Targeting Hedgehog in a CML Stem Cell Pathway

• Project/Area Number: 23501312
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Clinical oncology
• Research Institution: Tokyo Medical University
• Principal Investigator: OKABE Seiichi 東京医科大学, 医学部, 講師 (40366109)
• Co-Investigator(Kenkyū-buntansha): 木口 亨 東京医科大学, 医学部, 助教 (70453727)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2011: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 分子標的治療

Research Abstract

Hedgehog (Hh)-glioma-associated oncogene homolog (Gli) signaling is implicated in a large number of human cancers. In this study, we investigated the effects of the potent Hh antagonist GDC-0449 on the BCR-ABL-positive cell line and primary samples when leukemia cells were protected by a feeder cell line. The numbers of OM9;22 cells significantly increased with S9 cells. Treatment of OM9;22 cells with GDC-0449 caused cell growth inhibition. Treatment of Ph-positive leukemia cells with GDC-0449 and dasatinib in the presence of S9 caused significantly more cytotoxicity than that caused by each drug alone. Inhibition of Gli1 or Gli2 by siRNA transfection reduced the growth of the Ph-positive cell line K562 and increased cytotoxicity of dasatinib. Data from this study suggest that administration of the Hh inhibitor GDC-0449 inhibits BCR-ABL-positive cell growth and enhances the cytotoxic effects of dasatinib in the presence of feeder cells.

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] Effects of the hedgehog inhibitor GDC-0449, alone or in combination with dasatinib, on BCR-ABL-positive leukemia cells. (2012)
  • Author(s): Okabe S, Tauchi T, Tanaka Y, Katagiri S, Ohyashiki K.
  • Journal Title: Stem Cells Dev. Volume: 21 Issue: 16 Pages: 2939-48
  • DOI: 10.1089/scd.2012.0016
  • Peer Reviewed
• [Presentation] Targeting the hedgehog signaling pathway limits the self-renewal of BCR-ABL1 positive leukemia cells (2013)
  • Author(s): 田内 哲三、片桐 誠一朗、岡部 聖一、南陽介、直江 知樹、大屋敷 一馬
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: 札幌
  • Year and Date: 2013-10-11
• [Presentation] Targeting the Hedgehog Signaling Pathway Limits the Self-Renewal of BCR-ABL1 Positive Leukemia Cells : Molecular Mechanisms (2012)
  • Author(s): Tauchi T, Katagiri S, Okabe S, Minami Y, Naoe T, Ohyashiki K
  • Organizer: 54th ASH Annual Meeting and Exposition
  • Place of Presentation: アトランタ
  • Year and Date: 2012-12-10
• [Presentation] 治療抵抗性BCR-ABL1 陽性白血病に対するponatinib を併用したhedgehog 経路の標的療法 (2012)
  • Author(s): 片桐誠一朗、田内哲三、岡部聖一、木村晋也、前川平、大屋敷一馬
  • Organizer: 第74回日本血液学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2012-10-19
• [Presentation] Combined effects of Ponatinib and Dasatinib against T315I mutant forms of BCR-ABL1 (2012)
  • Author(s): Tauchi Tetsuzo, Katagiri Seiichiro, Okabe Seiichi, Kimura Shinya, Maekawa Taira, Ohyashiki Kazuma
  • Organizer: 臨床血液
  • Place of Presentation: 京都
• [Presentation] Targeting the Hedgehog pathway in therapy-resistant BCR-ABL1 positive leukemia with ponatinib (2012)
  • Author(s): Katagiri Seiichiro, Tauchi Tetsuzo, Okabe Seiichi, Kimura Shinya, Maekawa Taira, Ohyashiki Kazuma
  • Organizer: 臨床血液
  • Place of Presentation: 京都
• [Presentation] Co-treatment with ponatinib and HDAC inhibitor vorinostat: A treatment for Ph-positive cells (2012)
  • Author(s): Okabe Seiichi, Tauchi Tetsuzo, Kimura Shinya, Maekawa Taira, Ohyashiki Kazuma
  • Organizer: 臨床血液
  • Place of Presentation: 京都
• [Presentation] Activity of the Aurora Kinase Inhibitor, MLN8237 (alisertib) Alone or in Combination with Ponatinib Against Imatinib-Resistant BCR-ABL-Positive Cells (2012)
  • Author(s): Okabe Seiichi, Tauchi Tetsuzo, Katagiri Seiichiro, Tanaka Yuko, Ohyashiki Kazuma
  • Organizer: AMER SOC HEMATOLOGY
  • Place of Presentation: Atlanta
• [Presentation] Combining ABL1 Kinase Inhibitor, Imatinib and the Jak Kinase Inhibitor TG101348: A Potential Treatment for Residual BCR-ABL Positive Leukemia Cells (2012)
  • Author(s): Okabe Seiichi, Tauchi Tetsuzo, Katagiri Seiichiro, Tanaka Yuko, Ohyashiki Kazuma
  • Organizer: AMER SOC HEMATOLOGY
  • Place of Presentation: Atlanta
• [Presentation] Targeting the Hedgehog Signaling Pathway Limits the Self-Renewal of BCR-ABL1 Positive Leukemia Cells: Molecular Mechanisms (2012)
  • Author(s): Tetsuzo Tauchi, Seiichiro Katagiri, Seiichi Okabe, Yosuke Minami, Tomoki Naoe, Kazuma Ohyashiki
  • Organizer: AMER SOC HEMATOLOGY
  • Place of Presentation: Atlanta
• [Presentation] Targeting the hedgehog signaling pathway in therapy-resistant Bcr-Abl1 positive leukemia with ponatinib (2011)
  • Author(s): Katagiri S, Tauchi T, Okabe S, Ashihara E, Kimura S, Maekawa T, Ohyashiki K
  • Organizer: The 53rd American Society of Hematology Annual Meeting and Exposition
  • Place of Presentation: サンディエゴ
  • Year and Date: 2011-12-10
• [Presentation] BCR-ABL陽性細胞に対するhedgehog inhibitor の単独およびdasatinib 併用の効果 (2011)
  • Author(s): 岡部聖一、田内哲三、大屋敷一馬
  • Organizer: 第73回日本血液学会学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-14
• [Presentation] Combined Effects of a Pan-ABL1 Kinase Inhibitor, Ponatinib and Dasatinib Against T315I Mutant Forms of BCR-ABL1: In Vitro and In Vivo Studies (2011)
  • Author(s): Tetsuzo Tauchi, M.D.1*, Seiichiro Katagiri, M.D.1*, Seiichi Okabe, M.D.1*, Eishi Ashihara, MD, PhD2, Shinya Kimura, MD, PhD3*, Taira Maekawa, MD, DMSci2* and Kazuma Ohyashiki, MD, PhD1
  • Organizer: 53rd ASH（American Society of Hematology） Annual Meeting
  • Place of Presentation: San Diego, California
• [Presentation] Combining ABL1 Kinase Inhibitor, Ponatinib and the Histone Deacetylase (HDAC) Inhibitor Vorinostat: A Potential Treatment for BCR-ABL Positive Leukemia Cells (2011)
  • Author(s): Seiichi Okabe, M.D.1*, Tetsuzo Tauchi, MD, PhD1*, Shinya Kimura, MD, PhD2*, Taira Maekawa, MD, PhD3* and Kazuma Ohyashiki, MD, PhD1
  • Organizer: 53rd ASH（American Society of Hematology） Annual Meeting
  • Place of Presentation: San Diego, California
• [Presentation] Targeting the Hedgehog Signaling Pathway in Therapy-Resistant BCR-ABL1 Positive Leukemia with Ponatinib (2011)
  • Author(s): Seiichiro Katagiri, M.D.1*, Tetsuzo Tauchi, M.D.1*, Seiichi Okabe, M.D.1*, Eishi Ashihara, MD, PhD2, Shinya Kimura, MD, PhD3*, Taira Maekawa, MD, DMSci2* and Kazuma Ohyashiki, MD, PhD1
  • Organizer: 53rd ASH（American Society of Hematology） Annual Meeting
  • Place of Presentation: San Diego, California