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)

Osteosarcoma (OS) is the most common malignant tumor of the bone, with a high mortality rate and poor prognosis. Receptor tyrosine kinase-like orphan receptor 2 (ROR2) has been reported to be dysregulated in human malignancies. More recently, ROR2 has been demonstrated to promote OS cell migration and invasion. However, the role of ROR2 in the regulation of OS cell proliferation, as well as the underlying molecular mechanism, remains unclear. The present study aimed to investigate the underlying mechanism of ROR2 in osteosarcoma growth. Reverse transcription-quantitative polymerase chain reaction analysis and western blot analysis were used to examine the mRNA and protein expression. MTT assay, colony formation assay and cell cycle analysis were conducted to explore the function of ROR2 in osteosarcoma cells. In the present study, the expression of ROR2 was found to be frequently upregulated in OS tissues compared with matched adjacent normal tissues. It was also upregulated in the OS cell lines Saos-2, MG-63 and U-2 OS, relative to normal osteoblast hFOB 1.19 cells. Knockdown of ROR2 expression by transfection with ROR2-specific siRNA markedly inhibited the proliferation and colony formation of OS cells. Data from the cell cycle distribution assay revealed an accumulation of ROR2-knockdown cells in the G0/G1 phase, indicating that knockdown of ROR2 leads to an arrest in cell cycle progression. Mechanistic investigation revealed that the protein levels of c-myc, a target gene of the Wnt signaling, as well as cyclin D1, cyclin E and cyclin-dependent kinase 4 were markedly reduced in the ROR2-knockdown OS cells, suggesting that the inhibitory effect of ROR2 knockdown on OS cell proliferation is associated with the Wnt signaling pathway. In summary, the current study indicates an important role for ROR2 in the proliferation of OS cells. Therefore, ROR2 may be a promising therapeutic target in OS.
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PMID:Knockdown of receptor tyrosine kinase-like orphan receptor 2 inhibits cell proliferation and colony formation in osteosarcoma cells by inducing arrest in cell cycle progression. 2678 94

Receptor tyrosine kinase-like orphan receptor 2 (ROR2) has been identified as a highly relevant tumor-associated antigen in a variety of cancer indications of high unmet medical need, including renal cell carcinoma and osteosarcoma, making it an attractive target for targeted cancer therapy. Here, we describe the de novo discovery of fully human ROR2-specific antibodies and potent antibody drug conjugates (ADCs) derived thereof by combining antibody discovery from immune libraries of human immunoglobulin transgenic animals using the Transpo-mAb mammalian cell-based IgG display platform with functional screening for internalizing antibodies using a secondary ADC assay. The discovery strategy entailed immunization of transgenic mice with the cancer antigen ROR2, harboring transgenic IgH and IgL chain gene loci with limited number of fully human V, D, and J gene segments. This was followed by recovering antibody repertoires from the immunized animals, expressing and screening them as full-length human IgG libraries by transposon-mediated display in progenitor B lymphocytes ("Transpo-mAb Display") for ROR2 binding. Individual cellular "Transpo-mAb" clones isolated by single cell sorting and capable of expressing membrane-bound as well as secreted human IgG were directly screened during antibody discovery, not only for high affinity binding to human ROR2, but also functionally as ADCs using a cytotoxicity assay with a secondary anti-human IgG-toxin-conjugate. Using this strategy, we identified and validated 12 fully human, monoclonal anti-human ROR2 antibodies with nanomolar affinities that are highly potent as ADCs and could be promising candidates for the therapy of human cancer. The screening for functional and internalizing antibodies during the early phase of antibody discovery demonstrates the utility of the mammalian cell-based Transpo-mAb Display platform to select for functional binders and as a powerful tool to improve the efficiency for the development of therapeutically relevant ADCs.
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PMID:Novel Antibody Drug Conjugates Targeting Tumor-Associated Receptor Tyrosine Kinase ROR2 by Functional Screening of Fully Human Antibody Libraries Using Transpo-mAb Display on Progenitor B Cells. 3045 96