Pharmacologically-directed, novel strategy to overcome drug resistance in acute leukemia.

• Project/Area Number: 18K07294
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: University of Fukui
• Principal Investigator: Yamauchi Takahiro 福井大学, 学術研究院医学系部門, 教授 (90291377)
• Co-Investigator(Kenkyū-buntansha): 根来 英樹 福井大学, 学術研究院医学系部門(附属病院部), 助教 (40444228) ; 細野 奈穂子 福井大学, 学術研究院医学系部門(附属病院部), 講師 (50509312)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 化学療法 / 分子標的療法 / 血液腫瘍学 / 急性白血病 / クロファラビン / 抗アポトーシスタンパク / 耐性克服

Outline of Final Research Achievements

The aim of our present research was to examine thoroughly the mechanisms of drug resistance in the cultured leukemia cells, which we had developed to be resistant to the key drugs (cytarabine, clofarabine) for treating leukemia. In the resistant cell lines, the active drug metabolite production (triphosphate forms) was reduced due to the suppression of activating enzymes, dCK and dGK. In addition, the anti-apoptotic proteins Bcl-2 and Mcl-1 were overexpressed, while pro-apoptotic proteins were not changed. The Bcl-2 inhibitor, venetoclax, induced apoptosis as a single agent, and the combination exerted a synergistic effect. The effect of venetoclax was reduced by the increased Bcl-2 expression. The combined effect of the Mcl-1 inhibitor, alvocidib, was minimal. Thus, it was found that the introduction of a molecular-targeted drug aiming at anti-apoptosis is effective as a means for pharmacological overcoming drug resistance in leukemia.

Academic Significance and Societal Importance of the Research Achievements

抗がん薬に耐性化した白血病細胞を直截かつ網羅的に解析し、耐性分子病態を解明し克服戦略を確立することが本研究の目的である。その成果として、細胞内薬剤活性化に加えて、抗アポトーシス増強が耐性の主要因であることを突き止めた。アポトーシス経路はほとんどすべての抗がん薬の殺細胞作用に関わっており、それを標的とする戦略は他がん治療に応用できる普遍性を有する（学術的意義）。さらに、白血病では今後世界的に治療体系の核となるベネトクラクスが我が国でも承認された（2021年3月）。本研究は本薬の実臨床での単剤・併用治療法開発・発展のための重要な基礎理論となる（社会的意義）。

Research Products

• [Journal Article] Venetoclax plus LDAC for patients with untreated AML ineligible for intensive chemotherapy: phase 3 randomized placebo-controlled trial. (2020)
  • Author(s): Wei AH, Montesinos P, Ivanov V, DiNardo CD, Novak J, Laribi K, Kim I, Stevens D, Fiedler W, Pagoni M, Samoilova O, Hu Y, Anagnostopoulos A, Bergeron J, Hou JZ, Murthy V, Yamauchi T, McDonald AB, Chyla B, Gopalakrishnan S, Jiang Q, Mendes WL, Hayslip J, Panayiotidis P.
  • Journal Title: Blood. Volume: 135 Issue: 24 Pages: 2137-2145
  • DOI: 10.1182/blood.2020004856
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] JSH Practical Guidelines for Hematological Malignancies, 2018: I. Leukemia-1. Acute myeloid leukemia (AML). (2020)
  • Author(s): Kiyoi H, Yamaguchi H, Maeda Y, Yamauchi T
  • Journal Title: Int J Hematol Volume: 111 Issue: 5 Pages: 595-613
  • DOI: 10.1007/s12185-020-02856-3
  • Peer Reviewed
• [Journal Article] Venetoclax and alvocidib are both cytotoxic to acute myeloid leukemia cells resistant to cytarabine and clofarabine. (2020)
  • Author(s): Nishi R, Shigemi H, Negoro E, Okura M, Hosono N, Yamauchi T.
  • Journal Title: BMC Cancer. Volume: 20 Issue: 1
  • DOI: 10.1186/s12885-020-07469-x
  • Peer Reviewed
• [Journal Article] The clinical significance of CD49e and CD56 for multiple myeloma in the novel agents era. (2020)
  • Author(s): Okura M, Ida N, Yamauchi T.
  • Journal Title: Med Oncol. Volume: 37 Issue: 11 Pages: 103-103
  • DOI: 10.1007/s12032-020-01423-4
  • Peer Reviewed
• [Journal Article] Impact of relative dose intensity of standard regimens on survival in elderly patients aged 80 years and older with diffuse large B cell lymphoma. (2020)
  • Author(s): Lee S, Fujita K, Negoro E, Morishita T, Oiwa K, Tsukasaki H, Kinoshita K, Kawai Y, Ueda T, Yamauchi T.
  • Journal Title: Haematologica Volume: 105 Issue: 8 Pages: e415-e418
  • DOI: 10.3324/haematol.2019.234435
  • Peer Reviewed
• [Journal Article] Simultaneous Presentation of Lymphomatoid Granulomatosis and Multiple myeloma in an Immunodeficient Patient with Rheumatoid Arthritis (2019)
  • Author(s): Lee S, Negoro E, Oki H, Imamura Y, Yamauchi T.
  • Journal Title: Internal Medicine Volume: 58 Issue: 19 Pages: 2845-2849
  • DOI: 10.2169/internalmedicine.2811-19
  • NAID: 130007722387
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2019-10-01
  • Peer Reviewed
• [Journal Article] Whole-body bone marrow DWI correlates with age, anemia, and hematopoietic activity. (2019)
  • Author(s): Tsujikawa T, Oikawa H, Tasaki T, Hosono N, Tsuyoshi H, Yoshida Y, Yamauchi T, Kimura H, Okazawa H.
  • Journal Title: Eur J Radiol. Volume: 118 Pages: 223-230
  • DOI: 10.1016/j.ejrad.2019.07.022
  • Peer Reviewed
• [Journal Article] Safety and pharmacokinetics of quizartinib in Japanese patients with relapsed or refractory acute myeloid leukemia in a phase 1 study. (2019)
  • Author(s): Usuki K, Handa H, Choi I, Yamauchi T, Iida H, Hata T, Ohwada S, Okudaira N, Nakamura K, Sakajiri S.
  • Journal Title: Int J Hematol. Volume: 110 Issue: 6 Pages: 654-664
  • DOI: 10.1007/s12185-019-02709-8
  • Peer Reviewed
• [Journal Article] High ENT1 and DCK gene expression levels are a potential biomarker to predict favorable response to nelarabine therapy in T-cell acute lymphoblastic leukemia. (2019)
  • Author(s): Akahane K, Murakami Y, Kagami K, Abe M, Harama D, Shinohara T, Watanabe A, Goi K, Nishi R, Yamauchi T, Kimura S, Takita J, Look AT, Minegishi M, Sugita K, Inukai T.
  • Journal Title: Hematol Oncol. Volume: 37 Issue: 4 Pages: 516-519
  • DOI: 10.1002/hon.2654
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The impact of diagnostic wait time on the survival of patients with diffuse large B-cell lymphoma: effect modification by the International Prognostic Index. (2019)
  • Author(s): Lee S, Fujita K, Negoro E, Morishita T, Yamauchi H, Oiwa K, Ueda T, Yamauchi T.
  • Journal Title: Br J Haematol. Volume: 187 Issue: 2 Pages: 195-205
  • DOI: 10.1111/bjh.16078
  • Peer Reviewed
• [Journal Article] Distinct clinical and biological implications of CUX1 in myeloid neoplasms. (2019)
  • Author(s): Aly M, Ramdzan ZM, Nagata Y, Balasubramanian SK, Hosono N, Makishima H, Visconte V, Kuzmanovic T, Adema V, Nazha A, Przychodzen BP, Kerr CM, Sekeres MA, Abazeed ME, Nepveu A, Maciejewski JP.
  • Journal Title: Blood Adv. Volume: 3 Issue: 14 Pages: 2164-2178
  • DOI: 10.1182/bloodadvances.2018028423
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Phase II study of FLAGM (fludarabin, high-dose cytarabine, granulocyte colony-stimulating factor, mitoxantrone) for relapsed or refractory acute myeloid leukemia. (2019)
  • Author(s): Hatsumi N, Miyawaki S, Yamauchi T, Takeshita A, Komatsu N, Usui N, Arai Y, Ishida F, Morii T, Kano Y, Ogura M, Machida S, Nishii K, Honda S, Ohnishi K, Naoe T.
  • Journal Title: Int J Hematol Volume: 109(4) Issue: 4 Pages: 418-425
  • DOI: 10.1007/s12185-019-02606-0
  • Peer Reviewed
• [Journal Article] <b>Febuxostat is useful for cancer-associated hyperuricemia in patients with hematologic malignancies</b> (2018)
  • Author(s): Oiwa K, Morita M, Kawamichi M, Fujita K, Lee S, Negoro E, Ookura M, Matsuda Y, Tai K, Naoko Hosono N, Ueda T, Yamauchi T.
  • Journal Title: GOUT AND NUCLEIC ACID METABOLISM Volume: 42 Issue: 2 Pages: 157-164
  • DOI: 10.6032/gnam.42.157
  • NAID: 130007535820
  • ISSN: 1344-9796, 2186-6368
  • Year and Date: 2018-12-20
  • Peer Reviewed
• [Journal Article] An MDS-derived cell line and a series of its sublines serve as an in vitro model for the leukemic evolution of MDS (2018)
  • Author(s): Kida Jun-ichiro、Tsujioka Takayuki、Suemori Shin-ichiro、Okamoto Shuichiro、Sakakibara Kanae、Takahata Takayuki、Yamauchi Takahiro、Kitanaka Akira、Tohyama Yumi、Tohyama Kaoru
  • Journal Title: Leukemia Volume: 32 Issue: 8 Pages: 1846-1850
  • DOI: 10.1038/s41375-018-0189-7
  • Peer Reviewed
• [Journal Article] Successful treatment of disseminated intravascular coagulation by recombinant human soluble thrombomodulin in patients with acute myeloid leukemia. (2018)
  • Author(s): Ookura M, Hosono N, Tasaki T, Oiwa K, Fujita K, Ito K, Lee S, Matsuda Y, Morita M, Tai K, Negoro E, Kishi S, Iwasaki H, Ueda T, Yamauchi T.
  • Journal Title: Medicine (Baltimore) Volume: 97 Issue: 44 Pages: 12981-12981
  • DOI: 10.1097/md.0000000000012981
  • Peer Reviewed
• [Journal Article] Outcomes after R-CHOP in patients with newly diagnosed advanced follicular lymphoma: a 10-year follow-up analysis of the JCOG0203 trial. (2018)
  • Author(s): Watanabe T, Tobinai K, Wakabayashi M, Morishima Y, Kobayashi H, Kinoshita T, Suzuki T, Yamaguchi M, Ando K, Ogura M, Taniwaki M, Uike N, Yoshino T, Nawano S, Terauchi T, Hotta T, Nagai H, Tsukasaki K; JCOG0203 Collaborators（Yamauchi T et al.）.
  • Journal Title: Lancet Haematol Volume: 5 Issue: 11 Pages: 520-531
  • DOI: 10.1016/s2352-3026(18)30155-8
  • Peer Reviewed / Open Access
• [Presentation] Overcoming resistance to anticancer agents in leukemia. (2021)
  • Author(s): Takahiro Yamauchi
  • Organizer: The 4th International Symposium of Cancer
  • Int'l Joint Research / Invited
• [Presentation] Association between relative dose intensity and prognosis in patients aged 80 years and older with DLBCL (2021)
  • Author(s): 李心 藤田慧 森下 哲司, 根来 英樹, 大岩 加奈, 塚崎 光, 原 武志, 鶴見 寿, 上田 孝典, 山内 高弘
  • Organizer: 第18回日本臨床腫瘍学会学術集会
• [Presentation] Antibody-drug conjugate in acute leukemia. (2021)
  • Author(s): 山内高弘
  • Organizer: 第18回日本臨床腫瘍学会学術集会
  • Invited
• [Presentation] Venetoclax plus azacitidine in Japanese patients with newly diagnosed or relapsed/refractory AML (2020)
  • Author(s): Takahiro Yamauchi, Ilseung Choi, Noriko Fukuhara, Kensuke Usuki, Jalaja Potluri, Ahmed Hamed Salem, Wan-Jen Hong, Hideyuki Honda, Yasuko Nishimura, Sumiko Okubo, Shuichi Taniguchi.
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] 急性白血病の薬物療法の進歩 (2020)
  • Author(s): 山内高弘
  • Organizer: 第21回日本検査血液学会学術集会
  • Invited
• [Presentation] Lineage switchをきたした治療抵抗性の急性白血病 (2020)
  • Author(s): 久世彩歌，位田奈緒子，根来英樹，細野奈穂子，山内高弘
  • Organizer: 日本内科学会ことはじめ 2020
• [Presentation] Utility of the Geriatric 8 for the prediction of therapy-related toxicity in elderly DLBCL patients (2020)
  • Author(s): 大岩加奈、李心 藤田慧 森下哲司, 根来 英樹, 楠本茂, 上田孝典, 飯田真介, 山内 高弘
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] T細胞リンパ腫細胞株におけるDarinaparsinと他の新規末梢T細胞リンパ腫化学療法薬との併用効果の検討 (2020)
  • Author(s): 根来英樹 浦崎芳正 位田奈緒子 新家裕朗 大蔵美幸 松田安史 森田美穂子 細野奈穂子 上田孝典 山内高弘
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] The fluctuant quality of protective environment affected by seasons and office hours (2020)
  • Author(s): 新家裕朗 位田奈緒子 大蔵美幸 松田安史 森田美穂子 根来英樹 細野奈穂子 稲井邦博 岩崎博道 山内高弘
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] Impact of relative dose intensity on survival in elderly patients aged 80 years and older with DLBCL (2020)
  • Author(s): 李心 藤田慧 森下哲司, 根来 英樹, 大岩加奈, 塚崎光, 原武志, 鶴見寿, 上田孝典, 山内高弘
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] The geriatric nutritional risk index (GNRI) predicts the prognosis of elderly patients with DLBCL (2020)
  • Author(s): 藤田慧 李心 森下 哲司, 根来英樹, 大岩加奈, 塚崎 光, 原 武志, 鶴見 寿, 上田 孝典, 山内 高弘
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] Current status and issues of discarding autologous blood in predeposit autologous blood transfusion (2020)
  • Author(s): 松田安史 位田奈緒子 新家裕朗 森田美穂子 大蔵美幸 根来英樹 細野奈穂子 山内高弘
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] Treatment strategy for AML in Japan (2020)
  • Author(s): Hosono Naoko
  • Organizer: 第82回日本血液学会学術集会
  • Invited
• [Presentation] 未治療多発性骨髄腫に対するMPB療法変法のランダム化第II相試験（JCOG1105最終解析） (2020)
  • Author(s): 飯田真介, 丸山 大, 町田龍之介, 楠本 茂, 福原規子, 山内寛彦, 宮崎香奈, 吉満 誠, 黒田純也, 塚本憲史, 辻村秀樹, 半下石 明, 山内高弘, 内海貴彦, 水野石一, 高松 泰, 永田泰之, 皆内康一郎, 大塚英一, 花村一朗, 鈴木康裕, 吉田真一郎, 山崎 聡, 末廣陽子, 神山祐太郎, 渡部裕子, 飛内賢正, 塚崎邦弘, 永井宏和
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] 急性白血病化学療法時の真菌感染症管理の実態：JALSGアンケート調査2019 (2020)
  • Author(s): 細野奈穂子, 木村俊一, 藤田浩之, 半田 寛, 平本展大, 南口仁志, 高橋 勉, 加藤英明, 小野孝明, 神田善伸, 清井 仁, 松村 到, 宮﨑泰司
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] 急性骨髄性白血病におけるFlt3変異の重要性：HM-SCREEN 01試験の中間解析より (2020)
  • Author(s): 福島健太郎, 柴山浩彦, 宮本憲一, 細野奈穂子, 山内高弘, 片桐誠一朗, 後藤明彦, 森下喬允, 柳田正光, 山本一仁, 藤島直仁, 高橋直人, 小笠原励起, 近藤 健, 宇津欣和, 青墳信之, 臼杵憲祐, 小野孝明, 古林 勉, 黒田純也, 堀口拓人, 井山 諭, 福原 傑, 伊豆津宏二, 神原悠輔, 江口基紀, 湯田淳一朗, 山内寛彦, 南 陽介
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] T細胞性急性リンパ性白血病（T-ALL）から急性骨髄性白血病（AML）に形質転換した一例 (2020)
  • Author(s): 黒瀬智美, 山野智子, 関口清美, 杉本 充, 圓道麻利子, 橋本儀一, 山内高弘, 木村秀樹
  • Organizer: 第21回日本検査血液学会学術集会
• [Presentation] 急性白血病治療の最近の進歩 (2020)
  • Author(s): 山内高弘
  • Organizer: 第242回日本内科学会北陸地方会生涯教育講演会
  • Invited
• [Presentation] Genomic Analysis of FLT3 Mutations in a Comprehensive NGS Multicenter Study of AML: HM-Screen-Japan 01 (2020)
  • Author(s): Fukushima K, Chi S, Shibayama H, Hosono N, Yamauchi T, Katagiri S, Gotoh A, Morishita T, Yanada M, Yamamoto K, Fujishima N, Takahashi N, Ogasawara R, Kondo T, Utsu Y, Aotsuka N, Usuki K, Ono T, Kobayashi T, Kuroda J, Horiguchi H, Iyama S, Fukuhara S, Izutsu K, Nakamura M, Kojima K, Miyamoto K, Minami Y
  • Organizer: 62nd American Society of Hematology, Annual Meeting and Exposition
  • Int'l Joint Research
• [Presentation] Gilteritinib Significantly prolongs overall survival in patients with FLT3-mutated relapsed/refractory acute myeloid leukemia: results from the phase 3 ADMIRAL trial. (2019)
  • Author(s): Hosono N, Perl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, Montesinos P, Baer MR, Larson RA, Ustun C, Fabbiano F, Erba HP, Di Stasi A, Stuart R, Olin R, Kasner M, Ciceri F, Chou WC, Podoltsev N, Recher C, Yokoyama H, Yoon SS, Lee JH, Pardee T, Fathi AT, Liu C, Hasabou N, Liu X, Bahceci E, Levis MJ.
  • Organizer: 15th National conference on leukemia and lymphoma
  • Int'l Joint Research / Invited
• [Presentation] 腫瘍崩壊症候群のリスクマネジメント (2019)
  • Author(s): 山内高弘
  • Organizer: 第81回日本血液学会学術集会
  • Invited
• [Presentation] AMLに対する新規治療薬 (2019)
  • Author(s): 細野奈穂子
  • Organizer: 第81回日本血液学会学術集会
  • Invited
• [Presentation] 急性骨髄性白血病、新規薬剤による新時代の幕開け (2019)
  • Author(s): 細野奈穂子
  • Organizer: 第40回日本臨床薬理学会学術総会
  • Invited
• [Presentation] 急性骨髄性白血病および骨髄異形成症候群に対する治療薬の進歩 (2019)
  • Author(s): 細野奈穂子
  • Organizer: 第40回日本臨床薬理学会学術総会
• [Presentation] Bcl-2 inhibitor venetoclax augments cytotoxicity of cytarabine and clofarabine in drug-resistant leukemic cells in vitro. (2018)
  • Author(s): Rie Nishi, Naoko Hosono, Hiroko Shigemi, Takanori Ueda, Takahiro Yamauchi.
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Pralatrexate-Resistant Cell Lines Show Intact Internalization Via RFC1 but Collateral Sensitivity to Nucleoside Analogs (2018)
  • Author(s): Kana Oiwa, Naoko Hosono, Rie Nishi, Takanori Ueda, Luigi Scott, Owen A. O'Connor, Takahiro Yamauchi.
  • Organizer: 第60回米国血液学会総会
  • Int'l Joint Research
• [Presentation] Establishment and characterization of Leukemic Cell Lines Resistant to New-Generation Dihydrofolate Reductase Inhibitor, Pralatrexate. (2018)
  • Author(s): Kana Oiwa, Naoko Hosono, Rie Nishi, Takanori Ueda, Takahiro Yamauchi.
  • Organizer: 18th World Congress of Basic and Clinical Pharmacology
  • Int'l Joint Research
• [Presentation] 急性骨髄性白血病における治療課題と今後の展望～FLT3阻害薬ギルテリチニブによる新たな治療戦略～ (2018)
  • Author(s): 細野奈穂子
  • Organizer: 第77回日本血液学会学術集会
  • Invited
• [Book] ガイドライン外来診療2020 (2020)
  • Author(s): 山内高弘、上田孝典
  • Total Pages: 726
  • Publisher: 日経メディカル開発
• [Book] Year Note Topics 2020-2021 (2020)
  • Author(s): 森田美穂子、山内高弘
  • Total Pages: 200
  • Publisher: Medic Media
• [Book] 白血病治療マニュアル (2020)
  • Author(s): 山内高弘
  • Total Pages: 348
  • Publisher: 南江堂
• [Book] 白血病治療マニュアル (2020)
  • Author(s): 森田美穂子、山内高弘
  • Total Pages: 348
  • Publisher: 南江堂
• [Book] 急性白血病テキスト (2020)
  • Author(s): 山内高弘
  • Total Pages: 188
  • Publisher: 中外医学社
• [Book] 今日の治療指針2020 (2020)
  • Author(s): 山内高弘
  • Total Pages: 2115
  • Publisher: 医学書院
• [Book] 血液疾患最新の治療2020-2022 (2019)
  • Author(s): 大蔵美幸, 山内高弘
  • Total Pages: 390
  • Publisher: 南江堂
  • ISBN: 9784524249787
• [Book] 血液専門医テキスト改訂第3版 (2019)
  • Author(s): 大蔵美幸, 山内高弘
  • Total Pages: 660
  • Publisher: 南江堂
  • ISBN: 9784524248827
• [Book] 未来型血液治療学 (2019)
  • Author(s): 山内高弘
  • Total Pages: 254
  • Publisher: 中外医学社
  • ISBN: 9784498225183
• [Book] 一般社団日本血液学会編、造血器腫瘍診療ガイドライン2018年版 (2018)
  • Author(s): 山内高弘 他
  • Total Pages: 401
  • Publisher: 金原出版
  • ISBN: 9784307101929