Evaluation of the immune effects of tumor-treating electric fields (TTFields) in GBM patients
Ontology highlight
ABSTRACT:
PROVIDER: EGAS00001005392 | EGA |
REPOSITORIES: EGA
Similar Datasets
Project description:Introduction: The EORTC22033-26033 clinical trial investigated whether initial temozolomide (TMZ) chemotherapy confers survival advantage compared to radiotherapy (RT) in low grade glioma patients. In this study we performed gene expression profiling on tissues from this trial in order to identify markers associated with progression free survival and treatment response in this well-defined cohort of patients. Methods: Gene expression profiling, performed on 195 samples, was used to assign tumors to one of six intrinsic glioma subtypes (IGS; molecularly similar tumors predefined by unsupervised gene expression analysis) and to extract the cellular composition of immune infiltrates. DNA copy number changes were determined on samples assigned to IGS-16. Results: We confirm that IGS-subtypes are prognostic in EORTC22033-26033 clinical trial samples. Specific genetic changes segregate in distinct IGS subtypes: most samples assigned to IGS-9 have IDH-mutations combined with 1p19q codeletion, samples assigned to IGS-17 have IDH-mutations with intact 1p19q chromosomal arms and samples assigned to other intrinsic subtypes often are IDH-wildtype and 1p19q intact. A trend towards benefit from RT compared to TMZ was observed for samples assigned to IGS-9 (HR for TMZ is 1.90, 95% CI [0.95, 3.80], P=0.065), but not for samples assigned to IGS-17 (HR for TMZ vs RT is 0.87, 95% CI[0.50, 1.51], P=0.62). We did not identify genes significantly associated with progression free survival (PFS) within intrinsic subtypes, though follow-up time is limited. We also show that LGGs and GBMs differ in their immune-infiltrate with LGGs having higher suppressor and lower effector cell populations compared to GBMs. This suggests that LGGs are less amenable to checkpoint inhibitor type immune therapies than GBMs. Gene expression analysis and copy number analysis also identified one patient with a pilocytic astrocytoma (PA). Conclusion: Intrinsic glioma subtypes are prognostic for PFS in EORTC22033-26033 clinical trial samples.
2019-03-19 | GSE107850 | GEO
Project description:Purpose: Proficient DNA repair by homologous recombination (HR) facilitates resistance to chemo-radiation in glioma stem cells (GSCs). We evaluated whether compromising HR by targeting HSP90, a molecular chaperone required for the function of key HR proteins, using onalespib, a long-acting, brain-penetrant HSP90 inhibitor, would sensitize high-grade gliomas to chemo-radiation in vitro and in vivoExperimental Design: The ability of onalespib to deplete HR client proteins, impair HR repair capacity, and sensitize GBM to chemo-radiation was evaluated in vitro in GSCs, and in vivo using zebrafish and mouse intracranial glioma xenograft models. The effects of HSP90 inhibition on the transcriptome and cytoplasmic proteins was assessed in GSCs and in ex vivo organotypic human glioma slice cultures.Results: Treatment with onalespib depleted CHK1 and RAD51, two key proteins of the HR pathway, and attenuated HR repair, sensitizing GSCs to the combination of radiation and temozolomide (TMZ). HSP90 inhibition reprogrammed the transcriptome of GSCs and broadly altered expression of cytoplasmic proteins including known and novel client proteins relevant to GSCs. The combination of onalespib with radiation and TMZ extended survival in a zebra fish and a mouse xenograft model of GBM compared to the standard of care (radiation and TMZ) or onalespib with radiation.Conclusions: The results of this study demonstrate that targeting HR by HSP90 inhibition sensitizes GSCs to radiation and chemotherapy and extends survival in zebrafish and mouse intracranial models of GBM. These results provide a preclinical rationale for assessment of HSP90 inhibitors in combination with chemoradiation in GBM patients.
2022-04-15 | GSE193635 | GEO
Project description:Glioblastoma is an aggressive and highly invasive disease that often resists treatment. Tumour cells can restrict the DNA-damaging effects of temozolomide (TMZ) and radiation therapy (RT) using the DNA damage response (DDR) mechanism which activates cell cycle arrest and DNA repair pathways. Ataxia-telangiectasia and Rad3-Related protein (ATR) plays a pivotal role in the recognition of DNA damage induced by chemotherapy and radiation and downstream activation of DDR pathways. Furthermore, a growing body of evidence indicates DNA damage and inhibition of ATR can stimulate a proinflammatory response that activates innate immunity against tumour cells. Here, we investigated the change of gene expression of treated glioblastoma cell lines from TMZ+RT and ATR inhibition (using gartisertib (M4344)) combined with TMZ+RT.
2024-01-18 | GSE211272 | GEO
Project description:Comparison of treatment sensitive GSC clones (TSGC) with treatment resistant GSC clones (TRGC). We used microarrays to identify molecular signatures of TRGC (upregulated genes). We used radiation treatment (RT) or RT plus TMZ to select treatment resistant GSC clones (TRGC)
2013-11-01 | E-GEOD-46531 | biostudies-arrayexpress
Project description:To better understand the mechanism underlying the therapeutic effect of Delta-24-ACT, we evaluated the triggered immune response. Thus, we intratumorally injected Delta-24-ACT, Delta-24-RGD or PBS (mock group) 3 days after NP53 cell implantation (0D). Then, tumor immune infiltrate was analyzed by NanoString (15 days)
2022-05-11 | GSE197374 | GEO
Project description:Tremendous studies have found that the abnormality of long noncoding RNA (lncRNA) contributed to cancer initiation, progression, and recurrence via multiple signaling cascades. Nevertheless, the possible underlying mechanisms of lncRNA in temozolomide (TMZ)-resistant glioma were not well understood, hindering the improvement of TMZ-based therapies against glioma. The present study illustrated that the lncRNA KCNQ1OT1 increased in TMZ-resistant gliomas cells compared to the parental cells. Introduction of KCNQ1OT1 boosted glioma cell viability, clonogenicity and rhodamine 123 efflux while hampered apoptosis post-exposure to TMZ. Consistent with bioinformatic prediction, KCNQ1OT1 directly sponged miR-761, which was downregulated in TMZ-resistant glioma cell lines. Overexpression of miR-761 attenuated glioma cell viability and clonogenicity while triggered apoptosis and rhodamine 123 cellular accumulation post-exposure to TMZ, leading to rehabilitated glioma TMZ-sensitivity, which was against the function of KCNQ1OT1. miR-761 bound to 3’-untranslated region of PIM1, a proto-oncogene with constitutive serine/threonine kinase activity, attenuated PIM1-mediated signaling cascades. Furthermore, stable knockdown of KCNQ1OT1 by small hairpin RNA amplified the TMZ-induced tumor regression in TMZ-resistant U251 mouse models. Briefly, the present study evaluated KCNQ1OT1 conferred TMZ resistance by sponging miR-761 and releasing PIM1 expression, resulting in activation of PIM-mediated MDR1/c-Myc/Survivin signaling pathways. The findings mentioned above extended the knowledge of lnRNA KCNQ1OT1 in the regulation of chemoresistance in glioma and provided a promising therapeutic target for TMZ-resistant glioma patients. Long noncoding RNA profiling by array
2020-10-13 | GSE144784 | GEO
Project description:In homeostasis, because of the blood-brain barrier, immune cells rarely infiltrate the central nervous system (CNS). However, after spinal cord injury (SCI), many cells, including both myeloid and T cells, infiltrate the spinal cord. However, the role immune cells play in SCI remains controversial. We are curious whether after SCI there are self-peptides that are released and sensed by T cells that then modulate response to CNS injury.
2023-01-24 | MSV000091130 | MassIVE
Project description:Dying pancreatic cancer cells from chemoradiation can directly stimulate repopulation of surviving cells. We used microarrays to conduct the analysis of whole transcript profiles in pancreatic cancer cells treated with X-ray radiation.
2018-06-30 | GSE104965 | GEO
Project description:The predictive value of microRNAs for the efficacy of chemoradiation (CRTX) in locally advanced head and neck squamous cell carcinoma (HNSCC) was evaluated. Formalin-fixed, paraffin-embedded tumor material was collected from patients with locally advanced HNSCC treated within the ARO-0401 phase III trial with radiotherapy in combination with either 5-fluorouracil/cisplatin (CDDP-CRTX) or 5-fluorouracil/mitomycin C (MMC-CRTX).
2017-03-30 | E-MTAB-5198 | biostudies-arrayexpress
Project description:The transcription factor, NF-кB, plays a central role in the response to DNA damage. This ubiquitous family of proteins is made up of five subunits: p50 (NF-κB1, p105), p52 (NF-κB2, p100), p65 (relA), relB, and crel that appear in their mature form as dimers. Following stimulation, NF-κB dimers translocate to the nucleus where they bind specific consensus elements (κB-sites) in the promoter region of genes involved in cell survival, inflammation and the immune system. While there is a general propensity of NF-кB to mediate survival, this is not always the case and several reports note the pro-apoptotic nature of the NF-кB pathway. In examining the NF-кB response to DNA damage, we have found that the p50 subunit plays a central role in modulating cytotoxicity following TMZ treatment in malignant glioma. In the current study, given the importance of p50 to the cytotoxic response to TMZ, we set out to identify NF-кB-dependent factors that modulate the response to TMZ. U-87 glioma cells stably transfected with either control-shRNA or p105-shRNA and subsequently treated with temozolomide (TMZ) were selected for RNA extraction and hybridization on Affymetrix microarrays. Each category contains 3 biologic replicates.
2015-01-29 | E-GEOD-65363 | biostudies-arrayexpress