Accelerating glioblastoma drug discovery: Convergence of patient-derived models, genome editing and phenotypic screening.
Patients diagnosed with glioblastoma (GBM) continue to face a bleak prognosis. It is critical that new effective therapeutic strategies are developed. GBM stem cells have molecular hallmarks of neural stem and progenitor cells and it is possible to propagate both non-transformed normal neural stem cells and GBM stem cells, in defined, feeder-free, adherent culture. These primary stem cell lines provide an experimental model that is ideally suited to cell-based drug discovery or genetic screens in order to identify tumour-specific vulnerabilities. For many solid tumours, including GBM, the genetic disruptions that drive tumour initiation and growth have now been catalogued. CRISPR/Cas-based genome editing technologies have recently emerged, transforming our ability to functionally annotate the human genome. Genome editing opens prospects for engineering precise genetic changes in normal and GBM-derived neural stem cells, which will provide more defined and reliable genetic models, with critical matched pairs of isogenic cell lines. Generation of more complex alleles such as knock in tags or fluorescent reporters is also now possible. These new cellular models can be deployed in cell-based phenotypic drug discovery (PDD). Here we discuss the convergence of these advanced technologies (iPS cells, neural stem cell culture, genome editing and high content phenotypic screening) and how they herald a new era in human cellular genetics that should have a major impact in accelerating glioblastoma drug discovery.
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK; Institute of Genetics and Molecular Medicine, CRUK Edinburgh Centre, University of Edinburgh, UK.
Eoghan
E
O'Duibhir
Institute of Genetics and Molecular Medicine, CRUK Edinburgh Centre, University of Edinburgh, UK. Electronic address: n.carragher@ed.ac.uk.
Neil O
NO
Carragher
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK; Institute of Genetics and Molecular Medicine, CRUK Edinburgh Centre, University of Edinburgh, UK. Electronic address: steven.pollard@ed.ac.uk.
Steven M
SM
Pollard
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D064112:Clustered Regularly Interspaced Short Palindromic Repeats / Q000235:genetics; D055808:Drug Discovery / Q000379:methods*; D000072669:Gene Editing; D015894:Genome, Human / Q000235:genetics; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism
D000970:Antineoplastic Agents
CRISPR/Cas9; Genome editing; Glioblastoma stem cell; HCS; Neural stem cell; Phenotypic screening