| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2014: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Outline of Final Research Achievements |
Glioblastomas (GBMs) are resistant to series of therapy. We analyzed GBM cell lines, and clinical samples from patients in phase 1 clinical trials, and find that the promyelocytic leukemia (PML) mediates resistance to mTOR-targeted therapies. Direct mTOR inhibitors that block downstream mTOR signaling promote PML expression in GBMs, and genetic overexpression and knockdown approaches demonstrate that PML prevents mTOR-dependent cell death. Low doses of the PML inhibitor, arsenic trioxide, abrogate PML expression and reverse mTOR kinase inhibitor resistance in vivo, thus markedly inhibiting tumor growth and promoting tumor cell death in mice. These results identify a unique role for PML in mTOR inhibitor resistance and provide a strong rationale for a combination therapeutic strategy to overcome it.
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