Discovery of a drug targeting microenvironmental support for lymphoma cells by screening using patient-derived xenograft cells

• Project/Area Number: 25670449
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Hematology
• Research Institution: National Hospital Organization Nagoya Medical Center
• Principal Investigator: NAOE TOMOKI 独立行政法人国立病院機構(名古屋医療センター臨床研究センター), その他部局等, 院長 (50217634)
• Co-Investigator(Kenkyū-buntansha): HAYAKAWA Fumihiko 名古屋大学, 医学部附属病院, 講師 (30402580) ; SHIMADA Kazuyuki 名古屋大学, 学内共同利用施設等, 講師 (50631503) ; TOMITA Akihiro 名古屋大学, 医学(系)研究科(研究院), 准教授 (80378215)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 薬剤スクリーニング / 微小環境 / 悪性リンパ腫 / PDX / 酸化ストレス / 癌 / トランスレーショナルリサーチ / シグナル伝達 / 標準治療

Outline of Final Research Achievements

Cell lines have been used for drug discovery as useful models of cancers; however, they do not recapitulate cancers faithfully, especially in the points of rapid growth rate and microenvironment independency. Here, we developed a novel high throughput drug screening system using patient-derived xenograft (PDX) cells of lymphoma that maintained primary cancer cell phenotype more than cell lines. Pyruvinium pamoate showed the highest activity, and its strong anti-tumor effect was confirmed also in vivo. We extensively investigated its mechanism of action and found that it inhibited glutathione supply from stromal cells to lymphoma cells, implying the importance of the stromal protection from oxidative stress for lymphoma cell survival and a new therapeutic strategy for lymphoma. Our system introduces a primary cancer cell phenotype into cell-based phenotype screening and sheds new light on anti-cancer drug development.

Research Products

• [Journal Article] Target Antigen Density Governs the Efficacy of Anti-CD20-CD28-CD3 ζ Chimeric Antigen Receptor-Modified Effector CD8+ T Cells. (2015)
  • Author(s): Watanabe K, Terakura S, Martens AC, van Meerten T, Uchiyama S, Imai M, Sakemura R, Goto T, Hanajiri R, Imahashi N, Shimada K, Tomita A, Kiyoi H, Nishida T, Naoe T, Murata M
  • Journal Title: J Immunol Volume: 194(3) Pages: 911-920
  • Peer Reviewed
• [Journal Article] Progress in molecularly targeted therapies for acute myeloid leukemia (2015)
  • Author(s): Tomita A.
  • Journal Title: Rinsho Ketsueki Volume: 56 Issue: 2 Pages: 130-138
  • DOI: 10.11406/rinketsu.56.130
  • NAID: 130004920715
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed
• [Journal Article] Successful treatment of refractory cold hemagglutinemia in MYD88 L265P mutation-negative Waldenstrom's macroglobulinemia with bortezomib. (2015)
  • Author(s): Izumi M, Tsunemine H, Suzuki Y, Tomita A, Kusumoto T, Kodaka T, Itoh K, Takahashi T.
  • Journal Title: Int J Hematol Volume: epub Issue: 2 Pages: 238-43
  • DOI: 10.1007/s12185-015-1775-3
  • Peer Reviewed
• [Journal Article] Development of acute pure red cell aplasia after deferasirox administration in two cases of myelodysplastic syndrome. (2014)
  • Author(s): Hayakawa F, Tomita A, Naoe T
  • Journal Title: Rinsho Ketsueki Volume: 55（4） Pages: 445-449
  • NAID: 130004920671
  • Peer Reviewed
• [Journal Article] Efficacy of ofatumumab against rituximab-resistant B-CLL/SLL cells with low CD20 protein expression. (2014)
  • Author(s): Shimada K, Tomita A, Saito S, Kiyoi H.
  • Journal Title: Br J Haematol Volume: 165 Issue: 3 Pages: 455-7
  • DOI: 10.1111/bjh.12857
  • Peer Reviewed
• [Journal Article] Markedly improved outcomes and acceptable toxicity in adolescents and young adults with acute lymphoblastic leukemia following treatment with a pediatric protocol: a phase II study by the Japan Adult Leukemia Study Group. (2014)
  • Author(s): Hayakawa F, Sakura T, Yujiri T, Kondo E, Fujimaki K, Sasaki O, Miyatake J, Handa H, Ueda Y, Aoyama Y, Takada S, Tanaka Y, Usui N, Miyawaki S, Suenobu S, Horibe K, Kiyoi H, Ohnishi K, Miyazaki Y, Ohtake S, Kobayashi Y, Matsuo K, Naoe T; Japan Adult Leukemia Study Group (JALSG).
  • Journal Title: Blood Cancer J Volume: 4
  • NAID: 120006987091
  • Peer Reviewed
• [Journal Article] Prognostic significance of pleural or pericardial effusion and the implication of optimal treatment in primary mediastinal large B-cell lymphoma: a multicenter retrospective study in Japan. (2014)
  • Author(s): Aoki T, Izutsu K, Suzuki R, Nakaseko C, Arima H, Shimada K, Tomita A, Sasaki M, Takizawa J, Mitani K, Igarashi T, Maeda Y, Fukuhara N, Ishida F, Niitsu N, Ohmachi K, Takasaki H, Nakamura N, Kinoshita T, Nakamura S, Ogura M.
  • Journal Title: Haematologica Volume: 99(12) Issue: 12 Pages: 1817-25
  • DOI: 10.3324/haematol.2014.111203
  • Peer Reviewed / Open Access
• [Journal Article] De novo diffuse large B-cell lymphoma with a CD20 immunohistochemistry-positive and flow cytometry-negative phenotype: Molecular mechanisms and correlation with rituximab sensitivity. (2014)
  • Author(s): Tokunaga T, Tomita A, Sugimoto K, Shimada K, Iriyama C, Hirose T, Shirahata-Adachi M, Suzuki Y, Mizuno H, Kiyoi H, Asano N, Nakamura S, Kinoshita T, Naoe T.
  • Journal Title: Cancer Sci. Volume: 105 Issue: 1 Pages: 35-43
  • DOI: 10.1111/cas.12307
  • Peer Reviewed
• [Journal Article] Functionally Deregulated AML1/RUNX1 Cooperates with BCR-ABL to Induce a Blastic Phase-Like Phenotype of Chronic Myelogenous Leukemia in Mice. (2013)
  • Author(s): Kiyoko Yamamoto, Shinobu Tsuzuki, Yosuke Minami, Yukiya Yamamoto, Akihiro Abe, Koichi Ohshima, Masao Seto, Tomoki Naoe.
  • Journal Title: PLOS ONE Volume: 8 Issue: 9 Pages: e74864-e74864
  • DOI: 10.1371/journal.pone.0074864
  • Peer Reviewed
• [Presentation] PAX5 Tyrosine Phosphorylation By Syk Co-Operatively Works with Its Serine Phosphorylation By ERK1/2 and Cancels PAX5-Dependent Repression of BLIMP1: A Mechanism of Antigen-Triggering Plasma Cell Differentiation through B Cell Receptor Signal. (2014)
  • Author(s): 稲垣裕一郎、早川文彦、井本直人、森下喬允、直江知樹、清井仁
  • Organizer: 第56回米国血液学会
  • Place of Presentation: Moscone Center （サンフランシスコ、米国）
  • Year and Date: 2014-12-06 – 2014-12-09
• [Presentation] Clinical and Molecular Significance of Peripheral Blood Cell-Free DNA in B-Cell Lymphomas for Detection of Genetic Mutations and Correlation with Disease Status (2014)
  • Author(s): Yasuhiro Suzuki、Akihiro Tomita、 Kenichi Yoshida、Kazuyuki Shimada、 Chisako Iriyama、Masashi Sanada, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Satoru Miyano, Seishi Ogawa, Hitoshi Kiyoi
  • Organizer: 第56回米国血液学会
  • Place of Presentation: Moscone Center （サンフランシスコ、米国）
  • Year and Date: 2014-12-06 – 2014-12-09
• [Presentation] Development and Analysis of Novel Intravascular Large B-Cell Lymphoma NOD/Shi-Scid IL2R γnull Mouse Xenograft Model. (2014)
  • Author(s): Kazuyuki Shimada, Satoko Shimada, Keiki Sugimoto, Fumihiko Hayakawa, Miyuki Katayama, Akihiro Hirakawa, Yusuke Takagi, Shigeo Nakamura, Masao Seto, Tomoki Naoe, Akihiro Tomita, Hitoshi Kiyoi
  • Organizer: 第56回米国血液学会
  • Place of Presentation: Moscone Center （サンフランシスコ、米国）
  • Year and Date: 2014-12-06 – 2014-12-09
• [Presentation] AYA ALL に対する小児プロトコールの有効性と認容の検討：JALSG ALL202-U 研究より (2014)
  • Author(s): 早川文彦
  • Organizer: 第56回日本小児血液・がん学会学術集会シンポジウム
  • Place of Presentation: 岡山コンベンションセンター（岡山県岡山市北区）
  • Year and Date: 2014-11-28 – 2014-11-30
• [Presentation] 末梢血遊離DNAを用いたB細胞リンパ腫における遺伝子変異解析 (2014)
  • Author(s): 鈴木康裕、冨田章裕、入山智沙子、島田和之、清井仁、et al
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪国際会議場（大阪府大阪市北区）
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] Intravascular large B-cell lymphoma-from bench to bedside (2014)
  • Author(s): 島田和之
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪国際会議場（大阪府大阪市北区）
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] Biological and genetic analyses of intravascular large B-cell lymphoma using xenograft mouse model. (2014)
  • Author(s): 島田和之、島田聡子、杉本慶樹、早川文彦、片山幸、平川晃弘、中村栄男、瀬戸加大、直江知樹、冨田章裕、清井仁
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪国際会議場（大阪府大阪市北区）
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] B細胞受容体シグナル経路によるリン酸化を介したPAX5の機能調節 (2014)
  • Author(s): 稲垣裕一郎、早川文彦、清井仁
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪国際会議場（大阪府大阪市北区）
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] マウスモデルでのPAX5-PMLによる急性リンパ性白血病の解析 (2014)
  • Author(s): 井本直人、倉橋信悟、早川文彦、安田貴彦、清井 仁
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪国際会議場（大阪府大阪市北区）
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] 末梢血cell-free DNAを用いたB細胞リンパ腫における遺伝子変異解析 (2014)
  • Author(s): 鈴木康裕、冨田章裕、吉田健一、島田和之、入山智沙子、真田昌、白石友一、千葉健一、田中洋子、宮野悟、小川誠司、清井仁
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市西区）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] B細胞性腫瘍における抗CD20 抗体治療薬に対する薬剤耐性 (2014)
  • Author(s): 冨田章裕
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市西区）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Utilization of Peripheral Blood Cell-free DNA for Genetic Analyses in MDS (2014)
  • Author(s): Yasuhiro Suzuki, Akihiro Tomita, Chisako Iriyama, Kazuyuki Shimada, Hitoshi Kiyoi
  • Organizer: 第35回国際血液学会議
  • Place of Presentation: China National Convention Center（北京、中国）
  • Year and Date: 2014-09-04 – 2014-09-07
• [Presentation] 骨髄スメア標本とパイロシークエンス法を用いたB細胞性腫瘍におけるMYD88 L265P変異解析 (2014)
  • Author(s): 鈴木康裕、冨田章裕、入山智沙子、島田和之、山本絵里奈、金田典雄、清井仁
  • Organizer: 第12回日本臨床腫瘍学会総会
  • Place of Presentation: 福岡国際会議場（福岡県福岡市博多区）
  • Year and Date: 2014-07-17 – 2014-07-19
• [Presentation] リツキシマブ併用化学療法に抵抗性を示すDLBCL症例を予測するバイオマーカーと治療層別化の可能性 (2014)
  • Author(s): 冨田章裕
  • Organizer: 第54回 日本網内系学会総会
  • Place of Presentation: 山形国際ホテル（山形県山形市）
  • Year and Date: 2014-06-19 – 2014-06-21
• [Presentation] PAX5-PML Induces Pro B Acute Lymphoblastic Leukemia In Mice (2014)
  • Author(s): 井本直人、倉橋信悟、早川文彦、安田貴彦、清井 仁、et al
  • Organizer: 第5回日本血液学会（JSH)国際シンポジウム
  • Place of Presentation: アクトシティ浜松（静岡県浜松市中区）
  • Year and Date: 2014-05-24 – 2015-05-25
• [Presentation] Markedly Improved Outcome and Acceptable Toxicity in Adolescents and Young Adults with Acute Lymphoblastic Leukemia by Treatment with a Pediatric Protocol: a Phase Ⅱ Study by the Japan Adult Leukemia Study Group. (2014)
  • Author(s): Hayakawa Fumihiko、 Toru Sakura, Toshiaki Yujiri, Eisei Kondo, Katsumichi Fujimaki, Shuichi Miyawaki, So-ichi Suenobu, Shigeki Ohtake, Yukio Kobayashi, keitaro Matsuo, and Tomoki Naoe
  • Organizer: 第5回日本血液学会（JSH)国際シンポジウム
  • Place of Presentation: アクトシティ浜松（静岡県浜松市中区）
  • Year and Date: 2014-05-24 – 2014-05-25
• [Presentation] リンパ腫細胞環境をターゲットする薬剤開発 (2013)
  • Author(s): 杉本慶樹、早川文彦 直江 知樹
  • Organizer: 日本癌学会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
• [Remarks] JALSG(日本成人白血病治療共同研究グループ)
  • URL: http://www.jalsg.jp/