The Experts below are selected from a list of 8082 Experts worldwide ranked by ideXlab platform
Judith V.m.g. Bovée - One of the best experts on this subject based on the ideXlab platform.
-
Exploration of the Chondrosarcoma metabolome; the mTOR pathway as an important pro-survival pathway
Elsevier, 2019Co-Authors: Ruben D Addie, Gaia Alberti, Ivo Que, Hans Baelde, Yvonne De Jong, Alwine B Kruisselbrink, Judith V.m.g. BovéeAbstract:Background: Chondrosarcomas are malignant cartilage-producing tumors showing mutations and changes in gene expression in metabolism related genes. In this study, we aimed to explore the metabolome and identify targetable metabolic vulnerabilities in Chondrosarcoma. Methods: A custom-designed metabolic compound screen containing 39 compounds targeting different metabolic pathways was performed in Chondrosarcoma cell lines JJ012, SW1353 and CH2879. Based on the anti-proliferative activity, six compounds were selected for validation using real-time metabolic profiling. Two selected compounds (rapamycin and sapanisertib) were further explored for their effect on viability, apoptosis and metabolic dependency, in normoxia and hypoxia. In vivo efficacy of sapanisertib was tested in a Chondrosarcoma orthotopic xenograft mouse model. Results: Inhibitors of glutamine, glutathione, NAD synthesis and mTOR were effective in Chondrosarcoma cells. Of the six compounds that were validated on the metabolic level, mTOR inhibitors rapamycin and sapanisertib showed the most consistent decrease in oxidative and glycolytic parameters. Chondrosarcoma cells were sensitive to mTORC1 inhibition using rapamycin. Inhibition of mTORC1 and mTORC2 using sapanisertib resulted in a dose-dependent decrease in viability in all Chondrosarcoma cell lines. In addition, induction of apoptosis was observed in CH2879 after 24 h. Treatment of Chondrosarcoma xenografts with sapanisertib slowed down tumor growth compared to control mice. Conclusions: mTOR inhibition leads to a reduction of oxidative and glycolytic metabolism and decreased proliferation in Chondrosarcoma cell lines. Although further research is needed, these findings suggest that mTOR inhibition might be a potential therapeutic option for patients with Chondrosarcoma. Keywords: Chondrosarcoma, Metabolism, mTOR, Sapanisertib, Rapamyci
-
targeting glutaminolysis in Chondrosarcoma in context of the idh1 2 mutation
British Journal of Cancer, 2018Co-Authors: Elisabeth F P Peterse, Annemarie Cletonjansen, Bertine Niessen, Ruben D Addie, Yvonne De Jong, Arjen H G Cleven, Alwine B Kruisselbrink, Brendy E W M Van Den Akker, Remco J Molenaar, Judith V.m.g. BovéeAbstract:Chondrosarcoma is a malignant cartilage-forming bone tumour in which mutations in IDH1 and IDH2 frequently occur. Previous studies suggest an increased dependency on glutaminolysis in IDH1/2 mutant cells, which resulted in clinical trials with the drugs CB-839, metformin and chloroquine. In this study, the preclinical rationale for using these drugs as a treatment for Chondrosarcoma was evaluated. Expression of glutaminase was determined in 120 cartilage tumours by immunohistochemistry. Ten Chondrosarcoma cell lines were treated with the metabolic compounds CB-849, metformin, phenformin (lipophilic analogue of metformin) and chloroquine. A difference in glutaminase expression levels between the different tumour grades (p = 0.001, one-way ANOVA) was identified, with the highest expression observed in high-grade Chondrosarcomas. Treatment with CB-839, metformin, phenformin or chloroquine revealed that Chondrosarcoma cell lines are sensitive to glutaminolysis inhibition. Metformin and phenformin decreased mTOR activity in Chondrosarcoma cells, and metformin decreased LC3B-II levels, which is counteracted by chloroquine. Targeting glutaminolysis with CB-839, metformin, phenformin or chloroquine is a potential therapeutic strategy for a subset of high-grade Chondrosarcomas, irrespective of the presence or absence of an IDH1/2 mutation.
-
functional profiling of receptor tyrosine kinases and downstream signaling in human Chondrosarcomas identifies pathways for rational targeted therapy
Clinical Cancer Research, 2013Co-Authors: Yixiang Zhang, Jolieke G Van Oosterwijk, Ewa Sicinska, Samuel Moss, Stephen P Remillard, Tom Van Wezel, Claudia Buhnemann, Andrew Bassim Hassan, George D Demetri, Judith V.m.g. BovéeAbstract:Purpose: Chondrosarcomas are notoriously resistant to cytotoxic chemotherapeutic agents. We sought to identify critical signaling pathways that contribute to their survival and proliferation, and which may provide potential targets for rational therapeutic interventions. Experimental Design: Activation of receptor tyrosine kinases (RTK) was surveyed using phospho-RTK arrays. S6 phosphorylation and NRAS mutational status were examined in Chondrosarcoma primary tumor tissues. siRNA or small-molecule inhibitors against RTKs or downstream signaling proteins were applied to Chondrosarcoma cells and changes in biochemical signaling, cell cycle, and cell viability were determined. In vivo antitumor activity of BEZ235, a phosphoinositide 3-kinase (PI3K)/mTOR inhibitor, was evaluated in a Chondrosarcoma xenograft model. Results: Several RTKs were identified as critical mediators of cell growth, but the RTK dependencies varied among cell lines. In exploration of downstream signaling pathways, strong S6 phosphorylation was found in 69% of conventional Chondrosarcomas and 44% of dedifferentiated Chondrosarcomas. Treatment with BEZ235 resulted in dramatic reduction in the growth of all Chondrosarcoma cell lines. Tumor growth was similarly inhibited in a xenograft model of Chondrosarcoma. In addition, Chondrosarcoma cells with an NRAS mutation were sensitive to treatment with a mitogen-activated protein kinase/extracellular signal–regulated kinase kinase (MEK) inhibitor. Functional NRAS mutations were found in 12% of conventional central Chondrosarcomas. Conclusions: RTKs are commonly activated in Chondrosarcoma, but because of their considerable heterogeneity, targeted inhibition of the PI3K/mTOR pathway represents a rational therapeutic strategy. Chondrosarcomas with NRAS mutations may benefit from treatment with MEK inhibitors. Clin Cancer Res; 19(14); 3796–807. ©2013 AACR .
-
restoration of chemosensitivity for doxorubicin and cisplatin in Chondrosarcoma in vitro bcl 2 family members cause chemoresistance
Annals of Oncology, 2012Co-Authors: J G Van Oosterwijk, Bram Herpers, Danielle Meijer, I Briairede H Bruijn, A M Cletonjansen, Hans Gelderblom, B Van De Water, Judith V.m.g. BovéeAbstract:ABSTRACT Background Chondrosarcomas are malignant cartilage-forming tumors notorious for their resistance to conventional chemo- and radiotherapy. Postulated explanations describe the inaccessibility due to abundant hyaline cartilaginous matrix, presence of multidrug resistance (MDR) pumps, and expression of anti-apoptotic BCL-2 family members. Materials and methods We studied the sensitivity of Chondrosarcoma cell lines (SW1353, CH2879, JJ012, OUMS27) and two primary cultures for doxorubicin and cisplatin. We examined the role of extracellular matrix using three-dimensional (3D) pellet models and MDR pump activity using fluorescence-activated cell sorter analysis. The role of BCL-2 family members was investigated using the BH3 mimetic ABT-737. Results Chondrosarcoma cells showed highest resistance to cisplatin. 3D cell pellets, morphologically strongly resembling Chondrosarcoma in vivo, confirmed nuclear incorporation of doxorubicin. MDR pump activity was heterogeneous among cultures. Chondrosarcoma cells responded to ABT-737 and combination with doxorubicin led to complete loss of cell viability and apoptosis with cytochrome C release. Conclusions Despite MDR pump activity and abundance of hyaline cartilaginous matrix, doxorubicin is able to accumulate in the cell nuclei. By repairing the apoptotic machinery, we were able to sensitize Chondrosarcoma cells to doxorubicin and cisplatin, indicating an important role for BCL-2 family members in chemoresistance and a promising new treatment strategy for inoperable Chondrosarcoma.
-
3 o 10 incidence predictive factors and prognosis of central Chondrosarcoma in patients with ollier disease and maffucci syndrome report of 133 patients
Journal of Bone and Joint Surgery-british Volume, 2010Co-Authors: Suzan Hm Verdegaal, Judith V.m.g. Bovée, Twinkal C Pansuriya, Robert J Grimer, B Toker, Paul C Jutte, San M Julian, David Biau, I C M Van Der Geest, Andreas LeithnerAbstract:Enchondromatosis is a non-hereditary disease, characterised by the presence of multiple enchondromas. While Ollier Disease is typified by multiple enchondromas, in Maffucci Syndrome they are combined with haemangioma. Due to the rarity of these diseases, systematic studies on clinical behaviour providing information how to treat patients are lacking. This study intends to answer the following questions: What are predictive factors for developing Chondrosarcoma? When is extensive surgery necessary? How often patients die due to dedifferentiation or metastasis? Twelve institutes in eight countries participated in this descriptive retrospective EMSOS-study. 118 Patients with Ollier Disease and 15 patients with Maffucci Syndrome were included. Unilateral localization of disease was found in 60% of Ollier patients and 40% of patients with Maffucci Syndrome. One of the predictive factors for developing Chondrosarcoma is the location of the enchondromas; the risk increases especially when enchondromas are located in the scapula (33%), humerus (18%), pelvis (26%) or femur (15%). For the phalanges, this risk is 14% in the hand and 16% in the feet. The decision whether or not to perform extensive surgery is difficult, especially in patients who suffer multiple Chondrosarcomas. Malignant transformation was found in fourty-four patients with Ollier Disease (37%) and eight patients with Maffucci Syndrome (53%). Multiple synchronous or metachronous Chondrosarcomas were found in 15 patients. Nine patients died (range 21–54 yrs). Seven of them died disease related due to pulmonary metastasis (2 humerus, 2 pelvis, 3 femur). Two patients died from glioma of the brain. In conclusion, one important predictive factor for developing Chondrosarcoma is the location of the enchondromas; interestingly, only patients with Chondrosarcoma outside the small bones died of their disease. In this series, no dedifferentiation of Chondrosarcoma was seen. A first design flow-chart how to approach Chondrosarcoma in patients with Ollier Disease and Maffucci Syndrome is in preparation.
H T Temple - One of the best experts on this subject based on the ideXlab platform.
-
enchondroma versus Chondrosarcoma in the appendicular skeleton differentiating features
Radiographics, 1998Co-Authors: Mark D Murphey, S R Boyea, J A Bojescul, Donald J Flemming, Donald E. Sweet, H T TempleAbstract:Distinction of enchondroma versus intramedullary Chondrosarcoma affecting the appendicular skeleton (proximal to the metacarpals and metatarsals) is a frequent diagnostic dilemma. The authors studied a large series of patients with these lesions (92 with enchondromas, 95 with Chondrosarcomas) using statistical assessment of both clinical parameters and numerous radiologic manifestations on images from multiple modalities to identify differentiating features. Multiple clinical and imaging parameters demonstrated statistically significant differences between enchondroma and Chondrosarcoma, particularly pain related to the lesion, deep endosteal scalloping (greater than two-thirds of cortical thickness), cortical destruction and soft-tissue mass (at computed tomography or magnetic resonance imaging), periosteal reaction (at radiography), and marked uptake of radionuclide (greater than the anterior iliac crest) at bone scintigraphy. All of these features strongly suggested the diagnosis of Chondrosarcoma. The...
-
Enchondroma versus Chondrosarcoma in the appendicular skeleton: differentiating features.
Radiographics : a review publication of the Radiological Society of North America Inc, 1998Co-Authors: Mark D Murphey, S R Boyea, J A Bojescul, Donald J Flemming, Donald E. Sweet, H T TempleAbstract:Distinction of enchondroma versus intramedullary Chondrosarcoma affecting the appendicular skeleton (proximal to the metacarpals and metatarsals) is a frequent diagnostic dilemma. The authors studied a large series of patients with these lesions (92 with enchondromas, 95 with Chondrosarcomas) using statistical assessment of both clinical parameters and numerous radiologic manifestations on images from multiple modalities to identify differentiating features. Multiple clinical and imaging parameters demonstrated statistically significant differences between enchondroma and Chondrosarcoma, particularly pain related to the lesion, deep endosteal scalloping (greater than two-thirds of cortical thickness), cortical destruction and soft-tissue mass (at computed tomography or magnetic resonance imaging), periosteal reaction (at radiography), and marked uptake of radionuclide (greater than the anterior iliac crest) at bone scintigraphy. All of these features strongly suggested the diagnosis of Chondrosarcoma. These criteria allow distinction of appendicular enchondroma and Chondrosarcoma in at least 90% of cases.
Robin L Jones - One of the best experts on this subject based on the ideXlab platform.
-
Is the IDH Mutation a Good Target for Chondrosarcoma Treatment?
Current Molecular Biology Reports, 2020Co-Authors: Elena Cojocaru, Christopher Wilding, Bodil Engelman, Paul Huang, Robin L JonesAbstract:Chondrosarcomas are rare cancers of bone that arise from the malignant transformation of cells of chondrocytic lineage. They are known to be resistant to systemic cytotoxic chemotherapy and radiotherapy. The mainstay of management of localised disease is en bloc surgical resection with curative intent. Metastatic Chondrosarcoma has a dismal prognosis, and to date, there are no proven effective systemic therapies in the advanced setting. Genomic studies have demonstrated that 50 to 80% of Chondrosarcomas harbour a mutation in either the IDH1 or IDH2 gene. IDH inhibitors are currently under investigation in clinical trials, after showing promising results in phase 1 studies in IDH mutated cancers. In Chondrosarcoma, IDH mutations represent an attractive target, however, early results with IDH inhibitors in IDH mutated Chondrosarcoma are modest and the final results of ongoing trials are eagerly awaited.
-
novel therapeutic approaches in Chondrosarcoma
Future Oncology, 2017Co-Authors: Genovefa Polychronidou, Vasilios Karavasilis, Seth M Pollack, Paul H Huang, Alex Lee, Robin L JonesAbstract:Chondrosarcoma is a malignant tumor of bones, characterized by the production of cartilage matrix. Due to lack of effective treatment for advanced disease, the clinical management of Chondrosarcomas is exceptionally challenging. Current research focuses on elucidating the molecular events underlying the pathogenesis of this rare bone malignancy, with the goal of developing new molecularly targeted therapies. Signaling pathways suggested to have a role in Chondrosarcoma include Hedgehog, Src, PI3k-Akt-mTOR and angiogenesis. Mutations in IDH1/2, present in more than 50% of primary conventional Chondrosarcomas, make the development of IDH inhibitors a promising treatment option. The present review discusses the preclinical and early clinical data on novel targeted therapeutic approaches in Chondrosarcoma.
Mark D Murphey - One of the best experts on this subject based on the ideXlab platform.
-
improved differentiation of benign osteochondromas from secondary Chondrosarcomas with standardized measurement of cartilage cap at ct and mr imaging
Radiology, 2010Co-Authors: Stephanie A Bernard, Donald J Flemming, Mark D Murphey, Mark J KransdorfAbstract:This study supports application of a standardized measuring technique for improved distinction of benign osteochondromas from Chondrosarcomas, with a cartilage cap thickness of 2 cm or greater as the determinant of Chondrosarcoma.
-
from the archives of the afip imaging of primary Chondrosarcoma radiologic pathologic correlation
Radiographics, 2003Co-Authors: Mark D Murphey, Mark J Kransdorf, Eric A Walker, Anthony J Wilson, Thomas H Temple, Francis H GannonAbstract:Chondrosarcoma is a malignant tumor that produces cartilage matrix, and lesions that arise de novo are called primary. Primary Chondrosarcoma is the third most common primary malignant tumor of bone, constituting 20%-27% of all primary malignant osseous neoplasms. There are numerous types of primary Chondrosarcomas, including conventional intramedullary, clear cell, juxtacortical, myxoid, mesenchymal, extraskeletal, and dedifferentiated. The conventional intramedullary Chondrosarcoma is the most frequent type, and it most commonly involves the long bones or pelvis in up to 65% of cases. Although the pathologic appearance varies with specific lesion type, Chondrosarcomas grow with lobular type architecture, and these hyaline cartilage nodules demonstrate high water content and peripheral enchondral ossification. Imaging features directly reflect this pathologic appearance, and the various subtypes often show distinctive features. Radiographic findings often suggest the diagnosis of Chondrosarcoma because of identification of typical "ring-and-arc" chondroid matrix mineralization (representing the enchondral ossification) and aggressive features of deep endosteal scalloping and soft-tissue extension. These latter features are usually best assessed, as is lesion staging, with computed tomography (CT) or magnetic resonance (MR) imaging. CT is optimal to detect the matrix mineralization, particularly when it is subtle or when the lesion is located in anatomically complex areas. Both CT and MR imaging depict the high water content of these lesions as low attenuation and very high signal intensity with T2-weighting, respectively. Understanding and recognizing the spectrum of appearances of the various types of primary Chondrosarcoma allow improved patient assessment and are vital for optimal clinical management including diagnosis, biopsy, staging, treatment, and prognosis.
-
enchondroma versus Chondrosarcoma in the appendicular skeleton differentiating features
Radiographics, 1998Co-Authors: Mark D Murphey, S R Boyea, J A Bojescul, Donald J Flemming, Donald E. Sweet, H T TempleAbstract:Distinction of enchondroma versus intramedullary Chondrosarcoma affecting the appendicular skeleton (proximal to the metacarpals and metatarsals) is a frequent diagnostic dilemma. The authors studied a large series of patients with these lesions (92 with enchondromas, 95 with Chondrosarcomas) using statistical assessment of both clinical parameters and numerous radiologic manifestations on images from multiple modalities to identify differentiating features. Multiple clinical and imaging parameters demonstrated statistically significant differences between enchondroma and Chondrosarcoma, particularly pain related to the lesion, deep endosteal scalloping (greater than two-thirds of cortical thickness), cortical destruction and soft-tissue mass (at computed tomography or magnetic resonance imaging), periosteal reaction (at radiography), and marked uptake of radionuclide (greater than the anterior iliac crest) at bone scintigraphy. All of these features strongly suggested the diagnosis of Chondrosarcoma. The...
-
Enchondroma versus Chondrosarcoma in the appendicular skeleton: differentiating features.
Radiographics : a review publication of the Radiological Society of North America Inc, 1998Co-Authors: Mark D Murphey, S R Boyea, J A Bojescul, Donald J Flemming, Donald E. Sweet, H T TempleAbstract:Distinction of enchondroma versus intramedullary Chondrosarcoma affecting the appendicular skeleton (proximal to the metacarpals and metatarsals) is a frequent diagnostic dilemma. The authors studied a large series of patients with these lesions (92 with enchondromas, 95 with Chondrosarcomas) using statistical assessment of both clinical parameters and numerous radiologic manifestations on images from multiple modalities to identify differentiating features. Multiple clinical and imaging parameters demonstrated statistically significant differences between enchondroma and Chondrosarcoma, particularly pain related to the lesion, deep endosteal scalloping (greater than two-thirds of cortical thickness), cortical destruction and soft-tissue mass (at computed tomography or magnetic resonance imaging), periosteal reaction (at radiography), and marked uptake of radionuclide (greater than the anterior iliac crest) at bone scintigraphy. All of these features strongly suggested the diagnosis of Chondrosarcoma. These criteria allow distinction of appendicular enchondroma and Chondrosarcoma in at least 90% of cases.
Joachim Hassenpflug - One of the best experts on this subject based on the ideXlab platform.
-
minichromosome maintenance protein mcm6 in low grade Chondrosarcoma distinction from enchondroma and identification of progressive tumors
American Journal of Clinical Pathology, 2004Co-Authors: Andreas Helfenstein, Sven Olaf Frahm, Matthias Krams, Wolf Drescher, Reza Parwaresch, Joachim HassenpflugAbstract:The distinction between Chondrosarcoma and enchondroma is difficult, and no reliable immunohistochemical or molecular methods are available. Differentiation is important because the therapeutic consequences range from radiologic followup to radical operation. We studied 17 Chondrosarcomas (12 grade 1) and compared them with 14 enchondromas immunohistochemically by using the monoclonal antibodies Ki-MCM6 (minichromosome maintenance protein 6), Ki-S5 (Ki-67), and Ki-S2 (repp86), in addition to the established clinical criteria. In comparison with the other markers, Ki-MCM6 proved more effective at identifying proliferative activity in grade 1 Chondrosarcomas. The MCM6 labeling index correlated with tumor grade and was significantly increased in grade 1 Chondrosarcomas compared with enchondromas. The 5 cases of progressive Chondrosarcoma also had a significantly higher MCM6 labeling index than the nonprogressive cases. Furthermore, by means of the MCM6 labeling index, many cases of progressive disease were recognized among those of uncertain malignant potential, justifying their classification as low-grade Chondrosarcomas.
-
minichromosome maintenance protein mcm6 in low grade Chondrosarcoma
American Journal of Clinical Pathology, 2004Co-Authors: Andreas Helfenstein, Sven Olaf Frahm, Matthias Krams, Wolf Drescher, Reza Parwaresch, Joachim HassenpflugAbstract:The distinction between Chondrosarcoma and enchondroma is difficult, and no reliable immunohistochemical or molecular methods are available. Differentiation is important because the therapeutic consequences range from radiologic follow-up to radical operation. We studied 17 Chondrosarcomas (12 grade 1) and compared them with 14 enchondromas immunohistochemically by using the monoclonal antibodies Ki-MCM6 (minichromosome maintenance protein 6), Ki-S5 (Ki-67), and Ki-S2 (repp86), in addition to the established clinical criteria. In comparison with the other markers, Ki-MCM6 proved more effective at identifying proliferative activity in grade 1 Chondrosarcomas. The MCM6 labeling index correlated with tumor grade and was significantly increased in grade 1 Chondrosarcomas compared with enchondromas. The 5 cases of progressive Chondrosarcoma also had a significantly higher MCM6 labeling index than the nonprogressive cases. Furthermore, by means of the MCM6 labeling index, many cases of progressive disease were recognized among those of uncertain malignant potential, justifying their classification as low-grade Chondrosarcomas.
