Combination of Ponatinib with Hedgehog Antagonist Vismodegib for Therapy-Resistant BCR-ABL1–Positive Leukemia
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- Seiichiro Katagiri
- Authors' Affiliations: 1First Department of Internal Medicine, Tokyo Medical University, Shinjuku-ku, Tokyo; 2Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya; 3Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga; and 4Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Kyoto, Japan
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- Tetsuzo Tauchi
- Authors' Affiliations: 1First Department of Internal Medicine, Tokyo Medical University, Shinjuku-ku, Tokyo; 2Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya; 3Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga; and 4Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Kyoto, Japan
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- Seiichi Okabe
- Authors' Affiliations: 1First Department of Internal Medicine, Tokyo Medical University, Shinjuku-ku, Tokyo; 2Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya; 3Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga; and 4Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Kyoto, Japan
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- Yosuke Minami
- Authors' Affiliations: 1First Department of Internal Medicine, Tokyo Medical University, Shinjuku-ku, Tokyo; 2Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya; 3Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga; and 4Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Kyoto, Japan
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- Shinya Kimura
- Authors' Affiliations: 1First Department of Internal Medicine, Tokyo Medical University, Shinjuku-ku, Tokyo; 2Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya; 3Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga; and 4Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Kyoto, Japan
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- Taira Maekawa
- Authors' Affiliations: 1First Department of Internal Medicine, Tokyo Medical University, Shinjuku-ku, Tokyo; 2Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya; 3Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga; and 4Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Kyoto, Japan
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- Tomoki Naoe
- Authors' Affiliations: 1First Department of Internal Medicine, Tokyo Medical University, Shinjuku-ku, Tokyo; 2Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya; 3Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga; and 4Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Kyoto, Japan
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- Kazuma Ohyashiki
- Authors' Affiliations: 1First Department of Internal Medicine, Tokyo Medical University, Shinjuku-ku, Tokyo; 2Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya; 3Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga; and 4Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Kyoto, Japan
書誌事項
- 公開日
- 2013-03-14
- 資源種別
- journal article
- DOI
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- 10.1158/1078-0432.ccr-12-1777
- 公開者
- American Association for Cancer Research (AACR)
この論文をさがす
説明
<jats:title>Abstract</jats:title> <jats:p>Purpose: The Hedgehog signaling pathway is a key regulator of cell growth and differentiation during development. Whereas the Hedgehog pathway is inactive in most normal adult tissues, Hedgehog pathway reactivation has been implicated in the pathogenesis of several neoplasms including BCR-ABL1–positive leukemia. The clear link between the Hedgehog pathway and BCR-ABL1–positive leukemia led to an effort to identify small molecules to block the pathway.</jats:p> <jats:p>Experimental Design: We investigated the combined effects of vismodegib and ponatinib, a pan-ABL1 kinase inhibitor, in nonobese diabetic/severe-combined immunodeficiency (NOD/SCID) repopulating T315I BCR-ABL1–positive cells in vitro and in vivo.</jats:p> <jats:p>Results: We observed that combination with vismodegib and ponatinib helps to eliminate therapy-resistant NOD/SCID repopulating T315I BCR-ABL1–positive cells. The percentage of CD19-positive leukemia cells in peripheral blood was significantly lower in vismodegib + ponatinib–treated mice than that of the vehicle or ponatinib alone (P < 0.001). Spleen weights were also lower in vismodegib + ponatinib–treated mice than in ponatinib alone (P < 0.05). Overall tumor burden, as assessed by BCR-ABL mRNA from bone marrow cells, was significantly lower in vismodegib + ponatinib–treated mice than in ponatinib alone (P < 0.005). We also found that vismodegib significantly reduced BCR-ABL1–positive leukemia cell self-renewal in vitro as well as during serial transplantation in vivo.</jats:p> <jats:p>Conclusions: The combination with a Smo inhibitor and ABL1 tyrosine kinase inhibitors may help eliminate therapy-resistant T315I BCR-ABL1–positive leukemia cells. Our preclinical results indicate that vismodegib has potential as an important option for controlling minimal residual cells in BCR-ABL1–positive leukemia. Clin Cancer Res; 19(6); 1422–32. ©2012 AACR.</jats:p>
収録刊行物
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- Clinical Cancer Research
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Clinical Cancer Research 19 (6), 1422-1432, 2013-03-14
American Association for Cancer Research (AACR)
