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
Osteosarcoma (OS) is the most common primary malignant bone tumor in children and young adults, but it is unknown at what point, in the pathway of differentiation between a human mesenchymal stem cell (hMSC) and a mature osteoblast (OB), OS originates. Identifying the cell of origin is crucial in understanding the molecular pathogenesis of OS. These studies are hampered by the fact that the various steps in the differentiation of human MSC into its more differentiated progenitors are poorly characterized. In this study, hMSCs were derived from the freshly obtained bone marrow of patients as well as purchased through ATCC. Flow cytometry was used to detect the surface expression phenotype of MSC markers, where CD34 and CD45 were negative and CD44, CD73, CD90, and CD105 were positive. The hMSCs were characterized and all demonstrated multilineage differentiation capacity into adipocytes, chondroblasts, and osteoblasts, which was confirmed by Oil Red O, Alcian Blue, and Alizarin Red S stains, respectively. Osteoblasts were further characterized by measuring osteocalcin protein levels using ELISA. RNA was extracted from hMSCs and OB derived from the same patient and gene expression measured by microarray on the Affymetrix Gene 1.0 ST array. A list of differentially expressed genes was generated, which were narrowed to only include surface markers. Antibodies corresponding to surface markers were used for ELISA and flow cytometry on hMSCs and OBs, to confirm the change in gene expression with differentiation. Further studies will include flow cytometry to define intermediate stages in the differentiation pathway from hMSCs to OBs and their capacity to differentiate into the various mesenchymal lineages. It has been possible to derive hMSC with pluripotent differentiation capacity from patient bone marrows. These will be utilized to define the patterns of differentiation and ultimately relate to osteosarcoma to help define its progenitor cell. It is hoped that a clearer understanding of the progenitor cell of OS will help find prognostic factors and molecular therapeutic targets. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5333. doi:10.1158/1538-7445.AM2011-5333
Introduction: Osteosarcoma (OS) is the most common primary malignant tumor of bone in children and young adults. Knowledge about its cell of origin is limited, making new treatments difficult to develop. Our aim is to screen and identify the key surface markers of mesenchymal stem cell (MSC) to osteogenic differentiation and OS malignant transformation. Methods: A list of differentially expressed genes with a statistically significant p-value <0.05 was obtained by microarray analysis from MSCs and osteoblasts (OB). MSCs were differentiated into osteoblasts, adipocytes and chondrocytes and confirmed by alizarin red staining, oil red O staining and collagen II immunohistchemistry, respectively. Western blots were then performed to identify the expression of selected surface markers during the MSC differentiation and compared to those of OS cells. Results: Nine genes were obtained with a p-value <0.02, which are differentially expressed between MSC and OB. Four of them were correlated with cell adhesion and metastasis. The expression profile of CD49b was distinct, where it was down regulated only during MSC osteogenic differentiation and over expressed in OS cell lines. Conclusions: Cell adhesion may have an important role during MSC differentiation. CD49b is a unique marker during MSC osteogenic differentiation and may play a significant role in osteoasarcoma malignant transformation. In the future we plan to determine the function and mechanism of CD49b during MSCs osteogenic differentiation and osteosarcoma malignant transformation in vitro. We will define the clinical significance of CD49b in osteosarcoma through immunohistochemistry of patient samples and functional analyses. Citation Format: Tingting Ren, Sajida Piperdi, Amy Y. Park, Richard Gorlick. Screening and identification of key surface markers of mesenchymal stem cell osteogenic differentiation and osteosarcoma development. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1418. doi:10.1158/1538-7445.AM2015-1418
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.