Welcome to IOTA's blog: Window on Glioblastoma


CAR-T cell therapies in Glioblastoma

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Executive summary
The immune system surveys the body throughout a person’s life to detect and eliminate tumour cells as well as infections such as influenza. In cancer patients, tumour cells have escaped these body defences and grow unchecked. Scientists and clinicians now have the tools to create new defences, in the form of CAR T-cells, which are manufactured from the patient’s own white blood cells using genetic engineering. This article describes the results of preliminary clinical trials using specially designed CAR-T-cells in glioblastoma patients. The results provide a starting point from which potentially curative therapies can be developed.
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Background
The recent application of immunotherapies to control or even cure some cancers has been hailed as a ‘game changer’ in the field of cancer therapy and has prompted an explosion of related activity in academia and industry. It is perhaps not too fanciful to predict the eventual elimination of at least some cancers as chronic diseases1. Several different strategies are being employed, including vaccination with tumour antigens2, checkpoint inhibition with antibodies to cell surface molecules expressed on tumours3 and adoptive immunotherapy with patient-derived cytotoxic T lymphocytes4. While each approach has potential utility in treating glioblastomas (which will be highlighted in future Window on Glioblastoma articles), here we review some of the first clinical studies in this disease using adoptive immunotherapy with CAR T-cells.
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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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Targeting neuroligin-3 secretion in glioblastoma

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Executive summary
Tumours do not grow in isolation, but are supported by normal cells in the body, sometimes called the ‘tumour microenvironment’. The findings highlighted in this article describe a mouse model in which the brain microenvironment (neurons and astrocytes) can artificially stimulate the growth of implanted human glioblastoma cells. A specific protein, neuroligin-3 (NLGN3) was shown to be responsible for this growth, and the investigators identified a way in which its production can be stopped using a small molecule drug. Although there are technical reasons why this specific type of drug may not be clinically useful, the target NLGN3 itself is of great interest and may offer an effective way to treat glioblastoma and other brain cancers in the future.
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Background
Most attention in cancer research has understandably been focussed on the transformed cells that form the tumour mass and subsequent metastases. However, it is also appreciated that the tumour microenvironment is of critical importance in supporting tumour growth through crosstalk via signalling molecules.1 Aggressive brain cancers, such as glioblastoma (GBM), are no exception to this, as highlighted by work showing how neuronal activity stimulates the growth of two cell types thought to give rise to glioma, namely oligodendroglial precursor cells and earlier neural precursor cells.2 A subsequent paper by Venkatesh et al in 2015 (3 and commentaries in 4,5) took this one step further and identified the synaptic adhesion molecule neuroligin-3 (NLGN3) as a direct stimulator of glioma proliferation through the PI3K–mTOR signalling pathway. This Window on Glioblastoma article focusses on a subsequent (2017) paper by the same group in which they inhibit the secretion of NLGN3 from neuronal cells thereby preventing glioma cell growth in vivo.6 This inhibition was achieved using inhibitors of the ADAM10 sheddase enzyme, both of which are in clinical development for other cancers and therefore may also be of use in GBM treatment.
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Glioblastoma Stem Cells and Drug Discovery

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Executive summary
High grade glioblastoma (GBM) is treated using surgery, radiation and chemotherapy, but despite this, overall patient survival is very limited. In efforts to understand why this is the case, scientists have shown that a population of cells in GBM are resistant to treatment and eventually emerge to form further tumours. These glioblastoma ‘stem cells’ are therefore attractive targets for drug therapy. This article describes how these stem cells may be grown in the laboratory and how they can be used to gain information on specific vulnerabilities they possess which can be exploited in the clinic. The cells can also be used to discover novel chemicals as starting points in the development of future treatments.
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Background
Gliomas, including the aggressive and lethal type IV glioblastomas (GBM) form complex brain tumours with features that limit the efficacy of current medical interventions. A typical treatment regimen involves surgery, radiation and chemotherapy with the alkylating agent temozolomide, but overall survival is only 15 to 19 months.1 This dismal prognosis is due in part to the heterogeneity of tumour cell types, including a population of cancer stem cells that are resistant to therapy and drive the relapse of disease after apparently successful initial intervention. An understanding of the biology of these GBM stem cells is therefore an essential prerequisite for developing novel treatments for overcoming the resistance problem. Given the positioning of stem cells at the head of a hierarchy of cellular development, it seems appropriate that this first in a series of Window on Glioblastoma articles should be devoted to these cells in gliomas. We focus on a recent review from Steven Pollard’s lab at the University of Edinburgh who describe the use of GBM stem cells to identify novel molecular targets and drug candidates through technologies such as cellular reprogramming, genome editing and phenotypic screening.2
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