Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0029463 (osteosarcoma)
 16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although fibrous dysplasia (FD) is a benign fibro-osseous lesion, locally aggressive behaviour has rarely been described but is poorly characterised. In this study, we document clinical, radiological and pathological (including molecular genetics) findings in three cases of locally aggressive FD, two of which involved the ribs. Lesions in these cases, one of which was a recurrent lesion, were followed up for 2-7 years. All of the lesions showed typical histological features of FD but were characterised by extension through the bone cortex into the extra-osseous soft tissue. The lesions did not exhibit overexpression/amplification of CDK4 and MDM2; in two of the cases, a GNAS mutation was identified. Our findings confirm that FD can rarely exhibit locally aggressive behaviour with extension beyond the bone compartment into the surrounding soft tissue; these lesions can be distinguished from low-grade intramedullary osteosarcoma by lack of amplification/overexpression of CDK4 and MDM2 and the presence of a GNAS mutation.
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PMID:Locally aggressive fibrous dysplasia. 2376 Jul 83

Osteosarcoma is a malignant bone tumor with high metastatic potential. Metastasis at diagnosis is the most significant prognostic factor in predicting the clinical outcome of osteosarcoma. We compared the gene expression of metastases that were present at the time of initial diagnosis to those developed later in the course of the disease. We used quantitative real-time polymerase chain reaction to evaluate the gene expression of MDM2, CXCR4, RANKL, RB1, and OSTERIX in 98 samples of osteosarcoma taken from 47 patients (74 metastases and 24 primary tumors) and 30 nonmalignant lung tissues surrounding osteosarcoma metastases. In addition, we investigated the copy number changes of RB1 and MDM2 genes in 12 primary cultures of pulmonary metastases of osteosarcoma, using interphase fluorescence in situ hybridization. Metastases from metastatic patients at diagnosis were characterized by low expression of RB1 and RANKL (P = .0009 and P = .0109, respectively) and overexpression of CXCR4 and MDM2 (P = .0389 and P = .0325, respectively). The loss of RANKL and gain of CXCR4 could also be detected in the primary tumors of metastatic patients at diagnosis (P = .0121 and P = .0264, respectively). Thus, some early genetic events such as the loss of RANKL and the gain of CXCR4 expressions probably facilitate the metastatic progression concomitant with the primary tumor establishment, supporting the role of the CXCR4 receptor in directing osteosarcoma metastases to the lung. On the other hand, late events such as the loss of RB1 and gain of MDM2, crucial regulators of cell cycle, appear to be related to the final mechanisms contributing to the metastatic establishment of osteosarcoma.
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PMID:The metastatic behavior of osteosarcoma by gene expression and cytogenetic analyses. 2384 65

Osteosarcoma (OS) is the most common pediatric bone malignancy worldwide. The MDM2 gene is an important candidate gene for influencing the susceptibility to OS. The objective of this study aimed to detect the potential association between MDM2 genetic variants and OS susceptibility in Chinese Han population. We recruited 415 OS patients and 431 cancer-free controls in this case-control study. The c.44C>T and c.1002T>C genetic variants in MDM2 gene were investigated using created restriction site-polymerase chain reaction (CRS-PCR) and PCR-restriction fragment length polymorphism (PCR-RFLP), respectively. We found that the genotypes/alleles of c.44C>T and c.1002T>C were statistically associated with the increased risk of OS (for c.44C>T, TT versus (vs.) CC: OR = 2.43, 95% CI 1.49-3.95, p < 0.001; T vs. C: OR = 1.36, 95% CI 1.11-1.67, p = 0.003; for c.1002T>C, CC vs. TT: OR = 2.38, 95% CI 1.37-4.13, p = 0.002; C vs. T: OR = 1.27, 95% CI 1.02-1.56, p = 0.030). The T allele and TT genotype of c.44C>T and C allele and CC genotype of c.1002T>C could be increased risk factors for the susceptibility to OS. Results from this study suggest that MDM2 genetic variants are potentially related to OS susceptibility in Chinese Han population, and might be used as molecular markers for assessing OS susceptibility.
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PMID:Association analysis between genetic variants of MDM2 gene and osteosarcoma susceptibility in Chinese. 2393 91

Chondrosarcomas are cartilage-forming, poorly vascularized tumors. They represent the second malignant primary bone tumor of adults after osteosarcoma, but in contrast to osteosarcoma they are resistant to chemotherapy and radiotherapy, surgical excision remaining the only therapeutic option. Few cell lines and animal models are available, and the mechanisms behind their chemoresistance remain largely unknown. Our goal was to establish new cell lines and animal cancer models from human chondrosarcoma biopsies to study their chemoresistance. Between 2007 and 2012, 10 chondrosarcoma biopsies were collected and used for cell culture and transplantation into nude mice. Only one transplanted biopsy and one injected cell line has engrafted successfully leading to conventional central high-grade chondrosarcoma similar to the original biopsies. In culture, two new stable cell lines were obtained, one from a dedifferentiated and one from a grade III conventional central chondrosarcoma biopsy. Their genetic characterization revealed triploid karyotypes, mutations in IDH1, IDH2, and TP53, deletion in CDKN2A and/or MDM2 amplification. These cell lines expressed mesenchymal membrane markers (CD44, 73, 90, 105) and were able to produce a hyaline cartilaginous matrix when cultured in chondrogenic three-dimensional (3D) pellets. Using a high-throughput quantitative RT-PCR approach, we observed that cell lines cultured in monolayer had lost expression of several genes implicated in cartilage development (COL2A1, COMP, ACAN) but restored their expression in 3D cultures. Chondrosarcoma cells in monolayer were sensitive to several conventional chemotherapeutic agents but became resistant to low doses of mafosfamide or doxorubicin when cultured in 3D pellets, in parallel with an altered nucleic accumulation of the drug. Our results indicate that the cartilaginous matrix produced by chondrosarcoma cells may impair diffusion of several drugs and thus contribute to chemoresistance. Therefore, 3D chondrogenic cell pellets constitute a more relevant model to study chondrosarcoma chemoresistance and may be a valuable alternative to animal experimentations.
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PMID:New chondrosarcoma cell lines and mouse models to study the link between chondrogenesis and chemoresistance. 2395 80

A peculiar feature of several types of childhood cancer is that loss-of-function mutations of the TP53 (p53) tumor suppressor gene are uncommon, in contrast to many adult tumors. As p53 needs to be inactivated in order for tumor cells to survive and thrive, pediatric tumors typically make use of other mechanisms to keep p53 in check. One of the critical negative regulators of p53 is the MDM2 oncoprotein. Many anticancer drug development efforts in the past decade have therefore been devoted to the discovery and optimization of small molecules that selectively disrupt the interaction between MDM2 and p53, which could provide, in principle, a potent means to restore p53 function in tumor cells with wild-type p53. The nutlins are the class of selective inhibitors of the p53-MDM2 interaction that are currently most advanced in their clinical development. We review here the preclinical data that support the potential therapeutic use of nutlin drugs in the treatment of various pediatric tumors, including neuroblastoma, retinoblastoma, osteosarcoma, Ewing's sarcoma, rhabdomyosarcoma, medulloblastoma, and childhood acute lymphoblastic leukemia.
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PMID:Pharmacologic activation of wild-type p53 by nutlin therapy in childhood cancer. 2426 62

PATZ1 is a transcriptional factor functioning either as an activator or a repressor of gene transcription depending upon the cellular context. It appears to have a dual oncogenic/anti-oncogenic activity. Indeed, it is overexpressed in colon carcinomas, and its silencing inhibits colon cancer cell proliferation or increases sensitivity to apoptotic stimuli of glioma cells, suggesting an oncogenic role. Conversely, the development of B-cell lymphomas, sarcomas, hepatocellular carcinomas and lung adenomas in Patz1-knockout (ko) mice supports its tumour suppressor function. PATZ1 role in mouse lymphomagenesis is mainly because of the involvement of PATZ1 in BCL6-negative autoregulation. However, this does not exclude that PATZ1 may be involved in tumorigenesis by other mechanisms. Here, we report that PATZ1 interacts with the tumour suppressor p53 and binds p53-dependent gene promoters, including those of BAX, CDKN1A and MDM2. Knockdown of PATZ1 in HEK293 cells reduces promoter activity of these genes and inhibits their expression, suggesting a role of PATZ in enhancing p53 transcriptional activity. Consistently, Patz1-ko mouse embryonic fibroblasts (MEFs) show decreased expression of Bax, Cdkn1a and Mdm2 compared with wild-type (wt) MEFs. Moreover, Patz1-ko MEFs show a decreased percentage of apoptotic cells, either spontaneous or induced by treatment with 5-fluorouracil (5FU), compared with wt controls, suggesting a pro-apoptotic role for PATZ1 in these cells. However, PATZ1 binds p53-target genes also independently from p53, exerting, in the absence of p53, an opposite function on their expression. Indeed, knockdown of PATZ1 in p53-null osteosarcoma cells upregulates BAX expression and decreases survival of 5FU-treated cells, then suggesting an anti-apoptotic role of PATZ1 in p53-null cancer cells. Therefore, these data support a PATZ1 tumour-suppressive function based on its ability to enhance p53-dependent transcription and apoptosis. Conversely, its opposite and anti-apoptotic role in p53-null cancer cells provides the perspective of PATZ1 silencing as a possible adjuvant in the treatment of p53-null cancer.
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PMID:PATZ1 interacts with p53 and regulates expression of p53-target genes enhancing apoptosis or cell survival based on the cellular context. 2433 83

We recently reported the discovery of AM-8553 (1), a potent and selective piperidinone inhibitor of the MDM2-p53 interaction. Continued research investigation of the N-alkyl substituent of this series, focused in particular on a previously underutilized interaction in a shallow cleft on the MDM2 surface, led to the discovery of a one-carbon tethered sulfone which gave rise to substantial improvements in biochemical and cellular potency. Further investigation produced AMG 232 (2), which is currently being evaluated in human clinical trials for the treatment of cancer. Compound 2 is an extremely potent MDM2 inhibitor (SPR KD = 0.045 nM, SJSA-1 EdU IC50 = 9.1 nM), with remarkable pharmacokinetic properties and in vivo antitumor activity in the SJSA-1 osteosarcoma xenograft model (ED50 = 9.1 mg/kg).
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PMID:Discovery of AMG 232, a potent, selective, and orally bioavailable MDM2-p53 inhibitor in clinical development. 2445 72

We previously reported the discovery of AMG 232, a highly potent and selective piperidinone inhibitor of the MDM2-p53 interaction. Our continued search for potent and diverse analogues led to the discovery of novel morpholinone MDM2 inhibitors. This change to a morpholinone core has a significant impact on both potency and metabolic stability compared to the piperidinone series. Within this morpholinone series, AM-8735 emerged as an inhibitor with remarkable biochemical potency (HTRF IC50 = 0.4 nM) and cellular potency (SJSA-1 EdU IC50 = 25 nM), as well as pharmacokinetic properties. Compound 4 also shows excellent antitumor activity in the SJSA-1 osteosarcoma xenograft model with an ED50 of 41 mg/kg. Lead optimization toward the discovery of this inhibitor as well as key differences between the morpholinone and the piperidinone series will be described herein.
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PMID:Selective and potent morpholinone inhibitors of the MDM2-p53 protein-protein interaction. 2454 97

We previously reported the discovery of potent and selective morpholinone and piperidinone inhibitors of the MDM2-p53 interaction. These inhibitors have in common a carboxylic acid moiety that engages in an electrostatic interaction with MDM2-His96. Our continued search for potent and diverse inhibitors led to the discovery of novel replacements for these acids uncovering new interactions with the MDM2 protein. In particular, using pyridine or thiazole as isosteres of the carboxylic acid moiety resulted in very potent analogues. From these, AM-6761 (4) emerged as a potent inhibitor with remarkable biochemical (HTRF IC50 = 0.1 nM) and cellular potency (SJSA-1 EdU IC50 = 16 nM), as well as favorable pharmacokinetic properties. Compound 4 also shows excellent antitumor activity in the SJSA-1 osteosarcoma xenograft model with an ED50 of 11 mg/kg. Optimization efforts toward the discovery of these inhibitors as well as the new interactions observed with the MDM2 protein are described herein.
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PMID:Novel inhibitors of the MDM2-p53 interaction featuring hydrogen bond acceptors as carboxylic acid isosteres. 2460 44

Sclerosing rhabdomyosarcoma (SRMS), a recently characterized variant of rhabdomyosarcoma, can pose a significant diagnostic challenge given its rarity and its histological similarity to other malignancies. SRMS is characterized by dense hyalinized or sclerosing collagenous matrix and a pseudovascular pattern of growth. SRMS shares histologic similarities with several mesenchymal tumors including: leiomyosarcoma, osteosarcoma, chondrosarcoma, angiosarcoma, and sclerosing epithelioid fibrosarcoma. We herein report a case of SRMS mimicking a myoepithelial carcinoma of the parotid gland. The tumor contained small, spindled, and epithelioid tumor cells lining pseudovascular spaces within a dense hyalinized stroma. Initial stains for keratins, S100 and p63 were negative. However the tumor cells showed desmin and myogenin positivity. The tumor was negative for FKHR gene rearrangements and showed no MDM2 gene amplification. This is the second case of SRMS to be diagnosed in the parotid gland highlighting the potential for misdiagnosis as a primary salivary gland epithelial malignancy.
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PMID:Sclerosing rhabdomyosarcoma: presentation of a rare sarcoma mimicking myoepithelial carcinoma of the parotid gland and review of the literature. 2471 Jul 32


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