Despite Osteosarcoma (OS) being the most common primary malignant bone tumor in children and young adults, little clarity exists in where the cell of origin exists in the pathway of differentiation between a human mesenchymal stem cell (hMSC) and a mature osteoblast. It is similarly unclear the primary genetic alterations which initiate oteosarcoma formation in patients. Since high grade OS usually demonstrates histologic variability, and the potential for multilineage differentiation, along with some direct experimental observations some consider hMSC as the cell of origin of OS whereas others believe the pre-osteoblast or osteoblast to be the mot likely cell of origin. Our previous studies have shown that serially introducing 3 different viral constructs, hTERT, SV40TAg, and H-RAS, transforms hMSC into 2 distinct sarcomas cell lines, but not OS. This may be attributable to the fact that oncogenic H-Ras does not seem to play a direct role in the pathogenesis of OS. Therefore, the MSC-TS cell line, hMSC transfected with hTERT and SV40TAg can be used as a platform for further analysis of the impact of genetic transformation of hMSCs. The MSC-TS cells were transformed with lentivirus containing human β-catenin (β), and IGF-1R (I) , separately. Both β-catenin and IGF-1R have been suggested to be involved in the pathogenesis of OS due to their proliferative and/or anti-apoptotic effects. Drug resistant colonies were picked up 21 days after selection to obtain stably transfected cell lines, MSC-TS-β, and MSC-TS-I, respectively. Western blots were carried out to detect the protein of β-catenin and IGF-1R, respectively. Clones, which have highest, lowest, and intermediate protein levels were selected, and comparison between the lines and characterizations are completed and underway. Further characterization includes: 1) Soft Agar Assays , 2)Subcutaneous/Orthotopic Tumorigenicity Assays,3) Routine histological examination and also staining with immunohistochemical markers, 4) Microarray Analysis, 5) Spectral Karyotyping / Comparative Genomic Hybridization, 6) Motility and Migration Assays, and 7) Differentiation Assays. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 418.
Osteosarcoma (OS) is the most common primary malignant bone tumor in children and young adults. Despite significant advancements in the diagnosis and treatment of OS, overall survival trends have remained stagnant with conventional chemotherapy. New chemotherapeutic agents and combination regimens are being studied to target pathways that are believed to be active in OS. NKP-1339 is a novel small molecule anti-cancer compound that targets the GRP78 pathway. A NKP-1339 single agents Phase I has been completed [1]. GRP78 is a master regulator of endoplasmic reticulum stress. High GRP78 levels are found in a wide variety of cancer types and have been correlated with tumor proliferation, metastasis, angiogenesis and tumor cell survival. Treatment with anti-cancer agents, both cytotoxic and targeted agents, has been shown to give rise to further induction of GRP78, and such elevation been correlated to resistance. NKP-1339 down-regulates GRP78 levels selectively in tumor cells leading to tumor cell death. In this study, we explore NKP-1339 activity against OS cell lines. In vitro cytotoxicity assays were performed with NKP-1339, as a single agent, on both standard and patient derived OS cell lines. Three out of four standard cell lines (75%) and two out of four patient derived cell lines (50%) showed IC50 of 80-100 uM. These results, in terms of uM range and activity against tumor lines that are resistant to other agents, are consistent with previous in vitro studies of NKP-1339 with other tumor types. The IC50 uM levels of NKP-1339 are achievable in patient plasma. In vitro combination studies are underway to determine the synergistic anti-tumor effects of NKP-1339 with standard chemotherapeutic agents used in OS. Future studies will include treatment of OS xenograft models with NKP-1339 as a single agent and in combination, and if promising, an OS clinical trial will be initiated. [1] Thompson et al. ASCO 2012 abstract #3033 Citation Format: Amy Y. Park, Rebecca Sowers, Sajida Thein, Rebecca Baerga, Richard Gorlick. Novel therapy NKP-1339 is active in osteosarcoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5520. doi:10.1158/1538-7445.AM2013-5520
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