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A novel chordoma xenograft allows in vivo drug testing and reveals the importance of NF-kB signaling in chordoma biology [SNP array]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE50136 | GEO | 2013/12/22

SECONDARY ACCESSION(S): PRJNA216128

REPOSITORIES: GEO

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A novel chordoma xenograft allows in vivo drug testing and reveals the importance of NF-kB signaling in chordoma biology [expression array]

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

A novel chordoma xenograft allows in vivo drug testing and reveals the importance of NF-kB signaling in chordoma biology [expression array]

2013-12-22 | GSE50135 | GEO

A novel chordoma xenograft allows in vivo drug testing and reveals the importance of NF-kB signaling in chordoma biology [SNP array]

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 Î³-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 IÎºB, as well as inhibition of an NF-ÎºB gene expression signature demonstrated the importance of NF-ÎºB 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

Multimodal assessment of chordoma immunity reveals distinct immune contextures

Project description:Chordomas are cancers from the axial skeleton presenting immunological hallmarks of unknown significance. In recent years, some clinical trials demonstrated that chordomas can respond to immunotherapy. We present a comprehensive characterisation of immunological features of 76 chordomas through application of a multimodal approach comprising transcriptional profiling, multidimensional immunophenotyping and TCR profiling. Chordomas generally presented an immune “hot” microenvironment in comparison to other sarcomas, as indicated by the immunologic constant of rejection transcriptional signature. We identified two distinct groups of chordomas based on T cell infiltration. The highly infiltrated group was further characterised by high dendritic cell infiltration and the presence of multicellular immune aggregates in tumours, whereas low T cell infiltration was associated with lower overall cell densities of immune and stromal cells. Interestingly, patients with higher T cell infiltration displayed a more pronounced clonal enrichment of the T cell receptor repertoire compared to those with low T cell counts. Furthermore, we observed that the majority of chordomas maintained HLA class I expression. Our findings shed light on the natural immunity against chordomas. Understanding their immune landscape could guide the development and application of immunotherapies in a tailored manner, ultimately leading to an improved clinical outcome for chordoma patients.

2024-01-26 | GSE239531 | GEO

ATF4-Mediated Metabolic Stress Response as a Therapeutic Vulnerability in Chordoma [PDX RNA-seq]

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

ATF4-Mediated Metabolic Stress Response as a Therapeutic Vulnerability in Chordoma [MUG-Chor RNA-seq]

2024-08-31 | GSE275458 | GEO

Human skull base chordoma LC-MSMS

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

Characterization of a clival chordoma xenograft model reveals inherent tumor genomic instability

Project description:Patient-derived xenografts retain the genotype of the parent tumors more readily than tumor cells maintained in culture. The two reported clival chordoma xenografts are derived from recurrent tumors after radiation. In order to study the genetics of clival chordoma in the absence of prior radiation we sought to establish a patient-derived xenograft at primary resection of a clival chordoma.

2017-08-31 | GSE103342 | GEO

Chordoma ATAC-Seq

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