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Franshaw, Laura; Hayden, Elisha; Joshi, Swapna; Liu, Jie; Ehteda, Anahid; Pang, Chi Nam Ignatius; Tsoli, Maria; Ziegler, David S
Neuro-oncology, 12/2020, Letnik: 22, Številka: Supplement_3Journal Article
Abstract Diffuse Intrinsic Pontine Glioma (DIPG) are devastating paediatric brainstem tumours. Loss of function mutations in DIPG decrease genetic stability and impair DNA damage response pathways promoting tumourigenesis. Polo-like Kinase 1 (PLK1) is a pivotal controller of cell growth, regulating key intermediaries of DNA replication, homologous repair, the cell cycle and cell division. We have found DIPG cultures consistently overexpress PLK1 with inhibition resulting in decreased tumour cell growth, heightened cell cycle arrest and apoptosis. Single agent treatment using PLK1 inhibitors unprecedentedly doubled the median survival of animals harbouring DIPG tumours. Through gene expression analysis, we’ve showed PLK1 inhibition affected multiple pathways which control the cell cycle, cell death regulation, microtubule organization and regulation of cell migration. We found these pathways of differentially expressed genes were significantly enriched for known targets of both E2F1 and E2F4. Analysis of gene expression and proteomic studies also revealed PLK1 inhibition decreased the activation and expression of key tumour promoting mediators within multiple phases of the cell cycle, decreased expression of tumour promoters including MYC and the PI3K/mTOR pathway and reactivated tumour suppressors p53 and PTEN. Assessing these changes in the treated transcriptome and proteome, we aim to develop multiple potentially translatable combination treatment strategies for DIPG. We have performed mechanistic studies and identified synergism with PLK1 inhibitors and the epigenetic regulator panobinostat, bet/bromodomain inhibitor JQ1, dual PI3K/mTOR inhibitor bimiralisib and PI3K inhibitor BKM120. Finally, we found PLK1 inhibitors act as potent radiosensitizers, enhancing the therapeutic effects of radiotherapy in vitro and in vivo.
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Leto | Faktor vpliva | Izdaja | Kategorija | Razvrstitev | ||||
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Vir: Osebne bibliografije
in: SICRIS
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