Characterization of a clival chordoma xenograft model reveals inherent tumor genomic instability
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE103342 | GEO | 2017/08/31
SECONDARY ACCESSION(S): PRJNA401889
REPOSITORIES: GEO
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Project description:Chordoma is a rare primary bone malignancy that arises in the skull base, spine and sacrum and originates from remnants of the notochord. These tumors are typically resistant to conventional chemotherapy, and to date there are no FDA-approved agents to treat chordoma. The lack of in vivo models of chordoma has impeded the development of new therapies for this tumor. Primary tumor from a sacral chordoma was xenografted into NOD/SCID/IL-2R γ-null mice. The xenograft is serially transplantable and was characterized by both gene expression analysis and whole genome SNP genotyping. The NIH Chemical Genomics Center performed high-throughput screening of 2,816 compounds using two established chordoma cell lines, U-CH1 and U-CH2B. The screen yielded several compounds that showed activity and two, sunitinib and bortezomib, were tested in the xenograft. Both agents slowed the growth of the xenograft tumor. Sensitivity to an inhibitor of IκB, as well as inhibition of an NF-κB gene expression signature demonstrated the importance of NF-κB signaling for chordoma growth. This serially transplantable chordoma xenograft is thus a practical model to study chordomas and perform in vivo preclinical drug testing. The copy number and allelic balance pattern of a novel human chordoma xenograft samples was determined with Illumina BeadChips.
2013-12-22 | E-GEOD-50136 | biostudies-arrayexpress
Project description:Chordoma is a rare primary bone malignancy that arises in the skull base, spine and sacrum and originates from remnants of the notochord. These tumors are typically resistant to conventional chemotherapy, and to date there are no FDA-approved agents to treat chordoma. The lack of in vivo models of chordoma has impeded the development of new therapies for this tumor. Primary tumor from a sacral chordoma was xenografted into NOD/SCID/IL-2R γ-null mice. The xenograft is serially transplantable and was characterized by both gene expression analysis and whole genome SNP genotyping. The NIH Chemical Genomics Center performed high-throughput screening of 2,816 compounds using two established chordoma cell lines, U-CH1 and U-CH2B. The screen yielded several compounds that showed activity and two, sunitinib and bortezomib, were tested in the xenograft. Both agents slowed the growth of the xenograft tumor. Sensitivity to an inhibitor of IκB, as well as inhibition of an NF-κB gene expression signature demonstrated the importance of NF-κB signaling for chordoma growth. This serially transplantable chordoma xenograft is thus a practical model to study chordomas and perform in vivo preclinical drug testing. Total five microarray experiments were conducted, two of which are for chordoma xenograft sammples and three for chrodoma primary tumor. RNA extracted from xenograft samples and from chordomas was hybridized to Illumina arrays.
2013-12-22 | E-GEOD-50135 | biostudies-arrayexpress
Project description:Chordoma is a rare primary bone malignancy that arises in the skull base, spine and sacrum and originates from remnants of the notochord. These tumors are typically resistant to conventional chemotherapy, and to date there are no FDA-approved agents to treat chordoma. The lack of in vivo models of chordoma has impeded the development of new therapies for this tumor. Primary tumor from a sacral chordoma was xenografted into NOD/SCID/IL-2R γ-null mice. The xenograft is serially transplantable and was characterized by both gene expression analysis and whole genome SNP genotyping. The NIH Chemical Genomics Center performed high-throughput screening of 2,816 compounds using two established chordoma cell lines, U-CH1 and U-CH2B. The screen yielded several compounds that showed activity and two, sunitinib and bortezomib, were tested in the xenograft. Both agents slowed the growth of the xenograft tumor. Sensitivity to an inhibitor of IκB, as well as inhibition of an NF-κB gene expression signature demonstrated the importance of NF-κB signaling for chordoma growth. This serially transplantable chordoma xenograft is thus a practical model to study chordomas and perform in vivo preclinical drug testing.
2013-12-22 | GSE50136 | GEO
Project description:Chordoma is a rare primary bone malignancy that arises in the skull base, spine and sacrum and originates from remnants of the notochord. These tumors are typically resistant to conventional chemotherapy, and to date there are no FDA-approved agents to treat chordoma. The lack of in vivo models of chordoma has impeded the development of new therapies for this tumor. Primary tumor from a sacral chordoma was xenografted into NOD/SCID/IL-2R γ-null mice. The xenograft is serially transplantable and was characterized by both gene expression analysis and whole genome SNP genotyping. The NIH Chemical Genomics Center performed high-throughput screening of 2,816 compounds using two established chordoma cell lines, U-CH1 and U-CH2B. The screen yielded several compounds that showed activity and two, sunitinib and bortezomib, were tested in the xenograft. Both agents slowed the growth of the xenograft tumor. Sensitivity to an inhibitor of IκB, as well as inhibition of an NF-κB gene expression signature demonstrated the importance of NF-κB signaling for chordoma growth. This serially transplantable chordoma xenograft is thus a practical model to study chordomas and perform in vivo preclinical drug testing.
2013-12-22 | GSE50135 | GEO
Project description:mRNA profiling of three novel chordoma cell lines out of the same patient. The gene expression profiles of the primary tumour derived cell line U-CH17P was compared to the gene expression profiles of the metastases derived cell lines U-CH17S and U-CH17M in order to spot differently expressed genes, that are involved in the formation of metastases in chordoma.
2017-10-02 | GSE98021 | GEO
Project description:The prognostic factors of skull base chordoma associated with outcomes of patients after surgical resection remain poorly defined. This project aimed to identify a novel prognostic factor for patients with skull base chordoma. Using a proteomics approach, we screened tumor biomarkersthat upregulated in the rapid-recurrence group of chordoma, narrowed down by bioinformatics analysis, and finally potential biomarker was chosen for validation by immunohistochemistry using tissue microarray.
2021-11-03 | PXD025894 | Pride
Project description:IFN-g-induced gene expression profiles of UM-Chor1 cells were assessed by microarray analysis Chordoma is a rare bone tumor derived from notochord, which has shown to be resistant to conventional therapy, including chemotherapy and radiotherapy. Immunotherapy has the potential to be effective in cancers with resistance to conventional therapy. Checkpoint inhibition, including Programmed cell Death 1 (PD-1)/Programmed cell Death protein 1 (PD-L1) blockade has shown great promise in treating diverse cancers. The purpose of this study was to investigate the potential of anti-PD-L1 antibody therapy for chordoma. To this end, using 4 chordoma cell lines, we examined the expression of PD-L1 and performed in vitro NK cells killing assay for antibody-dependent cell-mediated cytotoxicity (ADCC) activity mediated by the anti-PD-L1 antibody, avelumab. Here, the expression of PD-L1 was markedly upregulated by IFN-g in all 4 chordoma cell lines, which resulted in increasing the sensitivity to ADCC. Next, to model a patient that received a tumor-antigen specific vaccine, chordoma cells were co-incubated with brachyury specific CD8+ T cells, culminating in significant upregulation of PD-L1 on the tumor cells mediated by CD8+ T cells IFN-g production. The functional consequence was the sensitivity of chordoma cells to ADCC mediated by avelumab. Finally, residential cancer stem cell subpopulations of chordoma cells were killed by avelumab-mediated ADCC to the same degree as non-cancer stem cell populations. Our findings show the potential of avelumab therapy in chordoma; a) alone, to enable endogenous NK cells to kill chordoma cells via ADCC, or b) in conjunction with T cells immunotherapy such a vaccine, to exploit enhanced NK cell killing of chordoma cells via ADCC.
2017-01-01 | GSE77732 | GEO
Project description:Chromatin profiling of chordoma collected by the Broad chordoma target discovery project paired end ATAC-Seq profiling in the UCH2 and MUGCHOR chordoma cell lines
2015-07-11 | E-GEOD-70771 | biostudies-arrayexpress
Project description:Chromatin profiling of chordoma collected by the Broad chordoma target discovery project
2015-07-11 | GSE70771 | GEO
Project description:Chordoma, a rare and challenging primary bone malignancy, currently lacks effective targeted therapies. Despite surgical resection and adjuvant radiotherapy, prognosis remains poor. Recent preclinical studies have highlighted potential therapeutic targets, including the transcription factor TBXT, although clinical outcomes have been modest. In this study, we investigated the therapeutic potential of tRNA synthetase inhibitors, specifically halofuginone and halofuginol, in chordoma treatment. We conducted extensive drug screening, identifying these compounds as effective in reducing cell viability in chordoma cell lines through an ATF4-mediated stress response rather than TBXT regulation. Our findings were validated using RNA sequencing, which revealed significant upregulation of ATF4 and associated stress response genes. Additionally, halofuginone demonstrated significant tumour growth inhibition in an in vivo patient-derived xenograft model. These results suggest that targeting metabolic stress pathways via ATF4 activation presents a novel therapeutic approach for chordoma, warranting further clinical investigation.
2024-08-31 | GSE275636 | GEO