"CS belong to a very diverse group of tumors having in common the production of cartilaginous matrix. Almost 90% of the CS are of the conventional subtype, but there are also the more rare subtypes with their own distinct histological and clinical features including clear cell, mesenchymal and dedifferentiated CS
. The prognosis for patients with CS is very diverse with a very good prognosis for atypical cartilaginous tumour/CS grade I which are slow growing and do not metastasize and a poor prognosis for grade III CS which have a high risk, up to 70%, for local recurrence and metastasis
[Show abstract][Hide abstract] ABSTRACT: Background
The majority of patients with chondrosarcoma of bone have an excellent overall survival after local therapy. However, in case of unresectable locally advanced or metastatic disease the outcome is poor and limited treatment options exist. Therefore we conducted a survey of clinical phase I or II trials and retrospective studies that described systemic therapy for chondrosarcoma patients.
Materials and methods
Using PubMed, clinicaltrials.gov, the Cochrane controlled trial register and American Society of Clinical Oncology (ASCO) abstracts a literature survey was conducted. From the identified items, data were collected by a systematic analysis. We limited our search to semi-recent studies published between 2000 and 2013 to include modern drugs, imaging techniques and disease evaluations.
A total of 31 studies were found which met the criteria: 9 phase I trials, 11 phase II and 8 retrospective studies. In these studies 855 chondrosarcoma patients were reported. The tested drugs were mostly non-cytotoxic, either alone or in combination with another non-cytotoxic agent or chemotherapy. Currently two phase I trials, one phase IB/II trial and three phase II trials are enrolling chondrosarcoma patients.
Because chondrosarcoma of bone is an orphan disease it is difficult to conduct clinical trials. The meagre outcome data for locally advanced or metastatic patients indicate that new treatment options are needed. For the phase I trials it is difficult to draw conclusions because of the low numbers of chondrosarcoma patients enrolled, and at different dose levels. Some phase II trials show promising results which support further research. Retrospective studies are encouraged as they could add to the limited data available. Efforts to increase the number of studies for this orphan disease are urgently needed.
"With the advent of systemic chemotherapy in the management of mesenchymal malignancies such as osteosarcoma and Ewing's sarcoma, there has been an increase in the long-term survival of patients. In contrast, chondrosarcomas continue to have a poor prognosis owing to the absence of an effective therapy –. Identifying new drugs that enables to reduce chondrosarcoma growth may improve survival of patients. Here, we identified, 3-Deazaneplanocin A (DZNep), a small molecule EZH2 inhibitor , , as a putative treatment of chondrosarcomas. "
[Show abstract][Hide abstract] ABSTRACT: Objective
Growing evidences indicate that the histone methyltransferase EZH2 (enhancer of zeste homolog 2) may be an appropriate therapeutic target in some tumors. Indeed, a high expression of EZH2 is correlated with poor prognosis and metastasis in many cancers. In addition, 3-Deazaneplanocin A (DZNep), an S-adenosyl-L homocysteine hydrolase inhibitor which induces EZH2 protein depletion, leads to cell death in several cancers and tumors. The aim of this study was to determine whether an epigenetic therapy targeting EZH2 with DZNep may be also efficient to treat chondrosarcomas.
EZH2 expression was determined by immunohistochemistry and western-blot. Chondrosarcoma cell line CH2879 was cultured in the presence of DZNep, and its growth and survival were evaluated by counting adherent cells periodically. Apoptosis was assayed by cell cycle analysis, Apo2.7 expression using flow cytometry, and by PARP cleavage using western-blot. Cell migration was assessed by wound healing assay.
Chondrosarcomas (at least with high grade) highly express EZH2, at contrary to enchondromas or chondrocytes. In vitro, DZNep inhibits EZH2 protein expression, and subsequently reduces the trimethylation of lysine 27 on histone H3 (H3K27me3). Interestingly, DZNep induces cell death of chondrosarcoma cell lines by apoptosis, while it slightly reduces growth of normal chondrocytes. In addition, DZNep reduces cell migration.
These results indicate that an epigenetic therapy that pharmacologically targets EZH2 via DZNep may constitute a novel approach to treat chondrosarcomas.
PLoS ONE 07/2014; 9(5):e98176. DOI:10.1371/journal.pone.0098176 · 3.23 Impact Factor
"They are the second most common type of skeletal malignancy after osteosarcomas . Chondrosarcomas are usually found within flat bones; the pelvis and femur are two common sites of involvement, although any bone may be affected [2, 3]. These malignant cartilaginous tumors may either arise de novo or develop from pre-existing benign lesion (e.g., enchondromas and osteochondromas), termed primary (or conventional), and secondary chondrosarcomas, respectively. "
[Show abstract][Hide abstract] ABSTRACT: Chondrosarcomas are a heterogeneous group of malignant bone tumors that are characterized by the production of cartilaginous extracellular matrix. They are the second most frequently occurring type of bone malignancy. Surgical resection remains the primary mode of treatment for chondrosarcomas, since conventional chemotherapy and radiotherapy are largely ineffective. Treatment of patients with high-grade chondrosarcomas is particularly challenging, owing to the lack of effective adjuvant therapies. Integrins are cell surface adhesion molecules that regulate a variety of cellular functions. They have been implicated in the initiation, progression, and metastasis of solid tumors. Deregulation of integrin expression and/or signaling has been identified in many chondrosarcomas. Therefore, the development of new drugs that can selectively target regulators of integrin gene expression and ligand-integrin signaling might hold great promise for the treatment of these cancers. In this review, we provide an overview of the current understanding of how growth factors, chemokines/cytokines, and other inflammation-related molecules can control the expression of specific integrins to promote cell migration. We also review the roles of specific subtypes of integrins and their signaling mechanisms, and discuss how these might be involved in tumor growth and metastasis. Finally, novel therapeutic strategies for targeting these molecules will be discussed.
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