of two cases (2016)
  • Author(s): Hiroaki Inoue,Yasuyoshi Morita,Shinya Rai,Hiroaki Kakutani,Yasuyo Ohyama,Yasuhiro Taniguchi,Hirokazu Tanaka,Takahiro Shimada,Yoichi Tatsumi,Takashi Ashida,Itaru Matsumura
  • Organizer: 第78回 日本血液学会学術集会
  • Place of Presentation: 横浜市 パシフィコ横浜
  • Year and Date: 2016-10-13
• [Presentation] Procoagulant microparticle is a new surrogate biomarker for thrombotic events in patients with myeloproliferative neoplasms. (2016)
  • Author(s): Yasuhiro Taniguchi,Hirokazu Tanaka,Takahiro Kumode,Shinya Rai,Itaru Matsumura
  • Organizer: 第21回欧州血液学会
  • Place of Presentation: コペンハーゲン・デンマーク
  • Year and Date: 2016-06-09
  • Int'l Joint Research
• [Presentation] CLEC-2 EXPRESSION IS A NEW MARKER FOR A SUBSET OF HEMATOPOIETIC STEM/PROGENITOR CELLS THAT CONTRIBUTES TO INFLAMMATION-INDUCED EMERGENT MEGAKARYOPOIESIS (2016)
  • Author(s): Takahiro Kumode,Hirokazu Tanaka,Shinya Rai,Yasuhiro Taniguchi,Itaru Matsumura
  • Organizer: 第21回欧州血液学会
  • Place of Presentation: コペンハーゲン・デンマーク
  • Year and Date: 2016-06-09
  • Int'l Joint Research
• [Presentation] 多発性骨髄腫のpoor mobilizerに対するplerixafor併用下でのPBSCH (2016)
  • Author(s): 芹澤憲太郎、森田泰慶、口分田貴裕、田中宏和、山田枝里佳、芦田隆司、松村 到
  • Organizer: 第64回日本輸血・細胞治療学会
  • Place of Presentation: 京都市 国立京都国際会館
  • Year and Date: 2016-04-28
• [Presentation] Phase1/2 study ponatinib safety and efficacy in Japanese patients(pts)with Ph+leukemia (2015)
  • Author(s): Kazuhito Yanamoto,Itaru Matsumura,Kazuma Ohyashiki ,et al.
  • Organizer: 第77回日本血液学会学術集会
  • Place of Presentation: 石川県立音楽堂、ANAクラウンプラザホテル金沢
  • Year and Date: 2015-10-16
• [Presentation] Antithymocyte globukin in second-line tretment of steroid-refractory acute GVHD (2015)
  • Author(s): 芦田隆司、松村 到 他
  • Organizer: 第77回日本血液学会学術集会
  • Place of Presentation: 石川県立音楽堂、ANAクラウンプラザホテル金沢
  • Year and Date: 2015-10-16
• [Presentation] Analysis of MECP regimen with relapsed or refractory malignant lymphoma in our institution (2015)
  • Author(s): 芹澤憲太郎、松村 到 他
  • Organizer: 第77回日本血液学会学術集会
  • Place of Presentation: 石川県立音楽堂、ANAクラウンプラザホテル金沢
  • Year and Date: 2015-10-16
  • Int'l Joint Research
• [Presentation] Target intracellular trafficking of FLT3-ITD and KIT D816V by Chlorpromazine shows promising preclinical activity against acute myeloid leukemia cells (2015)
  • Author(s): Rai S, Tanaka H, Watanabe T, Kanakura Y, and Matsumura I
  • Organizer: 第44回国際実験血液学会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2015-09-17
  • Int'l Joint Research
• [Presentation] CALM plays a critical role for oncogenic activvity of RTK mutants and would be a promising therapeutiic target (2015)
  • Author(s): Tanaka H, Rai S, Watanabe T, Kanakura Y, and Matsumura I
  • Organizer: 第44回国際実験血液学会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2015-09-17
  • Int'l Joint Research
• [Presentation] 臍帯血移植における前処置の比較-全身放射線照射と抗胸腺グロブリン (2015)
  • Author(s): 芦田隆司、松村 到 他
  • Organizer: 第63回日本輸血細胞治療学会
  • Place of Presentation: 京王プラザホテル（東京都）
  • Year and Date: 2015-05-28