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Title: Identification of MYC-dependent therapeutic vulnerabilities for targeting Group 3 medulloblastoma
Authors: Llargués Sistac, Gemma
Issue Date: 2020
Publisher: Newcastle University
Abstract: Introduction Group 3 medulloblastoma (MBGroup3) is a highly aggressive tumour characterised by MYC amplification and elevated expression (17% of MBGroup3). MYC amplification confers a dismal prognosis, and there is an urgent unmet need for novel therapeutic approaches. The identification and targeting of MYC’s biological dependencies thus represent a promising strategy to treat MYC-driven MBGroup3 tumours. Methods Three independent MYC-regulable isogenic MBGroup3 cell lines, in which MYC expression can be directly regulated by shRNA, were used to characterise MYC-dependency in these novel models of MBGroup3 tumours. The lines were used to investigate the role of MYC in drug resistance and sensitivity by characterising the MYC-dependent response to a panel of cancer therapeutics and small molecule inhibitors, to identify drugs whose efficacy is MYC-dependent, or which synergise with MYC knockdown. Three indirect MYC-targeting strategies (targeting MYC transcription and MYC mRNA translation) were assessed using candidate drugs, alongside undertaking a high-throughput compound screen (HTCS) (>500 inhibitors) using the models. Results Data from the MYC-dependent lines was used to identify MYC-dependent differences in drug-sensitivity between MYC-overexpressing and MYC-knockdown cell lines after inhibition of specific proteins. This approach identified several specific druggable dependencies (e.g. cell cycle regulators, DNA-damage response controllers, mitotic control machinery) with potential for the development of treatments against MBGroup3. Integration of drug-sensitivity results with data on MYC transcriptional (by RNA-seq) and biological (by whole-genome CRISPR screening) dependencies in the models, identified BRD4, PLK1, CHK1 and AURK as specific molecular targets. Subsequent validation of target inhibition revealed MYC-dependent effects, associated with downregulation of MYC and target-dependent pathways, across MBGroup3 models. Conclusions These findings support the development of PLK1, CHK and AURK inhibition as therapeutic approaches against MYC-dependent MBGroup3. Future work is now essential to validate our findings in vivo, to support the design of future clinical trials.
Description: Ph. D. Thesis
Appears in Collections:Translational and Clinical Research Institute

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