期刊
CANCER LETTERS
卷 504, 期 -, 页码 137-145出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2021.02.001
关键词
Pediatric brain tumor; Apoptosis; Sapanisertib; INK128; mTOR
类别
资金
- Alex's Lemonade Stand Foundation
- Spencer Grace Foundation
- Ace for a Cure Foundation
- Giant Food Pediatric Cancer Research Fund
- National Cancer Institute [P30CA006973]
- NIH [U24CA220341, U01CA217885, U24CA194107, U54CA209891, U01 CA184898]
By constructing a neural stem cell model, it was found that the combination of mTOR inhibitors and carboplatin may be an effective therapy for high-risk medulloblastoma.
Medulloblastoma is the most common malignant pediatric brain tumor. Tumors having high levels of c-MYC have the worst clinical prognosis, with only a minority of patients surviving. To address this unmet clinical need, we generated a human neural stem cell model of medulloblastoma that recapitulated the most aggressive subtype phenotypically and by mRNA expression profiling. An in silica analysis of these cells identified mTOR inhibitors as potential therapeutic agents. We hypothesized that the orally bioavailable TORC1/2 kinase inhibitor TAK228 would have activity against MYC-driven medulloblastoma. TAK228 inhibited mTORC1/2, decreased cell growth and caused apoptosis in high-MYC medulloblastoma cell lines. Comprehensive metabolic profiling of medulloblastoma orthotopic xenografts showed upregulation of glutathione compared to matched normal brain. TAK228 suppressed glutathione production. Because glutathione is required to detoxify platinum-containing chemotherapy, we hypothesized that TAK228 would cooperate with carboplatin in medulloblastoma. TAK228 synergized with carboplatin to inhibit cell growth and induce apoptosis and extended survival in orthotopic xenografts of high-MYC medulloblastoma. Brain-penetrant TORC1/2 inhibitors and carboplatin may be an effective combination therapy for high-risk medulloblastoma.
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