Metabolic Pathways and Targets in Chondrosarcoma

Micaily, Ida; Roche, Megan; Ibrahim, Mohammad; Martinez‐Outschoorn, Ubaldo; Mallick, Atrayee Basu

doi:10.3389/fonc.2021.772263

Cited by 10 publications

(11 citation statements)

References 79 publications

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“…Currently torisel and liposomal doxorubicin are tested in patients with advanced soft tissue and bone sarcomas in Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in a NCT00949325 trial. In another mTOR trial, sapanisertib was tested only in xenografts and cell lines [180].…”

Section: Targeted Treatmentmentioning

confidence: 99%

“…In addition to the signaling pathways mentioned, chondrosarcoma also exhibits strong activation of the Hedgehog pathway and GDC-0449 (Hedgehog inhibitor) is of interest in chondrosarcoma [180]. The French Sarcoma Group, in phase II of a collaborative study of antagonists of the Hedgehog signal pathway vismodegib (GDC-0449) in patients with advanced CS (11% DDCS), administered 150 mg/day GDC-0449 in a 28-day cycle.…”

Section: Targeted Treatmentmentioning

confidence: 99%

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Dedifferentiated Chondrosarcoma from Molecular Pathology to Current Treatment and Clinical Trials

Zając,

Dróżdż,

Kisielewska

et al. 2023

Cancers

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Dedifferentiated chondrosarcoma (DDCS) is a rare subtype of chondrosarcoma, a primary cartilaginous malignant neoplasm. It accounts for up to 1–2% of all chondrosarcomas and is generally associated with one of the poorest prognoses among all chondrosarcomas with the highest risk of metastasis. The 5-year survival rates range from 7% to 24%. DDCS may develop at any age, but the average presentation age is over 50. The most common locations are the femur, pelvis humerus, scapula, rib, and tibia. The standard treatment for localised disease is surgical resection. Most patients are diagnosed in unresectable and advanced stages, and chemotherapy for localised and metastatic dedifferentiated DDCS follows protocols used for osteosarcoma.

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Section: Targeted Treatmentmentioning

confidence: 99%

Section: Targeted Treatmentmentioning

confidence: 99%

Dedifferentiated Chondrosarcoma from Molecular Pathology to Current Treatment and Clinical Trials

Zając,

Dróżdż,

Kisielewska

et al. 2023

Cancers

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“…7 Chondrosarcomas are a group of different types of malignancies with distinct histopathological features characterized by the production of cartilage matrix. 8 Most chondrosarcomas are slow growing, rarely metastasize, and adequate surgery can lead to a good prognosis. 9 However, because of the poor sensitivity of high-grade chondrosarcoma to radiotherapy and chemotherapy, adequate surgical resection may be the better option.…”

Section: Introductionmentioning

confidence: 99%

“…7 Chondrosarcomas are a group of different types of malignancies with distinct histopathological features characterized by the production of cartilage matrix. 8…”

Section: Introductionmentioning

confidence: 99%

Development and validation of a nomogram for predicting prognosis of high-grade chondrosarcoma: A surveillance, epidemiology, and end results-based population analysis

Sun

Ouyang

et al. 2023

J Orthop Surg (Hong Kong)

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Background The incidence of chondrosarcoma is increasing every year, and the treatment and prognosis of patients with high-grade chondrosarcoma are becoming more and more important. Nomogram is a tool that can quickly and easily predict the overall survival of tumor patients. Therefore, the development and validation of a nomogram to predict overall survival in patients with high-grade chondrosarcoma was desired. Methods We retrospectively collected 396 patients with high-grade chondrosarcoma from the Surveillance, Epidemiology, and End Results (SEER) database from 2004 to 2015. Randomly divided into model and validation groups, the best cut-off values for age and tumor size grouping were derived by using X-tile software. Then, independent prognostic factors for high-grade chondrosarcoma were derived by SPSS.26 univariate and multivariate Cox analyses analysis in the model group, and the model was evaluated by using R software, using C-indix and ROC curves, and finally these independent prognostic factors were included in Nomogram. Results 396 patients were randomly assigned to the modelling group (n = 280) or the validation group (n = 116). Age, tissue-type, tumor size, AJCC stage, regional expansion and surgery were identified as independent prognostic factors ( p < 0.05) which further combined to construct a nomogram. The C-index of internal validation for overall survival(OS) was 0.757, while the C-index of external validation for overall survival(OS) was 0.832. Both internal and external calibration curves show a good agreement between nomogram prediction and actual survival. Conclusion In this study, we established age, tumour size, AJCC stage, tissue type, surgery and tumor extension as independent prognostic factors for high-grade chondrosarcoma and constructed a nomogram to predict 3- and 5-year survival rates for high-grade chondrosarcoma.

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“…However, the structure of Homo sapiens IDH2 and other point mutants associated with cancers remains unclear. Numerous studies have shown that IDH1/IDH2 mutations frequently occur in low-grade gliomas 7 , secondary glioblastoma 8 , chondrosarcoma 9 , acute myeloid leukemia (AML) 10 , and intrahepatic cholangiocarcinoma 11 . Point mutations are mainly found in the arginine residues within the isocitrate binding sites of IDH active sites , including IDH1/R132, IDH2/R140, and IDH2/R172.…”

Section: Introductionmentioning

confidence: 99%

Effects of cancer-associated point mutations on the structure, function, and stability of isocitrate dehydrogenase 2

Chen

Yang

Qiao

et al. 2022

Sci Rep

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Mutations in isocitrate dehydrogenase (IDH) are frequently found in low-grade gliomas, secondary glioblastoma, chondrosarcoma, acute myeloid leukemias, and intrahepatic cholangiocarcinoma. However, the molecular mechanisms of how IDH2 mutations induce carcinogenesis remain unclear. Using overlapping PCR, transfection, immunoblotting, immunoprecipitation, measurements of enzyme activity, glucose, lactic acid, ATP, and reactive oxygen species (ROS), cell viability, protein degradation assays post-inhibition of the 26S proteasome (bortezomib) or HSP90 (17-AAG), and a homology model, we demonstrated that the properties of ten cancer-associated IDH2 variants (R140G/Q/W and R172S/K/M/W/G/C/P) arising from point mutations are closely related to their structure and stability. Compared with wild-type IDH2, the R172 and R140 point mutations resulted in a decrease in IDH2 activity, ROS, and lactate levels and an increase in glucose and ATP levels under normal and hypoxic conditions, indicating that mutant IDH2 increases cell dependency on mitochondrial oxidative phosphorylation, and reduces glycolysis under hypoxia. Overexpression of most of IDH2 point mutants showed anti-proliferative effects in the 293T and BV2 cell lines by inhibition of PI3K/AKT signaling and cyclin D1 expression and/or induced the expression of TNF-α and IL-6. Furthermore, bortezomib treatment resulted in dramatic degradation of IDH2 mutants, including R140G, R140Q, R140W, R172S and R172K, whereas it had little impact on the expression of WT and other mutants (R172M, R172W, R172G, R172C and R172P). In addition, targeting HSP90 minimally affected the expression of mutated IDH2 due to a lack of interaction between HSP90 and IDH2. The homology model further revealed that changes in conformation and IDH2 protein stability appeared to be associated with these point mutations. Taken together, our findings provide information important for understanding the molecular mechanisms of IDH2 mutations in tumors.

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Metabolic Pathways and Targets in Chondrosarcoma

Cited by 10 publications

References 79 publications

Dedifferentiated Chondrosarcoma from Molecular Pathology to Current Treatment and Clinical Trials

Dedifferentiated Chondrosarcoma from Molecular Pathology to Current Treatment and Clinical Trials

Development and validation of a nomogram for predicting prognosis of high-grade chondrosarcoma: A surveillance, epidemiology, and end results-based population analysis

Effects of cancer-associated point mutations on the structure, function, and stability of isocitrate dehydrogenase 2

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