Basic research aimed at understanding and overcoming of the primary and secondary resistance in molecular target therapy

• Project/Area Number: 22390192
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Nagoya University
• Principal Investigator: NAOE Tomoki 名古屋大学, 医学系研究科, 教授 (50217634)
• Co-Investigator(Kenkyū-buntansha): TOMITA Akihiro 名古屋大学, 医学部附属病院, 講師 (80378215) ; MINAMI Yousuke 名古屋大学, 医学(系)研究科(研究院), COE 特任講師 (60513752)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2012: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2011: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2010: ¥8,060,000 (Direct Cost: ¥6,200,000、Indirect Cost: ¥1,860,000)
• Keywords: 分子標的治療 / 残存 / 耐性 / がん薬物治療 / キナーゼ阻害剤

Research Abstract

Although the outcome of patients with hematopoietic malignancies is significantly improved by using molecular target therapies, residual tumors and/or acquired resistance have become contemporary issues in the clinical field. In this study

Research Products

• [Journal Article] Combination of Ponatinib with Hedgehog Antagonist Vismodegib for Therapy-Resistant BCR-ABL1-Positive Leukemia. (2013)
  • Author(s): Katagiri S, Minami Y, Naoe T, et al.
  • Journal Title: Clin Cancer Res. Volume: 19 Issue: 6 Pages: 1422-1432
  • DOI: 10.1158/1078-0432.ccr-12-1777
  • Peer Reviewed
• [Journal Article] CML cells expressing the TEL/MDS1/EVI1 fusion are resistant to imatinib-induced apoptosis through inhibition of BAD, but are resensitized with ABT-737 (2012)
  • Author(s): Shimada K, Tomita A, Minami Y, Abe A, Hind CK, Kiyoi H, Cragg MS, Naoe T.
  • Journal Title: Exp Hematol Volume: 40 Pages: 724-737
  • Peer Reviewed
• [Journal Article] Using peripheral blood circulating DNAs to detect CpG global methylation status and genetic mutations in patients with myelodysplastic syndrome. (2012)
  • Author(s): Iriyama C, Tomita A, Hoshino H,Adachi-Shirahata M, Furukawa-Hibi Y, Yamada K, Kiyoi H, Naoe T.
  • Journal Title: Biochem Biophys Res Commun Volume: 419 Pages: 662-669
  • Peer Reviewed
• [Journal Article] Y654 of β-catenin is essential for FLT3/ITD-related tyrosine phosphorylation and nuclear localization of β-catenin. (2012)
  • Author(s): Kajiguchi T, Katsumi A, Tanizaki R, Kiyoi H, Naoe T
  • Journal Title: Eur J Haematol Volume: 88 Pages: 314-320
  • Peer Reviewed
• [Journal Article] Retention of CD34(+) CML stem/progenitor cells during imatinib treatment and rapid decline after treatment with second-generation BCR-ABL inhibitors. (2012)
  • Author(s): Minami Y, Abe A, Minami M, Kitamura K, Hiraga J, Mizuno S, Ymamoto K, Sawa M, Inagaki Y, Miyamura K, Naoe T
  • Journal Title: Leukemia Volume: 26 Pages: 2142-2143
  • Peer Reviewed
• [Journal Article] B Cell Receptor-ERK1/2 Signal Cancels PAX5-Dependent Repression of BLIMP1 through PAX5 Phosphorylation: A Mechanism of Antigen-Triggering Plasma Cell Differentiation. (2012)
  • Author(s): Yasuda T, Hayakawa F, Kurahashi S, Sugimoto K, Minami Y, Tomita A, Naoe T.
  • Journal Title: J Immunol Volume: 188 Pages: 6127-6134
  • Peer Reviewed
• [Journal Article] CML cells expressing the TEL/MDS1/EVI1 fusion are resistant to imatinib-induced apoptosis through inhibition of BAD, but are resensitized with ABT-737. (2012)
  • Author(s): Shimada K, Tomita A, Minami Y, Kiyoi H, Naoe T et al.
  • Journal Title: Exp Hematol. Volume: 40 Issue: 9 Pages: 724-737
  • DOI: 10.1016/j.exphem.2012.05.007
  • Peer Reviewed
• [Journal Article] Y654 of β-catenin is essential for FLT3/ITD-related tyrosine phosphorylation and nuclear localization of β-catenin (2012)
  • Author(s): Tomohiro Kajiguchi
  • Journal Title: Eur J Haematol Volume: (in press) Issue: 4 Pages: 314-320
  • DOI: 10.1111/j.1600-0609.2011.01738.x
  • Peer Reviewed
• [Journal Article] The mTOR inhibitor, everolimus (RAD001), overcomes resistanceto imatinib in quiescent Ph-positive acute lymphoblastic leukemia cells (2011)
  • Author(s): Kuwatsuka Y, Minami M, Minami Y, Sugimoto K, Hayakawa F, Miyata Y, Abe A, Goff DJ, Kiyoi H, Naoe T.
  • Journal Title: Blood Cancer J Volume: 1(5)
  • Peer Reviewed
• [Journal Article] Missense mutations in PML-RARA critical for the lack of responsiveness to arsenic trioxide treatment. (2011)
  • Author(s): Goto E, Tomita A, Hayakawa F, Atsumi A, Kiyoi H, Naoe T
  • Journal Title: Blood Volume: 118 Pages: 1600-1609
  • Peer Reviewed
• [Journal Article] Japan Adult Leukemia Study Group. BCR-ABL1 mutations in patients with imatinib-resistant Philadelphia chromosome-positive leukemia by use of the PCR-Invader assay. (2011)
  • Author(s): Ono T, Miyawaki S, Kimura F, Kanamori H, Ohtake S, Kitamura K, Fujita H, Sugiura I, Usuki K, Emi N, Tamaki S, Aoyama Y, Kaya H, Naoe T, Tadokoro K, Yamaguchi T, Ohno R, Ohnishi K
  • Journal Title: Leuk Res Volume: 35 Pages: 598-603
  • Peer Reviewed
• [Journal Article] PAX5-PML acts as a dual dominant-negative form of both PAX5 and PML (2011)
  • Author(s): Kurahashi S, Hayakawa F, Miyata Y, Yasuda T, Minami Y, Tsuzuki S, Abe A, Naoe T
  • Journal Title: Oncogene Volume: 30 Pages: 1822-1830
  • Peer Reviewed
• [Journal Article] The mTOR inhibitor, everolimus(RAD001), overcomes resistance to imatinib in quiescent Ph-positive acute lymphoblastic leukemia cells (2011)
  • Author(s): Kuwatsuka Y, Naoe T, et al
  • Journal Title: Blood Cancer Journal Volume: 1 Issue: 5 Pages: 1-7
  • DOI: 10.1038/bcj.2011.16
  • Peer Reviewed
• [Journal Article] Missense mutations in PML-RARA are critical for the lack of responsiveness to arsenic trioxide treatment (2011)
  • Author(s): Goto E, Naoe T, et al
  • Journal Title: Blood Volume: 118 Pages: 1600-1609
  • Peer Reviewed
• [Journal Article] Japan Adult Leukemia Study Group. BCR-ABL1 mutations in patients with imatinib-resistant Philadelphia chromosome-positive leukemia by use of the PCR-Invader assay (2011)
  • Author(s): Ono T, Naoe T, et al
  • Journal Title: Leuk Res Volume: 35 Pages: 598-603
  • Peer Reviewed
• [Journal Article] PAX5-PML acts as a dual dominant-negative form of both PAX5 and PML. Oncogene (2011)
  • Author(s): Kurahashi S, Naoe T, et al
  • Journal Title: Oncogene Volume: 30 Pages: 1822-1830
  • Peer Reviewed
• [Journal Article] BCR-ABL1 mutations in patients with imatinib-resistant Philadelphia chromosome-positive leukemia by use of the PCR-Invader assay. (2011)
  • Author(s): Ono T, Naoe T, et al.
  • Journal Title: Leuk Res. Volume: in press
  • Peer Reviewed
• [Journal Article] AX5-PML acts as a dual dominant-negative form of both PAX 5 and PML. (2011)
  • Author(s): Kurahashi S, Naoe T, et al.
  • Journal Title: Oncogene Volume: in press
  • Peer Reviewed
• [Journal Article] Trough plasma concentration of imatinib reflects BCR-ABL kinase inhibitory activity and clinical response in chronic-phase chronic myeloid leukemia: a report from the BINGO study. (2010)
  • Author(s): Ishikawa Y, Kiyoi H, Watanabe K, Miyamura K, Nakano Y, Kitamura K, Kohno A, Sugiura I, Yokozawa T, Hanamura A, Yamamoto K, Iida H, Emi N, Suzuki R, Ohnishi K, Naoe T.
  • Journal Title: Cancer Sci Volume: 101 Pages: 2186-2192
  • NAID: 10027832450
  • Peer Reviewed
• [Journal Article] Trough plasma concentration of imatinib reflects BCR-ABL kinase inhibitory activity and clinical response in chronic-phase chronic myeloid leukemia : a renort from the BINGO study. (2010)
  • Author(s): Ishikawa Y, Naoe T, et al.
  • Journal Title: Cancer Sci. Volume: 101 Pages: 2186-92
  • Peer Reviewed
• [Presentation] Usefulness of Peripheral Blood Circulating DNAs As an Alternative to DNA From Bone Marrow Cells to Detect CpG Global Methylation Status and Genetic Mutations in Patients with Myelodysplastic Syndromes (2012)
  • Author(s): Iriyama C, Tomita A, Naoe T,et al
  • Organizer: The American Society of Hematology 54th Annual Meeting
  • Place of Presentation: Atlanta USA
  • Year and Date: 2012-12-10
• [Presentation] Ri tuxi mab Sensitivity to De Novo DLBCL Cells Showing the Specific Phenotype of CD20 Protein Immunohistochemistry-Positive / Flow Cytometory-Negative: Analyses of Its Clinical Significances and the Molecular Mechanisms (2012)
  • Author(s): Tomi ta A, Naoe T,et al
  • Organizer: The American Society of Hematology 54th Annual Meeting
  • Place of Presentation: Atlanta USA
  • Year and Date: 2012-12-09
• [Presentation] Outcome of Pediatric-Type Therapy for Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia (ALL) in Adolescents and Young Adults (AYA): A Study by the Japan Adult Leukemia Study Group (JALSG ALL202-U study) (2012)
  • Author(s): Sakura T, Naoe T,et al
  • Organizer: The American Society of Hematology 54th Annual Meeting
  • Place of Presentation: Atlanta USA
  • Year and Date: 2012-12-08
• [Presentation] Incidence and Clinical Features of Core Binding Factor Acute Myeloid Leukemia: A Collaborative Study of the Japan Adult Leukemia Study Group and the Korean Society of Hematology (2012)
  • Author(s): Taki T, Kiyoi H, Naoe T, et al
  • Organizer: The American Society of Hematology 54th Annual Meeting
  • Place of Presentation: Atlanta USA
  • Year and Date: 2012-12-08
• [Presentation] Wnt signaling is associated with anti-apoptosis in the interaction between acute myeloid leukemia cells and stromal cells (2012)
  • Author(s): Minami Y, Naoe T, et al
  • Organizer: The American Society of Hematology 54th Annual Meeting
  • Place of Presentation: Atlanta USA
  • Year and Date: 2012-12-08
• [Presentation] EVI1 elicits resistance to apoptosis which can be overcome through application of AKTi or ABT-737 (2012)
  • Author(s): 島田和之,直江知樹,他
  • Organizer: 第74回日本血液学会学術集会
  • Place of Presentation: 国立京都国際会館(京都市)
  • Year and Date: 2012-10-20
• [Presentation] Correlation of serum IL-6 with exhaustion of CMV-specific T cells after allogeneic stem cell transplantation (2012)
  • Author(s): Nishida T, Naoe T,et al
  • Organizer: 平成24年日本血液学会.
  • Place of Presentation: 国立京都国際会議場(京都市)
  • Year and Date: 2012-10-19
• [Presentation] Leukaemia escape from HLA-specific T-lymphocyte pressure in a recipient of HLA one locus-mismatched BMT (2012)
  • Author(s): Murata M, Naoe T,et al
  • Organizer: The 38th Annual Meeting of the European Group for Blood and Marrow Transplantation.
  • Place of Presentation: Geneva, Switzerland
  • Year and Date: 2012-04-01
• [Presentation] Rituximab Sensitivity to De Novo DLBCL Cells Showing the Specific Phenotype of CD20 Protein Immunohistochemistry-Positive / Flow Cytometory-Negative: Analyses of Its Clinical Significances and the Molecular Mechanisms. (2012)
  • Author(s): Tomita A, Naoe T,et al.
  • Organizer: The American Society of Hematology 54th Annual Meeting.
  • Place of Presentation: Atlanta USA
• [Presentation] Usefulness of Peripheral Blood Circulating DNAs As an Alternative to DNA From Bone Marrow Cells to Detect CpG Global Methylation Status and Genetic Mutations in Patients with Myelodysplastic Syndromes. (2012)
  • Author(s): Iriyama C, Tomita A, Naoe T, et al.
  • Organizer: The American Society of Hematology 54th Annual Meeting.
  • Place of Presentation: Atlanta USA
• [Presentation] RhoH Downregulates Rac Through RhoGAP Family Protein (2011)
  • Author(s): Katsumi A, Naoe T,et al
  • Organizer: The American Society of Hematology 53th Annual Meeting
  • Place of Presentation: San Diego USA
  • Year and Date: 2011-12-12
• [Presentation] Retention of Slow-Cycling CD34+ cells During Imatinib Treatment and Rapid Decline After 2nd ABL-TKI Treatment in Ph+ Leukemia Cells (2011)
  • Author(s): Minami Y, Naoe T,et al
  • Organizer: The American Society of Hematology 53th Annual Meeting
  • Place of Presentation: San Diego USA
  • Year and Date: 2011-12-12
• [Presentation] A Novel STAT3 Inhibitor OPB-31121 Induces Tumor-Specific Growth Inhibition in a Wide Range of Hematopoietic Malignancies without Growth Suppression of Normal Hematopoietic Cells (2011)
  • Author(s): Hayakawa F, Naoe T,et al
  • Organizer: The American Society of Hematology 53th Annual Meeting
  • Place of Presentation: San Diego USA
  • Year and Date: 2011-12-12
• [Presentation] A Novel STAT3 Inhibitor OPB-31121 Induces Tumor-Specific Growth Inhibition in a Wide Range of Hematopoietic Malignancies without Growth Suppression of Normal Hematopoietic Cells (2011)
  • Author(s): Hayakawa F, Naoe T, et al
  • Organizer: 53^<rd> ASH Annual Meeting and Exposition
  • Place of Presentation: San Diego, CA U.S.A
  • Year and Date: 2011-12-12
• [Presentation] CD20 Protein Immunohistochemistry-Positive/Flow Cytometry-Negative Diffuse Large B-Cell Lymphoma-Analyses of the Molecular Mechanisms and Rituximab Effectiveness (2011)
  • Author(s): Tokunaga T, Naoe T,et al
  • Organizer: The American Society of Hematology 53th Annual Meeting
  • Place of Presentation: San Diego USA
  • Year and Date: 2011-12-11
• [Presentation] Biomarkers In Cell Death of Imatinib-Resistant Ph-Leukemia Cells During Treatment with mTOR Inhibitor, Everolimus (2010)
  • Author(s): Miho M, Naoe T, et al
  • Organizer: The American Society of Hematology 53th Annual Meeting
  • Place of Presentation: Orlando USA
  • Year and Date: 2010-12-06
• [Presentation] Biomarkers In Cell Death of Imatinib-Resistant Ph-Leukemia Cells During Treatment with mTOR Inhibitor, Everolimus. (2010)
  • Author(s): Miho M, Naoe T, et al.
  • Organizer: 52nd ASH Annual Meeting and Exposition
  • Place of Presentation: Orlando, FL U.S.A
  • Year and Date: 2010-12-06
• [Book] 造血器腫瘍取り扱い規約 (2010)
  • Author(s): 直江知樹 他
  • Total Pages: 265
  • Publisher: 金原出版
• [Book] 造血器腫瘍取り扱い規約 (2010)
  • Author(s): 直江知樹, 他
  • Publisher: 金原出版
• [Patent(Industrial Property Rights)] RNA 内包キャリア組成物 (2010)
  • Inventor(s): 国立大学法人岐阜大学、北海道システム・サイエンス株式会社、国立大学法人名古屋大学
  • Industrial Property Rights Holder: 国立大学法人岐阜大学、北海道システム・サイエンス株式会社、国立大学法人名古屋大学
  • Filing Date: 2010-10-19
• [Patent(Industrial Property Rights)] 細胞を用いたデリバリーシステムの構築 (2010)
  • Inventor(s): 直江知樹, 他
  • Industrial Property Rights Holder: 北海道システム/法人岐大/法人名大
  • Filing Date: 2010-10-19