Exploratory research of biomarkers associated arteriosclerosis by tyrosine kinase inhibitors

• Project/Area Number: 19K08809
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Hamamatsu University School of Medicine
• Principal Investigator: Ono Takaaki 浜松医科大学, 医学部附属病院, 講師 (40402276)
• Co-Investigator(Kenkyū-buntansha): 岩城 孝行 浜松医科大学, 医学部, 准教授 (70509463)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 慢性骨髄性白血病 / チロシンキナーゼ阻害剤 / 動脈硬化 / 酸化LDL / CD36 / Sortilin / ダサチニブ / チロシンキナーゼ阻害薬 / 心血管イベント / マクロファージ / オフターゲット効果 / 血清コレステロール / 動脈硬化抑制作用 / バイオマーカー

Outline of Research at the Start

慢性骨髄性白血病(CML)はチロシンキナーゼ阻害剤(TKI)の導入で生命予後が劇的に改善したが、長期服用により動脈硬化が進行して心筋梗塞などの血管閉塞の合併症が起こりうることが問題となっている。しかしこのような合併症が起こる原因は、はっきり分かっていない。今回の研究では、動脈硬化モデルマウスに本邦で使用できる全ての種類のTKIを投与し、動脈硬化の程度を比較する。また血管内皮細胞と血管平滑筋細胞から抽出したmRNAを解析して、血管内皮細胞や血管平滑筋に影響を与え、動脈硬化に関わりうる分子の同定を試みる。これによってCML患者さんの適切な治療薬選択と血管閉塞合併症の予測が可能になると考えられる。

Outline of Final Research Achievements

Mice treated with dasatinib (DAS) had reduced arteriosclerotic lesions throughout the aorta and at the origin compared to DMSO, imatinib, and nilotinib. Total cholesterol and LDL cholesterol were elevated in DAS-treated mice. Uptake of DiI-ox LDL in bone marrow-derived macrophages was reduced in the DAS-exposed group. Comprehensive analysis by RNA sequencing in the liver showed that Sort1 expression was reduced in DAS. In Western blotting, Sortilin expression was reduced in DAS compared to other TKIs. On the other hand, the expression of Cd36, which is a scavenger receptor, was decreased in peritoneal macrophages.

Academic Significance and Societal Importance of the Research Achievements

慢性骨髄性白血病はBCR-ABL1チロシンキナーゼ阻害剤(TKI)の導入により、健常人とほぼ同等の余命が得られるようになった。本研究は、長期にわたるTKI投与により併発する血管閉塞性イベントの機序を解明するために計画された。本研究において、ダサチニブは他のTKIと異なり、CD36発現低下を介し、酸化LDLの取り込みを障害していることが示された。さらに、コレステロールの取り込みと排出の両者に重要な役割を果たすSortilinの発現低下を認めた。本研究から、TKIごとで、コレステロールの代謝に異なる影響を与えることが示唆された。今後、さらに研究を進めていきたい。

Research Products

• [Journal Article] Dasatinib suppresses atherosclerotic lesions by suppressing cholesterol uptake in a mouse model of hypercholesterolemia (2022)
  • Author(s): Takaba M, Ono T, Iwaki T et al
  • Journal Title: Journal of Pharmacological Sciences Volume: in press
  • Peer Reviewed
• [Journal Article] Which Tyrosine Kinase Inhibitors Should Be Selected as the First-Line Treatment for Chronic Myelogenous Leukemia in Chronic Phase? (2021)
  • Author(s): Ono T
  • Journal Title: Cancers Volume: 13(20) Issue: 20 Pages: 5116-5116
  • DOI: 10.3390/cancers13205116
  • Peer Reviewed / Open Access
• [Journal Article] Prognostic effect of comorbidities in patients with chronic myeloid leukemia treated with a tyrosine kinase inhibitor (2020)
  • Author(s): Ono Takaaki、Takahashi Naoto、Kizaki Masahiro、Kawaguchi Tatsuya、Suzuki Ritsuro、Yamamoto Kazuhito、Ohnishi Kazunori、Naoe Tomoki、Matsumura Itaru
  • Journal Title: Cancer Science Volume: 111 Issue: 10 Pages: 3714-3725
  • DOI: 10.1111/cas.14580
  • Peer Reviewed / Open Access
• [Journal Article] Real-world management of infection during chemotherapy for acute leukemia in Japan: from the results of a nationwide questionnaire-based survey by the Japan Adult Leukemia Study Group (2020)
  • Author(s): Kimura Shun-ichi、Japan Adult Leukemia Study Group (JALSG)、Fujita Hiroyuki、Handa Hiroshi、Hiramoto Nobuhiro、Hosono Naoko、Minamiguchi Hitoshi、Takahashi Tsutomu、Kato Hideaki、Ono Takaaki、Kanda Yoshinobu、Kiyoi Hitoshi、Matsumura Itaru、Miyazaki Yasushi
  • Journal Title: International Journal of Hematology Volume: 112 Issue: 3 Pages: 409-417
  • DOI: 10.1007/s12185-020-02921-x
  • Peer Reviewed
• [Journal Article] Phase 2 study of bosutinib in Japanese patients with newly diagnosed chronic phase chronic myeloid leukemia. (2020)
  • Author(s): Hino M, Matsumura I, Fujisawa S, Ishizawa K, Ono T, Sakaida E, Sekiguchi N, Tanetsugu Y, Fukuhara K, Ohkura M, Koide Y, Takahashi N.
  • Journal Title: International Journal of Hematology Volume: Epub ahead of print Issue: 1 Pages: 24-32
  • DOI: 10.1007/s12185-020-02878-x
  • NAID: 120007036312
  • Peer Reviewed / Open Access
• [Journal Article] Polaprezinc for prevention of oral mucositis in patients receiving chemotherapy followed by hematopoietic stem cell transplantation: A multi‐institutional randomized controlled trial (2020)
  • Author(s): Kitagawa Junichi、Kobayashi Ryo、Nagata Yasuyuki、Kasahara Senji、Ono Takaaki、Sawada Michio、Ohata Koichi、Kato‐Hayashi Hiroko、Hayashi Hideki、Shimizu Masahito、Itoh Yoshinori、Tsurumi Hisashi、Suzuki Akio
  • Journal Title: International Journal of Cancer Volume: 148 Issue: 6 Pages: 1462-1469
  • DOI: 10.1002/ijc.33316
  • NAID: 120007165668
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy and safety of tyrosine kinase inhibitors for newly diagnosed chronic-phase chronic myeloid leukemia over a 5-year period: results from the Japanese registry obtained by the New TARGET system. (2019)
  • Author(s): Kizaki M, Takahashi N, Iriyama N, Okamoto S, Ono T, Usui N, Inokuchi K, Nakaseko C, Kurokawa M, Sumi M, Nakamura F, Kawaguchi T, Suzuki R, Yamamoto K, Ohnishi K, Matsumura I, Naoe T; New TARGET investigators.
  • Journal Title: Int J Hematol Volume: 109 Issue: 4 Pages: 426-439
  • DOI: 10.1007/s12185-019-02613-1
  • Peer Reviewed / Open Access
• [Presentation] Reducing cholesterol uptake by suppressing Sort1 by dasatinib in a hypercholesterolemic mouse model. (2021)
  • Author(s): Masamitsu Takaba, Takayuki Iwaki, Tomohiro Arakawa, Takaaki Ono, Kazuo Umemura.
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] Efficacy and Safety of Bosutinib in Japanese Patients with Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia: Final 3-Year Results of a Phase 2 Study. (2021)
  • Author(s): Ono T, Hino M, Matusmura I, Fujisawa S, Ishizawa K, Sakaida E, Sekiguchi N, Ono C, Aizawa M, Tanetsugu Y, Koide Y, Takahashi N
  • Organizer: American society of hematology (ASH) Annual Meeting & Exposition Atlanta, USA,
  • Int'l Joint Research
• [Presentation] No association between age itself and survival in patients with chronic myeloid leukemia. (2020)
  • Author(s): 1.Takaaki Ono, Naoto Takahashi, Masahiro Kizaki, Tatsuya Kawaguchi, Ritsuro Suzuki, Kazuhit Yamamoto, Kazunori Ohnishi, Tomoki Naoe, and Itaru Matsumura.
  • Organizer: 第82回日本血液学会総会
• [Presentation] Evaluation of atherosclerotic lesions by BCR/ABL1 tyrosine kinase inhibitor effects in a familial typeⅡa model mouse (2020)
  • Author(s): 高羽理光・岩城孝行・松本祐直・梅村和夫
  • Organizer: 第93回日本薬理学会年会
• [Presentation] Prognostic Effects of Pretreatment Statuses at Diagnosis in Patients with Chronic Myeloid Leukemia: Results of the New Target Observational Study 1 (2019)
  • Author(s): Takaaki Ono, Naoto Takahashi, Masahiro Kizaki, Tatsuya Kawaguchi, Ritsuro Suzuki, Kazuhito Yamamoto, Kazunori Ohnishi, Tomoki Naoe, and Itaru Matsumura
  • Organizer: American society of hematology (ASH) 52nd Annual Meeting & Exposition
  • Int'l Joint Research
• [Presentation] Clinical features and outcomes of elderly patients with chronic myeloid leukemia according to the New TARGET observational study 1 (2019)
  • Author(s): Takaaki Ono, Naoto Takahashi, Masahiro Kizaki, Tatsuya Kawaguchi, Ritsuro Suzuki, Kazuhito Yamamoto, Kazunori Ohnishi, Tomoki Naoe, and Itaru Matsumura
  • Organizer: 第81回日本血液学会総会
• [Presentation] Impact of pre-treatment status on outcome in patients with chronic myeloid leukemia: results of the New TARGET observational study 1 (2019)
  • Author(s): Takaaki Ono, Naoto Takahashi, Masahiro Kizaki, Tatsuya Kawaguchi, Ritsuro Suzuki, Kazuhito Yamamoto, Kazunori Ohnishi, Tomoki Naoe, and Itaru Matsumura
  • Organizer: 第81回日本血液学会総会