Transcriptional changes in GBM through therapy
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ABSTRACT:
PROVIDER: EGAS00001003790 | EGA |
REPOSITORIES: EGA
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Project description:Primary glioblastoma (GBM) tumours recur following treatment. This is likely due to intratumour heterogeneity (ITH), which reduces the effectiveness of cancer therapies by enabling therapy-driven tumour evolution: Darwinian selection of genotypically and/or phenotypically distinct cells (subclones) that resist treatment to seed regrowth of an even less treatable recurrence. To investigate this we sequenced a pilot cohort of nine paired primary and locally recurrent GBM tumours, alongside matched blood samples, in order to begin characterising therapy resistant cells and thereby infer the mechanisms by which they evaded treatment. These data were included in the first data release from the Glioma Longitudinal AnalySiS (GLASS) consortium.
| EGAS00001003546 | EGA
Project description:The scarcity of effective treatment options for high grade brain tumours has led to a wide ranging search for alternative means of therapy for these difficult to treat tumours. Electrical field therapy is one such area that has been considered. The OptuneTM system is an FDA approved novel anti-mitotic device that delivers continuous alternating electric fields to the patient for the treatment of primary and recurrent Glioblastoma multiforme (GBM) (tumor treating fields - TTFields). Alternative electric fields delivery systems are also being investigated for the treatment of various cancers.To further explore alternative potential mechanisms of electric fields as a whole, we ran Optune, DBS electric fields treated and control untreated KNS42, U87 and GIN-31 (primary) cell lines on Clariom S Human Assays to produce genome-wide expression data.
2020-10-01 | E-MTAB-9043 | biostudies-arrayexpress
Project description:Glioblastomas (GBM) are the most common primary CNS tumor. GBMs often recur as highly aggressive, intractable, therapy resistant tumors. Key molecular regulators of acquired radiation resistance in recurrent GBM are largely unknown with a dearth of accurate pre-clinical models. To address this, we generated eight GBM patient-derived xenograft (PDX) models of acquired radiation-therapy selected (RTS) resistance compared with same-patient, treatment naïve (RTU) PDX. A novel bioinformatics pipeline analyzed phenotypic, transcriptomic and kinomic alterations, identifying long non-coding RNAs (lncRNAs) and targetable, PDX-specific kinases. We observed differential transcriptional enrichment of DNA damage repair (DDR) pathways in our RTS models. Multiple molecular routes to acquired radiation-resistance were revealed in our models including PDX-specific kinases that we validated with targeted small molecule inhibitors (SMIs). We identified 184, mostly novel, lncRNAs differentially regulated between RTU and RTS PDX. Several of these lncRNAs were associated with transcriptional changes in DDR, cell cycle progression, stemness, and chromatin remodeling pathways. This study identifies lncRNAs as potential key regulators in recurrent GBM and therapy resistance. We also demonstrate that SMIs aimed at lncRNA-related signaling pathways may represent a novel therapeutic approach for recurrent GBM tumors.
2022-07-01 | GSE206225 | GEO
Project description:Intratumor spatial heterogeneity facilitates therapeutic resistance in glioblastoma (GBM). Nonetheless, understanding of GBM is limited to the resectable tumor core lesion while the seeds for recurrence reside in the unresectable tumor edge. In this study, stratification of GBM to core and edge demonstrated clinically relevant surgical sequelae. We establish regionally derived models of GBM edge and core that retain their spatial identity in a cell autonomous manner. Edge cells show a higher capacity for infiltrative growth, while core cells demonstrate greater therapy resistance. Investigation of intercellular signaling between these two cell populations uncovered the paracrine crosstalk from tumor core that provokes malignancy and therapy resistance of edge cells. These phenotypic alterations were initiated by HDAC1 in GBM core cells which subsequently affect edge cells by secreting the soluble form of CD109 protein. Our data reveal the role of intracellular communication between regionally different populations of GBM cells in tumor recurrence.
2020-07-03 | GSE153746 | GEO
Project description:<h4><strong>BACKGROUND:</strong> Elevated choline kinase alpha (ChoK) is observed in most solid tumours including glioblastomas (GBM), yet until recently, inhibitors of ChoK have demonstrated limited efficacy in GBM models. Given that hypoxia is associated with GBM therapy resistance, we hypothesised that tumour hypoxia could be responsible for such limitations. We therefore evaluated in GBM cells, the effect of hypoxia on the function of JAS239, a potent ChoK inhibitor.</h4><h4><strong>METHODS:</strong> Rodent (F98 and 9L) and human (U-87 MG and U-251 MG) GBM cell lines were subjected to 72 hours of hypoxia conditioning and treated with JAS239 for 24 hours. NMR metabolomic measurements and analyses were performed to evaluate the signalling pathways involved. In addition, cell proliferation, cell cycle progression and cell invasion were measured in cell monolayers and 3D spheroids, with or without JAS239 treatment in normoxic or hypoxic cells to assess how hypoxia affects JAS239 function.</h4><h4><strong>RESULTS:</strong> Hypoxia and JAS239 treatment led to significant changes in the cellular metabolic pathways, specifically the phospholipid and glycolytic pathways associated with a reduction in cell proliferation via induced cell cycle arrest. Interestingly, JAS239 also impaired GBM invasion. However, JAS239 effects were variable depending on the cell line, reflecting the inherent heterogeneity observed in GBMs.</h4><h4><strong>CONCLUSION:</strong> Our findings indicate that JAS239 and hypoxia can deregulate cellular metabolism, inhibit proliferation and alter cell invasion. These results may be useful for the design of new therapeutic strategies based on ChoK inhibition that can act on multiple pro-tumorigenic features.</h4>
2024-06-18 | MTBLS6212 | MetaboLights
Project description:The purpose of this study is to determine whether the combination of two agents, INC280 and bevacizumab, is safe and effective when administered to patients with Glioblastoma Multiforme (GBM) who have progressed after receiving prior therapy or who have unresectable GBM.
| 2185625 | ecrin-mdr-crc
Project description:Glioblastoma multiforme (GBM) is a highly aggressive and vascularized malignant brain tumor. Anti-VEGF therapy is widely used for the treatment of GBM, however it has shown only minor impact on patient survival. Thus, more precise molecular mechanisms for glioma angiogenesis are needed for the advance in the treatment of GBM. Here, we investigated gene expression profile of brain endothelial cells and glioma endothelial cells using RNA sequencing to validated special molecular features of glioma endothelial cells.
2017-11-24 | GSE90459 | GEO
Project description:Glioblastoma (GBM) is the most lethal brain tumour that occurs in adults and treatment for GBM has been largely unsuccessful. Ionizing radiation (IR) and chemotherapeutic agents are employed as standard of care treatment for GBM patients and both result in DNA damage. Previous data identified phosphorylation of PTEN at tyrosine 240 (pY240) in samples from patients with recurrent GBM receiving standard of care treatment and was associated with decreased overall survival. Here we demonstrate that pY240 PTEN that was triggered by FGFR2 signaling, enhanced DNA repair by facilitating the loading of PTEN onto chromatin through its interaction with KI-67 and subsequent recruitment of the DNA repair protein, RAD51, to sites of DNA damage. Thus, tumour cells with pY240 PTEN are efficient at repairing DNA damage which would be predicted to result in resistance to therapy. These findings suggest the FGFR-pY240 PTEN-DNA repair mechanism as a therapeutic target for enhancing GBM therapy.
2017-08-07 | MSV000081423 | MassIVE
Project description:Macrophages accumulate with glioblastoma multiforme (GBM) progression, and can be acutely targeted via inhibition of colony stimulating factor-1 receptor (CSF-1R) to regress high-grade tumors in animal models. However, whether and how resistance emerges in response to sustained CSF-1R blockade is unknown. Here, we investigate whether long-term CSF-1R inhibition can stably regress GBM in preclinical trials. We show that while overall survival is significantly prolonged, tumors recur eventually in >50% of mice. Upon isolation and transplantation of recurrent tumor cells into naïve animals, gliomas re-establish sensitivity to CSF-1R inhibition, indicating that resistance is microenvironment-driven. PI3K pathway activity was elevated in recurrent GBM, driven by macrophage-derived IGF-1 and tumor cell IGF-1R. Consequently, combining IGF-1R or PI3K blockade with continuous CSF-1R inhibition in recurrent tumors significantly prolonged overall survival. By contrast, monotherapy with IGF-1R or PI3K inhibitors in rebound or treatment-naïve tumors was less effective, indicating the necessity of combination therapy to expose PI3K signaling-dependency in recurrent disease. Our findings thus reveal a potential therapeutic approach for treating resistance to CSF-1R inhibitors in the clinical setting.
2016-05-20 | GSE80399 | GEO
Project description:Glioblastoma multiforme (GBM), is the most common form of adult malignant brain tumor, highly heterogeneous and relatively resistant to therapy with a poor prognosis. As other cancers, GBM starts from a relatively small fraction of poorly differentiated and particularly aggressive cancer stem cells (CSCs), responsible for aberrant proliferation and invasion, rapidly spreading the tumor growth in the other parts of the central nervous system. Due to the extreme tumor heterogeneity, standard therapies (i.e., surgery, chemotherapy and radiotherapy) provide poor positive outcomes and cancers usually recur. Therefore, alternative approaches, possibly targeting CSCs, are necessary for searching effective therapeutic strategies against GBM. Among many emerging new therapeutic strategies, ultra-short pulsed electric fields (PEF) are considered extremely promising in cancer therapy and our previous results demonstrated the capability of a specific electric pulse protocol, characterized by a high pulse amplitude and a short duration, to selectively affect medulloblastoma CSCs preserving normal cells. Here, we tested the same exposure protocol to investigate the response of U87 GBM cells, and of U87-derived neurospheres. By analyzing different in vitro biological endpoints and taking advantage of transcriptomic and bioinformatics analyses, we found that, independently of CSCs content, PEF exposure affected cell proliferation and differentially regulated hypoxia, inflammation and P53/cell cycle checkpoints. PEF exposure also significantly reduced the clonogenic potential, reducing the ability to form new neurospheres, and inhibited the invasion potential. Importantly, exclusively in U87 neurospheres, PEF exposure changed the expression of stemness/differentiation genes. Our results, confirm this physical stimulus as a promising treatment to destabilize the extreme intra-tumoral GBM heterogeneity opening up the possibility to develop future therapeutic strategies mediated by PEF exposure.
2022-03-31 | GSE195506 | GEO