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Adrienne M. Flanagan - One of the best experts on this subject based on the ideXlab platform.
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High-resolution Whole-Genome Analysis of Skull Base Chordomas Implicates FHIT Loss in Chordoma Pathogenesis
Neoplasia (New York N.Y.), 2012Co-Authors: Roberto J. Diaz, Fitim Berisha, Mustafa Güdük, Rocco Romagnuolo, Christian A. Smith, Paul A. Northcott, David Shih, Adrienne M. Flanagan, David G. Munoz, Michael D. CusimanoAbstract:Chordoma is a rare tumor arising in the sacrum, clivus, or vertebrae. It is often not completely resectable and shows a high incidence of recurrence and progression with shortened patient survival and impaired quality of life. Chemotherapeutic options are limited to investigational therapies at present. Therefore, adjuvant therapy for control of tumor recurrence and progression is of great interest, especially in skull base lesions where complete tumor resection is often not possible because of the proximity of cranial nerves. To understand the extent of genetic instability and associated chromosomal and gene losses or gains in skull base Chordoma, we undertook whole-genome single-nucleotide polymorphism microarray analysis of flash frozen surgical Chordoma specimens, 21 from the clivus and 1 from C1 to C2 vertebrae. We confirm the presence of a deletion at 9p involving CDKN2A, CDKN2B, and MTAP but at a much lower rate (22%) than previously reported for sacral Chordoma. At a similar frequency (21%), we found aneuploidy of chromosome 3. Tissue microarray immunohistochemistry demonstrated absent or reduced fragile histidine triad (FHIT) protein expression in 98% of sacral Chordomas and 67%of skull base Chordomas. Our data suggest that chromosome 3 aneuploidy and epigenetic regulation of FHIT contribute to loss of the FHIT tumor suppressor in Chordoma. The finding that FHIT is lost in a majority of Chordomas provides new insight into Chordoma pathogenesis and points to a potential new therapeutic target for this challenging neoplasm.
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potential therapeutic targets for Chordoma pi3k akt tsc1 tsc2 mtor pathway
British Journal of Cancer, 2009Co-Authors: Nadege Presneau, Asem Shalaby, B Idowu, Panagiotis D Gikas, S R Cannon, I Gout, T C Diss, Roberto Tirabosco, Adrienne M. FlanaganAbstract:Chordomas are radio- and chemo-resistant tumours and metastasise in as many as 40% of patients. The aim of this study was to identify potential molecular targets for the treatment of Chordoma. In view of the reported association of Chordoma and tuberous sclerosis complex syndrome, and the available therapeutic agents against molecules in the PI3K/AKT/TSC1/TSC2/mTOR pathway, a tissue microarray of 50 Chordoma cases was analysed for expression of active molecules involved in this signalling pathway by immunohistochemistry and a selected number by western blot analysis. Chordomas were positive for p-AKT (92%), p-TSC2 (96%), p-mTOR (27%), total mTOR (75%), p-p70S6K (62%), p-RPS6 (22%), p-4E-BP1 (96%) and eIF-4E (98%). Phosphatase and tensin homologue deleted on chromosome 10 expression was lost in 16% of cases. Mutations failed to be identified in PI3KCA and RHEB1 in the 23 cases for which genomic DNA was available. Fluorescence in situ hybridisation analysis for mTOR and RPS6 loci showed that 11 of 33 and 21 of 44 tumours had loss of one copy of the respective genes, results which correlated with the loss of the relevant total proteins. Fluorescence in situ hybridisation analysis for loci containing TSC1 and TSC2 revealed that all cases analysed harboured two copies of the respective genes. On the basis of p-mTOR and or p-p70S6K expression there is evidence indicating that 65% of the Chordomas studied may be responsive to mTOR inhibitors, rapamycin or its analogues, and that patients may benefit from combined therapy including drugs that inhibit AKT.
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potential therapeutic targets for Chordoma pi3k akt tsc1 tsc2 mtor pathway
British Journal of Cancer, 2009Co-Authors: Nadege Presneau, Asem Shalaby, Bernadine Idowu, Panagiotis D Gikas, S R Cannon, I Gout, T C Diss, Roberto Tirabosco, Adrienne M. FlanaganAbstract:Chordomas are radio- and chemo-resistant tumours and metastasise in as many as 40% of patients. The aim of this study was to identify potential molecular targets for the treatment of Chordoma. In view of the reported association of Chordoma and tuberous sclerosis complex syndrome, and the available therapeutic agents against molecules in the PI3K/AKT/TSC1/TSC2/mTOR pathway, a tissue microarray of 50 Chordoma cases was analysed for expression of active molecules involved in this signalling pathway by immunohistochemistry and a selected number by western blot analysis. Chordomas were positive for p-AKT (92%), p-TSC2 (96%), p-mTOR (27%), total mTOR (75%), p-p70S6K (62%), p-RPS6 (22%), p-4E-BP1 (96%) and eIF-4E (98%). Phosphatase and tensin homologue deleted on chromosome 10 expression was lost in 16% of cases. Mutations failed to be identified in PI3KCA and RHEB1 in the 23 cases for which genomic DNA was available. Fluorescence in situ hybridisation analysis for mTOR and RPS6 loci showed that 11 of 33 and 21 of 44 tumours had loss of one copy of the respective genes, results which correlated with the loss of the relevant total proteins. Fluorescence in situ hybridisation analysis for loci containing TSC1 and TSC2 revealed that all cases analysed harboured two copies of the respective genes. On the basis of p-mTOR and or p-p70S6K expression there is evidence indicating that 65% of the Chordomas studied may be responsive to mTOR inhibitors, rapamycin or its analogues, and that patients may benefit from combined therapy including drugs that inhibit AKT.
Edwin Choy - One of the best experts on this subject based on the ideXlab platform.
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CDK4 expression in Chordoma: A potential therapeutic target
Journal of orthopaedic research : official publication of the Orthopaedic Research Society, 2017Co-Authors: Tang Liu, Edwin Choy, Francis J Hornicek, Henry J. Mankin, Jacson K. Shen, Yu Zhang, Zhenfeng DuanAbstract:Chordomas are rare bone tumors and treatment is commonly based on a combination of surgery and radiotherapy. There is no standard chemotherapy treatment for Chordoma. The aim of this study was to determine the expression of cyclin-dependent kinase 4 (CDK4) in Chordoma and its therapeutic implications. We evaluated CDK4 expression both in Chordoma cell lines and in Chordoma tissues. Also, we investigated the functional roles of CDK4 in Chordoma cell growth and proliferation. Furthermore, the therapeutic implications of targeting CDK4 in Chordoma were evaluated. We found CDK4 highly expressed in Chordoma cell lines and in a majority (97.7%) of Chordoma tissues. Higher CDK4 expression correlated with metastasis and recurrence of Chordoma. Treatment of Chordoma cells using CDK4 inhibitor palbociclib could efficiently inhibit Chordoma cells growth and proliferation. These data demonstrate that targeting CDK4 may be useful as a novel strategy in the treatment of Chordoma. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1581-1589, 2018.
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frequency and risk factors for additional lesions in the axial spine in subjects with Chordoma indications for screening
Spine, 2017Co-Authors: Ronnie Sebro, Petur G Nielsen, Edwin Choy, Francis J Hornicek, Joseph H Schwab, Thomas F Delaney, Daniel I RosenthalAbstract:STUDY DESIGN Retrospective cohort study. OBJECTIVE We aim to evaluate the frequency and clinical significance of additional lesions in the axial spine in subjects with Chordoma and to assess the need for screening. SUMMARY OF BACKGROUND DATA Chordomas are rare tumors that may be multicentric or metastasize and affect several bones in the axial spine. The incidence of multiple lesions in the axial spine is unknown. Understanding the incidence rate of multiple lesions in the spine in subjects with Chordomas will help guide utilization of total spine screening imaging. METHODS We performed a retrospective review of medical records of 42 subjects with histologically confirmed Chordomas who had complete imaging of the axial spine. Lesions with imaging characteristics suggestive of Chordomas/notochordal remnants were identified. Data on age at diagnosis, sex, size (in maximal dimension), type of Chordoma (conventional, chondroid, or dedifferentiated), and whether pulmonary metastases were present were recorded. Binomial two-sample tests of proportions were used to compare proportions. Logistic regression was used to assess predictors of additional lesions. RESULTS Forty-two subjects (57.1% male) were identified. The proportion of subjects with additional lesions in the axial spine was 16.7% (7/42). Age, sex, size, and subtype of Chordoma were not significant predictors of having additional lesions (P > 0.05 for each variable). However, having pulmonary metastases was a significant predictor of having additional lesions (P < 0.05). CONCLUSION Approximately 17% of subjects with Chordomas had additional lesions in the axial spine. It is unclear whether these represent metastases, synchronous primary Chordomas or notochordal remnant tissue. Screening imaging of the axial spine may reveal additional lesions in particular in subjects with pulmonary metastases. LEVEL OF EVIDENCE 3.
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differences in sex distribution anatomic location and mr imaging appearance of pediatric compared to adult Chordomas
BMC Medical Imaging, 2016Co-Authors: Ronnie Sebro, Petur G Nielsen, Edwin Choy, Francis J Hornicek, Joseph H Schwab, Thomas F Delaney, Daniel I RosenthalAbstract:Chordomas are rare malignancies that primarily affect adults, but also rarely affect pediatric patients. We compared the imaging appearance, demographic and anatomic distributions of adult and pediatric Chordomas in a large cohort. We performed a retrospective review of medical records of 220 subjects with histologically confirmed Chordomas of the axial skeleton and pre-treatment magnetic resonance imaging studies. Age, sex, type of Chordoma (conventional, chondroid or dedifferentiated), the anatomic location of the Chordoma, as well as whether the lesion was primarily extra-osseous were recorded. Pediatric subjects were less than 21 years at the time of diagnosis. Binomial two-sample tests of proportions and Fisher’s exact tests were used to compare proportions between the pediatric and adult subjects. Fifty six pediatric subjects (58.9 % female) and 164 adult subjects (42.1 % female) were identified. The proportion of female subjects with Chordomas was significantly higher in the pediatric cohort compared to the adult cohort (P = 0.04). Most Chordomas occur in Caucasians, however African-Americans were more represented in the pediatric cohort than in the adult cohort (P = 0.01). 69.6 % (39/56) of the pediatric Chordomas involved the clivus/skull base and cervical spine compared to 29.3 % (48/164) of the adult Chordomas (P = 1.99 × 10−7). Only 1.8 % (1/56) of the pediatric Chordomas was in the sacrococcygeal region compared to 36.0 % (59/164) of the adult Chordomas (P = 2.55 × 10−8). In cases where pre-treatment imaging was available, 93.8 % (16/17) of pediatric Chordomas were predominantly extra-osseous compared to 76.7 % (46/60) of adult Chordomas (P = 0.17). Pediatric Chordomas more often affect females and occur most frequently at the craniocervical junction with decrease in incidence distally in the spine, whereas adult Chordomas most frequently involve the craniocervical and sacrococcygeal regions.
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expression of programmed cell death ligand 1 pd l1 and prevalence of tumor infiltrating lymphocytes tils in Chordoma
Oncotarget, 2015Co-Authors: Edwin Choy, Gregory M Cote, Ivan Chebib, Jacson Shen, Yong Feng, Yan Gao, Yunfei Liao, Henry J. MankinAbstract:Chordomas are primary malignant tumors of the notochord that are resistant to conventional chemotherapy. Expression of programmed cell death ligand 1 (PD-L1), prevalence of tumor-infiltrating lymphocytes (TILs), and their clinical relevance in Chordoma remain unknown. We evaluated PD-L1 expression in three Chordoma cell lines and nine Chordoma tissue samples by western blot. Immunohistochemical staining was performed on a Chordoma tissue microarray (TMA) that contained 78 tissue specimens. We also correlated the expression of PD-L1 and TILs with clinical outcomes. PD-L1 protein expression was demonstrated to be induced by IFN-γ in both UCH1 and UCH2 cell lines. Across nine human Chordoma tissue samples, PD-L1 protein was differentially expressed. 94.9% of Chordoma samples showed positive PD-L1 expression in the TMA. The expression score of PD-L1 for metastatic Chordoma tumors was significant higher as compared with non-metastatic Chordoma tumors. Expression of PD-L1 protein significantly correlates with the presence of elevated TILs, which correlates with metastasis. In summary, our study showed high levels of PD-L1 are expressed in Chordoma, which is correlated with the prevalence of TILs. The current study suggests targeting PD-L1 may be a novel immunotherapeutic strategy for Chordoma clinical trials.
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genotyping cancer associated genes in Chordoma identifies mutations in oncogenes and areas of chromosomal loss involving cdkn2a pten and smarcb1
PLOS ONE, 2014Co-Authors: Edwin Choy, Francis J Hornicek, Gregory M Cote, Laura E Macconaill, Jacson Shen, Gunnlaugur P Nielsen, A J Iafrate, Levi A Garraway, Zhenfeng DuanAbstract:The molecular mechanisms underlying Chordoma pathogenesis are unknown. We therefore sought to identify novel mutations to better understand Chordoma biology and to potentially identify therapeutic targets. Given the relatively high costs of whole genome sequencing, we performed a focused genetic analysis using matrix-assisted laser desorption/ionization-time of flight mass spectrometer (Sequenom iPLEX genotyping). We tested 865 hotspot mutations in 111 oncogenes and selected tumor suppressor genes (OncoMap v. 3.0) of 45 human Chordoma tumor samples. Of the analyzed samples, seven were identified with at least one mutation. Six of these were from fresh frozen samples, and one was from a paraffin embedded sample. These observations were validated using an independent platform using homogeneous mass extend MALDI-TOF (Sequenom hME Genotyping). These genetic alterations include: ALK (A877S), CTNNB1 (T41A), NRAS (Q61R), PIK3CA (E545K), PTEN (R130), CDKN2A (R58*), and SMARCB1 (R40*). This study reports on the largest comprehensive mutational analysis of Chordomas performed to date. To focus on mutations that have the greatest chance of clinical relevance, we tested only oncogenes and tumor suppressor genes that have been previously implicated in the tumorigenesis of more common malignancies. We identified rare genetic changes that may have functional significance to the underlying biology and potential therapeutics for Chordomas. Mutations in CDKN2A and PTEN occurred in areas of chromosomal copy loss. When this data is paired with the studies showing 18 of 21 Chordoma samples displaying copy loss at the locus for CDKN2A, 17 of 21 Chordoma samples displaying copy loss at PTEN, and 3 of 4 Chordoma samples displaying deletion at the SMARCB1 locus, we can infer that a loss of heterozygosity at these three loci may play a significant role in Chordoma pathogenesis.
Nadege Presneau - One of the best experts on this subject based on the ideXlab platform.
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the role of epidermal growth factor receptor in Chordoma pathogenesis a potential therapeutic target
The Journal of Pathology, 2011Co-Authors: Asem Shalaby, Nadege Presneau, Dina Halai, Fitim Berisha, Bernadine Idowu, Andreas Leithner, Bernadette Liegl, Tim Rw Briggs, Krisztian Bacsi, Lars Gunnar KindblomAbstract:Chordoma, the molecular hallmark of which is T (brachyury), is a rare malignant bone tumour with a high risk of local recurrence and a tumour from which metastatic disease is a common late event. Currently, there is no effective drug therapy for treating Chordomas, although there is evidence that some patients respond to the empirical use of epidermal growth factor receptor (EGFR) antagonists. The aim of this study was to determine the role of EGFR in the pathogenesis of Chordoma. Paraffin-embedded material from 173 Chordomas from 160 patients [sacro-coccygeal (n = 94), skull-based (n = 50), and mobile spine (n = 16)] was analysed by immunohistochemistry and revealed total EGFR expression in 69% of cases analysed. Of 147 informative Chordomas analysed by FISH, 38% revealed high-level EGFR polysomy, 4% high-level polysomy with focal amplification, 18% low-level polysomy, and 39% disomy. Phospho-receptor tyrosine kinase array membranes showed EGFR activation in the Chordoma cell line U-CH1 and all of the three Chordomas analysed. Direct sequencing of EGFR (exons 18-21), KRAS, NRAS, HRAS (exons 2, 3), and BRAF (exons 11, 15) using DNA from 62 Chordomas failed to reveal mutations. PTEN expression was absent by immunohistochemistry in 19 of 147 (13%) analysed Chordomas, only one of which revealed high-level polysomy of EGFR. The EGFR inhibitor tyrphostin (AG 1478) markedly inhibited proliferation of the Chordoma cell line U-CH1 in vitro and diminished EGFR phosphorylation in a dose-dependant manner, a finding supported by inhibition of phosphorylated Erk1/2. p-Akt was suppressed to a much lesser degree in these experiments. There was no reduction of T as assessed by western blotting. These data implicate aberrant EGFR signalling in the pathogenesis of Chordoma. This study provides a strategy for patient stratification for treatment with EGFR antagonists.
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role of the transcription factor t brachyury in the pathogenesis of sporadic Chordoma a genetic and functional based study
The Journal of Pathology, 2011Co-Authors: Nadege Presneau, Asem Shalaby, Dina Halai, Bernadine Idowu, Nischalan Pillay, R Tirabosco, D Whitwell, Thomas S Jacques, Lars Gunnar KindblomAbstract:A variety of analyses, including fluorescence in situ hybridization (FISH), quantitative PCR (qPCR) and array CGH (aCGH), have been performed on a series of Chordomas from 181 patients. Twelve of 181 (7%) tumours displayed amplification of the T locus and an additional two cases showed focal amplification; 70/181 (39%) tumours were polysomic for chromosome 6, and 8/181 (4.5%) primary tumours showed a minor allelic gain of T as assessed by FISH. No germline alteration of the T locus was identified in non-neoplastic tissue from 40 patients. Copy number gain of T was seen in a similar percentage of sacrococcygeal, mobile spine and base of skull tumours. Knockdown of T in the cell line, U-CH1, which showed polysomy of chromosome 6 involving 6q27, resulted in a marked decrease in cell proliferation and morphological features consistent with a senescence-like phenotype. The U-CH1 cell line was validated as representing Chordoma by the generation of xenografts, which showed typical Chordoma morphology and immunohistochemistry in the NOD/SCID/interleukin 2 receptor [IL2r]gamma(null) mouse model. In conclusion, chromosomal aberrations resulting in gain of the T locus are common in sporadic Chordomas and expression of this gene is critical for proliferation of Chordoma cells in vitro. Copyright (C) 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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potential therapeutic targets for Chordoma pi3k akt tsc1 tsc2 mtor pathway
British Journal of Cancer, 2009Co-Authors: Nadege Presneau, Asem Shalaby, B Idowu, Panagiotis D Gikas, S R Cannon, I Gout, T C Diss, Roberto Tirabosco, Adrienne M. FlanaganAbstract:Chordomas are radio- and chemo-resistant tumours and metastasise in as many as 40% of patients. The aim of this study was to identify potential molecular targets for the treatment of Chordoma. In view of the reported association of Chordoma and tuberous sclerosis complex syndrome, and the available therapeutic agents against molecules in the PI3K/AKT/TSC1/TSC2/mTOR pathway, a tissue microarray of 50 Chordoma cases was analysed for expression of active molecules involved in this signalling pathway by immunohistochemistry and a selected number by western blot analysis. Chordomas were positive for p-AKT (92%), p-TSC2 (96%), p-mTOR (27%), total mTOR (75%), p-p70S6K (62%), p-RPS6 (22%), p-4E-BP1 (96%) and eIF-4E (98%). Phosphatase and tensin homologue deleted on chromosome 10 expression was lost in 16% of cases. Mutations failed to be identified in PI3KCA and RHEB1 in the 23 cases for which genomic DNA was available. Fluorescence in situ hybridisation analysis for mTOR and RPS6 loci showed that 11 of 33 and 21 of 44 tumours had loss of one copy of the respective genes, results which correlated with the loss of the relevant total proteins. Fluorescence in situ hybridisation analysis for loci containing TSC1 and TSC2 revealed that all cases analysed harboured two copies of the respective genes. On the basis of p-mTOR and or p-p70S6K expression there is evidence indicating that 65% of the Chordomas studied may be responsive to mTOR inhibitors, rapamycin or its analogues, and that patients may benefit from combined therapy including drugs that inhibit AKT.
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potential therapeutic targets for Chordoma pi3k akt tsc1 tsc2 mtor pathway
British Journal of Cancer, 2009Co-Authors: Nadege Presneau, Asem Shalaby, Bernadine Idowu, Panagiotis D Gikas, S R Cannon, I Gout, T C Diss, Roberto Tirabosco, Adrienne M. FlanaganAbstract:Chordomas are radio- and chemo-resistant tumours and metastasise in as many as 40% of patients. The aim of this study was to identify potential molecular targets for the treatment of Chordoma. In view of the reported association of Chordoma and tuberous sclerosis complex syndrome, and the available therapeutic agents against molecules in the PI3K/AKT/TSC1/TSC2/mTOR pathway, a tissue microarray of 50 Chordoma cases was analysed for expression of active molecules involved in this signalling pathway by immunohistochemistry and a selected number by western blot analysis. Chordomas were positive for p-AKT (92%), p-TSC2 (96%), p-mTOR (27%), total mTOR (75%), p-p70S6K (62%), p-RPS6 (22%), p-4E-BP1 (96%) and eIF-4E (98%). Phosphatase and tensin homologue deleted on chromosome 10 expression was lost in 16% of cases. Mutations failed to be identified in PI3KCA and RHEB1 in the 23 cases for which genomic DNA was available. Fluorescence in situ hybridisation analysis for mTOR and RPS6 loci showed that 11 of 33 and 21 of 44 tumours had loss of one copy of the respective genes, results which correlated with the loss of the relevant total proteins. Fluorescence in situ hybridisation analysis for loci containing TSC1 and TSC2 revealed that all cases analysed harboured two copies of the respective genes. On the basis of p-mTOR and or p-p70S6K expression there is evidence indicating that 65% of the Chordomas studied may be responsive to mTOR inhibitors, rapamycin or its analogues, and that patients may benefit from combined therapy including drugs that inhibit AKT.
Henry J. Mankin - One of the best experts on this subject based on the ideXlab platform.
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CDK4 expression in Chordoma: A potential therapeutic target
Journal of orthopaedic research : official publication of the Orthopaedic Research Society, 2017Co-Authors: Tang Liu, Edwin Choy, Francis J Hornicek, Henry J. Mankin, Jacson K. Shen, Yu Zhang, Zhenfeng DuanAbstract:Chordomas are rare bone tumors and treatment is commonly based on a combination of surgery and radiotherapy. There is no standard chemotherapy treatment for Chordoma. The aim of this study was to determine the expression of cyclin-dependent kinase 4 (CDK4) in Chordoma and its therapeutic implications. We evaluated CDK4 expression both in Chordoma cell lines and in Chordoma tissues. Also, we investigated the functional roles of CDK4 in Chordoma cell growth and proliferation. Furthermore, the therapeutic implications of targeting CDK4 in Chordoma were evaluated. We found CDK4 highly expressed in Chordoma cell lines and in a majority (97.7%) of Chordoma tissues. Higher CDK4 expression correlated with metastasis and recurrence of Chordoma. Treatment of Chordoma cells using CDK4 inhibitor palbociclib could efficiently inhibit Chordoma cells growth and proliferation. These data demonstrate that targeting CDK4 may be useful as a novel strategy in the treatment of Chordoma. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1581-1589, 2018.
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expression of programmed cell death ligand 1 pd l1 and prevalence of tumor infiltrating lymphocytes tils in Chordoma
Oncotarget, 2015Co-Authors: Edwin Choy, Gregory M Cote, Ivan Chebib, Jacson Shen, Yong Feng, Yan Gao, Yunfei Liao, Henry J. MankinAbstract:Chordomas are primary malignant tumors of the notochord that are resistant to conventional chemotherapy. Expression of programmed cell death ligand 1 (PD-L1), prevalence of tumor-infiltrating lymphocytes (TILs), and their clinical relevance in Chordoma remain unknown. We evaluated PD-L1 expression in three Chordoma cell lines and nine Chordoma tissue samples by western blot. Immunohistochemical staining was performed on a Chordoma tissue microarray (TMA) that contained 78 tissue specimens. We also correlated the expression of PD-L1 and TILs with clinical outcomes. PD-L1 protein expression was demonstrated to be induced by IFN-γ in both UCH1 and UCH2 cell lines. Across nine human Chordoma tissue samples, PD-L1 protein was differentially expressed. 94.9% of Chordoma samples showed positive PD-L1 expression in the TMA. The expression score of PD-L1 for metastatic Chordoma tumors was significant higher as compared with non-metastatic Chordoma tumors. Expression of PD-L1 protein significantly correlates with the presence of elevated TILs, which correlates with metastasis. In summary, our study showed high levels of PD-L1 are expressed in Chordoma, which is correlated with the prevalence of TILs. The current study suggests targeting PD-L1 may be a novel immunotherapeutic strategy for Chordoma clinical trials.
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tissue microarray immunohistochemical detection of brachyury is not a prognostic indicator in Chordoma
PLOS ONE, 2013Co-Authors: Petur G Nielsen, Shunan Ye, Edwin Choy, Linlin Zhang, Joseph H Schwab, Henry J. Mankin, Zhan Zhang, Francis J HornicekAbstract:Brachyury is a marker for notochord-derived tissues and neoplasms, such as Chordoma. However, the prognostic relevance of brachyury expression in Chordoma is still unknown. The improvement of tissue microarray technology has provided the opportunity to perform analyses of tumor tissues on a large scale in a uniform and consistent manner. This study was designed with the use of tissue microarray to determine the expression of brachyury. Brachyury expression in Chordoma tissues from 78 Chordoma patients was analyzed by immunohistochemical staining of tissue microarray. The clinicopathologic parameters, including gender, age, location of tumor and metastatic status were evaluated. Fifty-nine of 78 (75.64%) tumors showed nuclear staining for brachyury, and among them, 29 tumors (49.15%) showed 1+ (<30% positive cells) staining, 15 tumors (25.42%) had 2+ (31% to 60% positive cells) staining, and 15 tumors (25.42%) demonstrated 3+ (61% to 100% positive cells) staining. Brachyury nuclear staining was detected more frequently in sacral Chordomas than in Chordomas of the mobile spine. However, there was no significant relationship between brachyury expression and other clinical variables. By Kaplan-Meier analysis, brachyury expression failed to produce any significant relationship with the overall survival rate. In conclusion, brachyury expression is not a prognostic indicator in Chordoma.
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blockage of stat3 with cddo me inhibits tumor cell growth in Chordoma
Spine, 2010Co-Authors: Cao Yang, Edwin Choy, Francis J Hornicek, Joseph H Schwab, Henry J. Mankin, Kirkham B Wood, Zhenfeng DuanAbstract:Study Design. An experimental study to investigate the activation of Src/Stat3 pathways in Chordomas and blockage of this pathway as a potential strategy for Chordoma treatment. Objective. To investigate the activation of Src/Stat3 pathway in Chordomas cells and to determine the efficiency of inhibiting this pathway by 2-cyano-3,12-di-oxooleana-1,9 (11)-dien-28-oic acid-methyl ester (CDDO-Me) as a potential chemotherapeutic agent for Chordoma treatment. Summary of Background Data. The advent of molecularly targeted therapies has raised interest for their use in the treatment of Chordomas. Unfortunately, the current understanding of molecular markers in Chordomas is limited. Constitutive activation of Stat3 is a common finding in a wide spectrum of human cancers. The function of Stat3 pathway in Chordomas has not been elucidated. Methods. The expression of key components of the Src/Stat3 signaling cascade was evaluated by Western blot in Chordoma tissues and Chordoma cell lines. The effects of CDDO-Me on Chordoma cell growth were evaluated in these Chordoma cell lines by MTT assay. The expression of key components of the Src/Stat3 signaling cascade and poly (ADP-ribose) polymerase cleavage in these CDDO-Me treated cells were analyzed by Western blot and immunofluorescence. Furthermore, the synergistic effect of CDDO-Me on cisplatin and doxorubicin-induced cytotoxicity was evaluated by MTT. Finally, Chordoma cells were grown in a 3-dimensional (3D) culture and treated with CDDO-Me. Results. The key components of the Src/Stat3 signaling cascade, including Stat3, pStat3, Src, pSrc, Bcl-xL, and Myeloid Cell Leukemia-1, were all highly expressed in Chordomas. Expression of the key components of the Src/Stat3 signaling cascade was inhibited in Chordoma cells after treatment with CDDO-Me. The growth of Chordoma cells was inhibited and apoptosis associated poly (ADP-ribose) polymerase cleavage was detected after treatment with CDDO-Me. Additionally, CDDO-Me has a synergistic effect on cisplatin or doxorubicin-induced Chordoma cell death (P < 0.001). Finally, expression of pSrc and pStat3 and Chordoma cell growth was inhibited by treatment of CDDO-Me using 3D culture. Conclusion. The Src/Stat3 signaling pathway was activated in Chordomas. Blockage of Src/Stat3 pathway by CDDO-Me is a potential strategy for Chordoma treatment and may be focus for future research.
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characterization and analysis of human Chordoma cell lines
Spine, 2010Co-Authors: Cao Yang, Petur G Nielsen, Edwin Choy, Francis J Hornicek, Joseph H Schwab, Kirkham B Wood, Andrew E. Rosenberg, John Iafrate, Ramnik J Xavier, Henry J. MankinAbstract:Chordoma is an uncommon neoplasm with the majority arising in the axial skeleton, most commonly the sacrum, followed by the skull base and the mobile spine.1–3 Morphologically, immunohistochemically, and ultrastructurally, Chordomas are identical to the normal notochord, and it has been hypothesized that they arise from benign notochordal rests or so-called benign notochordal cell tumors.4 Chordomas are relatively resistant to radiation and refractory to chemotherapy.4–7 Therefore, surgery is the primary modality to achieve the best long-term control.3,8–11 However, as Chordomas are typically large and locally invasive at the time of diagnosis, obtaining tumor-free margins around the spine are challenging and frequently impossible to achieve.9–12 A large number of patients with Chordoma (~50%–70%) are not cured and ultimately die.8 The overall median survival for Chordoma has been estimated to be ~6 years, with a survival rate of 70% at 5 years, falling to 40% at 10 years.8 To date, there is limited understanding of the biology of Chordomas. Cultured Chordoma cell lines are invaluable tools for the study of these tumors and the identification of drugs that can affect their growth. To date, only 3 cultured human Chordoma cell lines have been successfully created; however, their characterization is incomplete.13–15 Complete characterization of Chordoma cell lines is necessary for them to be a useful preclinical model. In this study, we sought to further characterize Chordoma cell lines by (a) measuring the growth rates of cell lines in different media, levels of oxygen, and collagen substrates; (b) studying cell lines in 3-dimensional (3D) culture; and (c) assessing each of the cell lines for sensitivity to a variety of chemotherapeutic agents.
Bernadine Idowu - One of the best experts on this subject based on the ideXlab platform.
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the role of epidermal growth factor receptor in Chordoma pathogenesis a potential therapeutic target
The Journal of Pathology, 2011Co-Authors: Asem Shalaby, Nadege Presneau, Dina Halai, Fitim Berisha, Bernadine Idowu, Andreas Leithner, Bernadette Liegl, Tim Rw Briggs, Krisztian Bacsi, Lars Gunnar KindblomAbstract:Chordoma, the molecular hallmark of which is T (brachyury), is a rare malignant bone tumour with a high risk of local recurrence and a tumour from which metastatic disease is a common late event. Currently, there is no effective drug therapy for treating Chordomas, although there is evidence that some patients respond to the empirical use of epidermal growth factor receptor (EGFR) antagonists. The aim of this study was to determine the role of EGFR in the pathogenesis of Chordoma. Paraffin-embedded material from 173 Chordomas from 160 patients [sacro-coccygeal (n = 94), skull-based (n = 50), and mobile spine (n = 16)] was analysed by immunohistochemistry and revealed total EGFR expression in 69% of cases analysed. Of 147 informative Chordomas analysed by FISH, 38% revealed high-level EGFR polysomy, 4% high-level polysomy with focal amplification, 18% low-level polysomy, and 39% disomy. Phospho-receptor tyrosine kinase array membranes showed EGFR activation in the Chordoma cell line U-CH1 and all of the three Chordomas analysed. Direct sequencing of EGFR (exons 18-21), KRAS, NRAS, HRAS (exons 2, 3), and BRAF (exons 11, 15) using DNA from 62 Chordomas failed to reveal mutations. PTEN expression was absent by immunohistochemistry in 19 of 147 (13%) analysed Chordomas, only one of which revealed high-level polysomy of EGFR. The EGFR inhibitor tyrphostin (AG 1478) markedly inhibited proliferation of the Chordoma cell line U-CH1 in vitro and diminished EGFR phosphorylation in a dose-dependant manner, a finding supported by inhibition of phosphorylated Erk1/2. p-Akt was suppressed to a much lesser degree in these experiments. There was no reduction of T as assessed by western blotting. These data implicate aberrant EGFR signalling in the pathogenesis of Chordoma. This study provides a strategy for patient stratification for treatment with EGFR antagonists.
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role of the transcription factor t brachyury in the pathogenesis of sporadic Chordoma a genetic and functional based study
The Journal of Pathology, 2011Co-Authors: Nadege Presneau, Asem Shalaby, Dina Halai, Bernadine Idowu, Nischalan Pillay, R Tirabosco, D Whitwell, Thomas S Jacques, Lars Gunnar KindblomAbstract:A variety of analyses, including fluorescence in situ hybridization (FISH), quantitative PCR (qPCR) and array CGH (aCGH), have been performed on a series of Chordomas from 181 patients. Twelve of 181 (7%) tumours displayed amplification of the T locus and an additional two cases showed focal amplification; 70/181 (39%) tumours were polysomic for chromosome 6, and 8/181 (4.5%) primary tumours showed a minor allelic gain of T as assessed by FISH. No germline alteration of the T locus was identified in non-neoplastic tissue from 40 patients. Copy number gain of T was seen in a similar percentage of sacrococcygeal, mobile spine and base of skull tumours. Knockdown of T in the cell line, U-CH1, which showed polysomy of chromosome 6 involving 6q27, resulted in a marked decrease in cell proliferation and morphological features consistent with a senescence-like phenotype. The U-CH1 cell line was validated as representing Chordoma by the generation of xenografts, which showed typical Chordoma morphology and immunohistochemistry in the NOD/SCID/interleukin 2 receptor [IL2r]gamma(null) mouse model. In conclusion, chromosomal aberrations resulting in gain of the T locus are common in sporadic Chordomas and expression of this gene is critical for proliferation of Chordoma cells in vitro. Copyright (C) 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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potential therapeutic targets for Chordoma pi3k akt tsc1 tsc2 mtor pathway
British Journal of Cancer, 2009Co-Authors: Nadege Presneau, Asem Shalaby, Bernadine Idowu, Panagiotis D Gikas, S R Cannon, I Gout, T C Diss, Roberto Tirabosco, Adrienne M. FlanaganAbstract:Chordomas are radio- and chemo-resistant tumours and metastasise in as many as 40% of patients. The aim of this study was to identify potential molecular targets for the treatment of Chordoma. In view of the reported association of Chordoma and tuberous sclerosis complex syndrome, and the available therapeutic agents against molecules in the PI3K/AKT/TSC1/TSC2/mTOR pathway, a tissue microarray of 50 Chordoma cases was analysed for expression of active molecules involved in this signalling pathway by immunohistochemistry and a selected number by western blot analysis. Chordomas were positive for p-AKT (92%), p-TSC2 (96%), p-mTOR (27%), total mTOR (75%), p-p70S6K (62%), p-RPS6 (22%), p-4E-BP1 (96%) and eIF-4E (98%). Phosphatase and tensin homologue deleted on chromosome 10 expression was lost in 16% of cases. Mutations failed to be identified in PI3KCA and RHEB1 in the 23 cases for which genomic DNA was available. Fluorescence in situ hybridisation analysis for mTOR and RPS6 loci showed that 11 of 33 and 21 of 44 tumours had loss of one copy of the respective genes, results which correlated with the loss of the relevant total proteins. Fluorescence in situ hybridisation analysis for loci containing TSC1 and TSC2 revealed that all cases analysed harboured two copies of the respective genes. On the basis of p-mTOR and or p-p70S6K expression there is evidence indicating that 65% of the Chordomas studied may be responsive to mTOR inhibitors, rapamycin or its analogues, and that patients may benefit from combined therapy including drugs that inhibit AKT.