Targeting MYC-driven replication stress in medulloblastoma with AZD1775 and gemcitabine
| Autor: | Ilango Balakrishnan, Andrea Griesinger, Rajeev Vibhakar, Nicholas K. Foreman, John DeSisto, Adam L. Green, Daniel C. Moreira, Angela Pierce, Eric Prince, Charles G Eberhardt, Apurva Subramanian, Sujatha Venkataraman |
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| Rok vydání: | 2020 |
| Předmět: |
Cancer Research
Programmed cell death Genes myc Antineoplastic Agents Cell Cycle Proteins Mice Transgenic Pyrimidinones medicine.disease_cause Deoxycytidine Article 03 medical and health sciences 0302 clinical medicine In vivo Cell Line Tumor medicine Animals Humans Enzyme Inhibitors Cerebellar Neoplasms WEE1 Inhibitor AZD1775 Medulloblastoma biology business.industry Protein-Tyrosine Kinases medicine.disease Gemcitabine Wee1 Neurology Oncology 030220 oncology & carcinogenesis Cancer research biology.protein Pyrazoles Female Neurology (clinical) Carcinogenesis business 030217 neurology & neurosurgery Ex vivo medicine.drug |
| Zdroj: | J Neurooncol |
| ISSN: | 1573-7373 0167-594X |
| DOI: | 10.1007/s11060-020-03457-0 |
| Popis: | 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: 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. CONCLUSION: Our results identified a potent new synergistic treatment combination for MYC-driven medulloblastoma that warrants exploration in early phase clinical trials. |
| Databáze: | OpenAIRE |
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