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Glioblastoma: Emerging Treatments and Novel Trial Designs
Article

Transcriptomics-Based Phenotypic Screening Supports Drug Discovery in Human Glioblastoma Cells

1
IOTA Pharmaceuticals Ltd., St Johns Innovation Centre, Cowley Road, Cambridge CB4 0WS, UK
2
Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK
*
Author to whom correspondence should be addressed.
Academic Editor: Stanley Stylli
Cancers 2021, 13(15), 3780; https://doi.org/10.3390/cancers13153780
Received: 9 June 2021 / Revised: 16 July 2021 / Accepted: 20 July 2021 / Published: 27 July 2021
(This article belongs to the Special Issue Novel Treatment Strategies for Glioblastoma)
Glioblastoma (GBM) remains a particularly challenging cancer, with an aggressive phenotype and few promising treatment options. Future therapy will rely heavily on diagnosing and targeting aggressive GBM cellular phenotypes, both before and after drug treatment, as part of personalized therapy programs. Here, we use a genome-wide drug-induced gene expression (DIGEX) approach to define the cellular drug response phenotypes associated with two clinical drug candidates, the phosphodiesterase 10A inhibitor Mardepodect and the multi-kinase inhibitor Regorafenib. We identify genes encoding specific drug targets, some of which we validate as effective antiproliferative agents and combination therapies in human GBM cell models, including HMGCoA reductase (HMGCR), salt-inducible kinase 1 (SIK1), bradykinin receptor subtype B2 (BDKRB2), and Janus kinase isoform 2 (JAK2). Individual, personalized treatments will be essential if we are to address and overcome the pharmacological plasticity that GBM exhibits, and DIGEX will play a central role in validating future drugs, diagnostics, and possibly vaccine candidates for this challenging cancer.
We have used three established human glioblastoma (GBM) cell lines—U87MG, A172, and T98G—as cellular systems to examine the plasticity of the drug-induced GBM cell phenotype, focusing on two clinical drugs, the phosphodiesterase PDE10A inhibitor Mardepodect and the multi-kinase inhibitor Regorafenib, using genome-wide drug-induced gene expression (DIGEX) to examine the drug response. Both drugs upregulate genes encoding specific growth factors, transcription factors, cellular signaling molecules, and cell surface proteins, while downregulating a broad range of targetable cell cycle and apoptosis-associated genes. A few upregulated genes encode therapeutic targets already addressed by FDA approved drugs, but the majority encode targets for which there are no approved drugs. Amongst the latter, we identify many novel druggable targets that could qualify for chemistry-led drug discovery campaigns. We also observe several highly upregulated transmembrane proteins suitable for combined drug, immunotherapy, and RNA vaccine approaches. DIGEX is a powerful way of visualizing the complex drug response networks emerging during GBM drug treatment, defining a phenotypic landscape which offers many new diagnostic and therapeutic opportunities. Nevertheless, the extreme heterogeneity we observe within drug-treated cells using this technique suggests that effective pan-GBM drug treatment will remain a significant challenge for many years to come. View Full-Text
Keywords: glioblastoma; drug-inducible gene expression; Mardepodect; Regorafenib; drug targets; tumor antigens glioblastoma; drug-inducible gene expression; Mardepodect; Regorafenib; drug targets; tumor antigens
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MDPI and ACS Style

Shapovalov, V.; Kopanitsa, L.; Pruteanu, L.-L.; Ladds, G.; Bailey, D.S. Transcriptomics-Based Phenotypic Screening Supports Drug Discovery in Human Glioblastoma Cells. Cancers 2021, 13, 3780. https://doi.org/10.3390/cancers13153780

AMA Style

Shapovalov V, Kopanitsa L, Pruteanu L-L, Ladds G, Bailey DS. Transcriptomics-Based Phenotypic Screening Supports Drug Discovery in Human Glioblastoma Cells. Cancers. 2021; 13(15):3780. https://doi.org/10.3390/cancers13153780

Chicago/Turabian Style

Shapovalov, Vladimir, Liliya Kopanitsa, Lavinia-Lorena Pruteanu, Graham Ladds, and David S. Bailey. 2021. "Transcriptomics-Based Phenotypic Screening Supports Drug Discovery in Human Glioblastoma Cells" Cancers 13, no. 15: 3780. https://doi.org/10.3390/cancers13153780

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