| 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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| 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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