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. 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. RESULTS: CONCLUSION: Our results identified a potent new synergistic treatment combination for MYC-driven medulloblastoma that warrants exploration in early phase clinical trials.
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Authors | Daniel C Moreira, Sujatha Venkataraman, Apurva Subramanian, John Desisto, Ilango Balakrishnan, Eric Prince, Angela Pierce, Andrea Griesinger, Adam Green, Charles G Eberhardt, Nicholas K Foreman, Rajeev Vibhakar |
Journal | Journal of neuro-oncology
(J Neurooncol)
Vol. 147
Issue 3
Pg. 531-545
(May 2020)
ISSN: 1573-7373 [Electronic] United States |
PMID | 32180106
(Publication Type: Journal Article)
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Chemical References |
- Antineoplastic Agents
- Cell Cycle Proteins
- Enzyme Inhibitors
- Pyrazoles
- Pyrimidinones
- Deoxycytidine
- Protein-Tyrosine Kinases
- WEE1 protein, human
- adavosertib
- Gemcitabine
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Topics |
- Animals
- Antineoplastic Agents
(administration & dosage)
- Cell Cycle Proteins
(metabolism)
- Cell Line, Tumor
- Cerebellar Neoplasms
(drug therapy, metabolism)
- Deoxycytidine
(administration & dosage, analogs & derivatives)
- Enzyme Inhibitors
(administration & dosage)
- Female
- Genes, myc
(genetics)
- Humans
- Medulloblastoma
(drug therapy, metabolism)
- Mice, Transgenic
- Protein-Tyrosine Kinases
(metabolism)
- Pyrazoles
(administration & dosage)
- Pyrimidinones
(administration & dosage)
- Gemcitabine
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