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Targeting MYC-driven replication stress in medulloblastoma with AZD1775 and gemcitabine.
- Source :
-
Journal of neuro-oncology [J Neurooncol] 2020 May; Vol. 147 (3), pp. 531-545. Date of Electronic Publication: 2020 Mar 16. - Publication Year :
- 2020
-
Abstract
- Purpose: MYC-driven medulloblastomas are highly aggressive childhood tumors with dismal outcomes and a lack of new treatment paradigms. We identified that targeting replication stress through WEE1 inhibition to suppress the S-phase replication checkpoint, combined with the attenuation of nucleotide synthesis with gemcitabine, is an effective strategy to induce apoptosis in MYC-driven medulloblastoma that could be rapidly translated into early phase clinical trials in children. Attenuation of replication stress is a key component of MYC-driven oncogenesis. Previous studies revealed a vulnerability in MYC medulloblastoma through WEE1 inhibition. Here, we focused on elucidating combinations of agents to synergize with WEE1 inhibition and drive replication stress toward cell death.<br />Methods: We first analyzed WEE1 expression in patient tissues by immunohistochemistry. Next, we used high-throughput drug screens to identify agents that would synergize with WEE1 inhibition. Synergy was confirmed by in vitro live cell imaging, ex vivo slice culture models, and in vivo studies using orthotopic and flank xenograft models.<br />Results: WEE1 expression was significantly higher in Group 3 and 4 medulloblastoma patients. The WEE1 inhibitor AZD1775 synergized with inhibitors of nucleotide synthesis, including gemcitabine. AZD1775 with gemcitabine suppressed proliferation and induced apoptosis. Ex vivo modeling demonstrated efficacy in Group 3 medulloblastoma patients, and in vivo modeling confirmed that combining AZD1775 and gemcitabine effectively suppressed tumor growth.<br />Conclusion: Our results identified a potent new synergistic treatment combination for MYC-driven medulloblastoma that warrants exploration in early phase clinical trials.
- Subjects :
- Animals
Cell Line, Tumor
Cerebellar Neoplasms drug therapy
Deoxycytidine administration & dosage
Enzyme Inhibitors administration & dosage
Female
Humans
Medulloblastoma drug therapy
Mice, Transgenic
Gemcitabine
Antineoplastic Agents administration & dosage
Cell Cycle Proteins metabolism
Cerebellar Neoplasms metabolism
Deoxycytidine analogs & derivatives
Genes, myc genetics
Medulloblastoma metabolism
Protein-Tyrosine Kinases metabolism
Pyrazoles administration & dosage
Pyrimidinones administration & dosage
Subjects
Details
- Language :
- English
- ISSN :
- 1573-7373
- Volume :
- 147
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Journal of neuro-oncology
- Publication Type :
- Academic Journal
- Accession number :
- 32180106
- Full Text :
- https://doi.org/10.1007/s11060-020-03457-0