Analysis and basic research of targeted therapy for CML stem cells
| Project/Area Number |
22790908
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Hematology
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| Research Institution | Nagoya University |
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Principal Investigator |
MINAMI Yosuke 名古屋大学, 医学系研究科, COE特任講師 (60513752)
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| Project Period (FY) |
2010 – 2011
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| Project Status |
Completed (Fiscal Year 2011)
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| Budget Amount *help |
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2011: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2010: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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| Keywords | 白血病 / 幹細胞 / キナーゼ阻害剤 / BCR-ABL / mTORシグナル / mTOR阻害剤 |
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| Research Abstract |
Several mathematical models and ex-vivo examinations suggested that imatinib(IM) therapy does not eradicate BCR-ABL-positive leukemia stem cells(LSCs). In optimal responders to IM therapy, BCR-ABL transcripts in the HSC population tended to be more retentive than other populations. Treatment with the second-generation of ABL-tyrosine kinase inhibitors(2nd TKIs) induced more rapid reduction of BCR-ABL transcripts even in the HSC population. In Ph^+leukemia cells serially xenotransplanted into immunodeficient NOG mice, slow-cycling CD34^+cells were insensitive to IM. From comprehensive drug screening of other small compounds using this co-culturing system, we found that inhibitors of PI3K/AKT/mTOR-axis signaling, including rapamycin, were promising candidates. In vitro and in vivo, combination treatment with IM and rapamycin analogue, everolimus(RAD001), induced substantial cell death in the slow-cycling CD34^+population with p70-S6K dephosphorylation. The dual PI3K/mTOR inhibitor, NVP-BEZ235(BEZ), also induced substantial cell death including slow-cycling CD34^+cells at lower doses.
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Report
(3 results)
Research Products
(25 results)
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[Journal Article] Retention of CD34^+CML stem/progenitor cells during imatinib treatment and rapid decline after treatment with second-generation BCR-ABL inhibitors2012
Author(s)
Y Minami, A Abe, M Minami, K Kitamura, J Hiraga, S Mizuno, K Ymamoto, M Sawa, Y Inagaki, K Miyamura, and T Naoe
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Journal Title
Leukemia
Volume: (in press)
Related Report
Peer Reviewed
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[Journal Article] Treatment with mTOR inhibitor, everolimus(RAD001), overcomes resistance to imatinib in quiescent Ph-positive acute lymphoblastic leukemia cells2011
Author(s)
Y Kuwatsuka, M Minami, Y Minami, K Sugimoto, F Hayakawa, Y Miyata, A Abe, DJ Goff, H Kiyoi and T Naoe
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Journal Title
Related Report
Peer Reviewed
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[Presentation] Retention of slow-cycling CD34^+cells during imatinib treatment and rapid decline after 2nd ABL-TKI treatment in Ph^+leukemia cells2011
Author(s)
Y Minami, A Abe, M Minami, Y Kuwatsuka, N Fukushima, K Kitamura, J Hiraga, K Ymamoto, C Jamieson, and T Naoe
Organizer
53rd ASH meeting
Place of Presentation
San Diego, USA
Related Report
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