21 research outputs found

    Receptor Tyrosine Kinases in Osteosarcoma: 2019 Update

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    The primary conclusions of our 2014 contribution to this series were as follows: Multiple receptor tyrosine kinases (RTKs) likely contribute to aggressive phenotypes in osteosarcoma and, therefore, inhibition of multiple RTKs is likely necessary for successful clinical outcomes. Inhibition of multiple RTKs may also be useful to overcome resistance to inhibitors of individual RTKs as well as resistance to conventional chemotherapies. Different combinations of RTKs are likely important in individual patients. AXL, EPHB2, FGFR2, IGF1R, and RET were identified as promising therapeutic targets by our in vitro phosphoproteomic/siRNA screen of 42 RTKs in the highly metastatic LM7 and 143B human osteosarcoma cell lines. This chapter is intended to provide an update on these topics as well as the large number of osteosarcoma clinical studies of inhibitors of multiple tyrosine kinases (multi-TKIs) that were recently published

    Exploring targeted therapy of osteosarcoma using proteomics data

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    Parunya Chaiyawat,1 Jongkolnee Settakorn,2 Apiruk Sangsin,1 Pimpisa Teeyakasem,1 Jeerawan Klangjorhor,1 Aungsumalee Soongkhaw,2 Dumnoensun Pruksakorn1,3 1Orthopedic Laboratory and Research Netting Center, Department of Orthopedics, 2Department of Pathology, Faculty of Medicine, 3Excellence Center in Osteology Research and Training Center, Chiang Mai University, Chiang Mai, Thailand Abstract: Despite multimodal therapeutic treatments of osteosarcoma (OS), some patients develop resistance to currently available regimens and eventually end up with recurrent or metastatic outcomes. Many attempts have been made to discover effective drugs for improving outcome; however, due to the heterogeneity of the disease, new therapeutic options have not yet been identified. This study aims to explore potential targeted therapy related to protein profiles of OS. In this review of proteomics studies, we extracted data on differentially expressed proteins (DEPs) from archived literature in PubMed and our in-house repository. The data were divided into three experimental groups, DEPs in 1) OS/OB: OS vs osteoblastic (OB) cells, 2) metastasis: metastatic vs non-metastatic sublines plus fresh tissues from primary OS with and without pulmonary metastasis, and 3) chemoresistance: spheroid (higher chemoresistance) vs monolayer cells plus fresh tissues from biopsies from good and poor responders. All up-regulated protein entities in the list of DEPs were sorted and cross-referenced with identifiers of targets of US Food and Drug Administration (FDA)-approved agents and chemical inhibitors. We found that many targets of FDA-approved antineoplastic agents, mainly a group of epigenetic regulators, kinases, and proteasomes, were highly expressed in OS cells. Additionally, some overexpressed proteins were targets of FDA-approved non-cancer drugs, including immunosuppressive and antiarrhythmic drugs. The resulting list of chemical agents showed that some transferase enzyme inhibitors might have anticancer activity. We also explored common targets of OS/OB and metastasis groups, including amidophosphoribosyltransferase (PPAT), l-lactate dehydrogenase B chain (LDHB), and pyruvate kinase M2 (PKM2) as well as the common target of all categories, cathepsin D (CTSD). This study demonstrates the benefits of a text mining approach to exploring therapeutic targets related to protein expression patterns. These results suggest possible repurposing of some FDA-approved medicines for the treatment of OS and using chemical inhibitors in drug screening tests. Keywords: osteosarcoma, proteomics, targeted therapy, text mining, FDA-approved drug
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