Molecularly targeted therapy for Glioblastoma

2014 Fiscal Year Final Research Report

• Project/Area Number: 24791563
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Orthopaedic surgery
• Research Institution: Keio University
• Principal Investigator: IWANAMI AKIO 慶應義塾大学, 医学部, 助教 (40327557)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: グリオーマ / 分子標的療法 / PML / 脊髄腫瘍 / 脳腫瘍

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.

Free Research Field

脊椎脊髄