Welcome to IOTA's blog: Window on Glioblastoma


Discovery of new epigenetic targets by screening engineered GBM cells in vivo

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Executive summary
Drug molecules for treating glioblastoma are usually discovered by testing collections of chemical compounds to identify those that can inhibit cancer cell growth in vitro (i.e. in a test tube or equivalent), assuming that the cells behave in the same way as in the tumour itself (i.e. in vivo). The current study shows that this assumption is not necessarily true. By complex genetic engineering, the authors identify a new series of genes (and their corresponding proteins) as potential targets for GBM drug discovery.
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Background
A fundamental question in glioblastoma (GBM) research is why patients treated with drugs that are highly effective in preclinical models show poor clinical responses. In the last Window on Glioblastoma article, we highlighted GBM stem cells as the tumour cell population responsible for re-emergence of tumours after initial drug treatments and discussed how these cells can be isolated and used in drug discovery programmes. One reason for treatment failure could be the difference in behaviour of GBM cells (of whatever type) in vitro compared to those within authentic GBM tumours in patients in vivo, where GBM tumours occur in a microenvironment of stromal cells and stress conditions that are difficult to fully replicate in vitro. This Window article reviews a recent paper in Nature by Miller et al (together with an accompanying News & Views article) which directly addresses the in vitro/vivo issue and, in the process reveals some potential epigenetic targets for GBM drug development.1,2
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Drugs for targeting transcription factors in GBM: OLIG2 as a case study

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Executive summary
In trying to find new targets for drugs to treat cancers like glioblastoma, scientists often look at the basic components of tumour cells to see how they differ from their normal counterparts. One difference is in the action of proteins called transcription factors (TFs) that bind to DNA and increase or reduce the expression of specific genes that code for proteins. TFs are often ‘switched on’ in cancers and this article describes one of them, OLIG2, which is associated with glioblastoma cells. Using both computer analysis and laboratory science, the authors of the highlighted paper show how they have identified chemical compounds that block the action of OLIG2 in glioblastoma cells and from which a candidate molecule has been selected for further development as a medicine. In addition, the methods they use are of interest to investigators wanting to inhibit other classes of transcription factors using small chemical molecules.
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Background
The human genome encodes more than 1,500 transcription factors (TFs), each binding to specific regions of DNA, as regulators of gene expression.1 Not surprisingly therefore, dysregulation of TF action is a feature of many cancers and TF proteins are potential drug targets for these diseases.2 Several transcription factors (particularly those relating to neuronal development) have been implicated in glioblastoma (e.g. in 3) and may feature in future Window on Glioblastoma articles. Here, we highlight the OLIG2 transcription factor, a basic HLH (helix-loop-helix) protein associated with glioblastoma, for example, in 4. We focus on a paper by Tsigelny et al 5 in which small molecule inhibitors of OLIG2 dimerisation (identified by virtual screening) were shown to inhibit the growth of glioblastoma in vitro and in mouse xenograft models in vivo.
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