Chondrosarcoma is the only primary bone cancer that lacks an effective systemic treatment. It is the most common primary bone tumor in adults and survival is only 10-25%, with most patients succumbing to lung metastases. However, the mechanisms of metastasis, a strong potential target for therapeutics, are unknown. The long-term goal is to identify molecular targets for treatment. CXCR4 expression is endogenously upregulated in chondrosarcoma and its signaling increases expression of pro-metastatic factors. Specific microRNAs are also overexpressed in chondrosarcoma, and miR-181a in particular functions as an oncomir by enhancing CXCR4 signaling. Both CXCR4 signaling and miR-181a expression are also increased by hypoxia. The objective of this application is to use both cellular and animal model approaches to determine how overexpression of miR-181a is linked to metastasis in chondrosarcoma, and determine its appropriateness as a therapeutic target. CXCR4 is a G-protein-coupled receptor. Regulator of G-protein signaling protein sixteen (RGS16) has an inhibitory effect on CXCR4 signaling. Overexpression of specific microRNAs in cancer can disrupt inhibitory pathways, thereby promoting tumor progression. The central hypothesis is that miR-181a overexpression enhances CXCR4 signaling by inhibiting RGS16 and potentially other inhibitory pathways. This novel hypothesis is based on preliminary data produced in the applicant's laboratory. The rationale for this project is that the current antagonists for CXCR4 are only partly effective, suggesting a two-pronged approach based on targeting microRNA as well as the receptor, may be more effective. In this application, miR-181a as a CXCR4- enhancing oncomiR will be systematically investigated by pursuing two specific aims: 1) Determine the mechanistic link between hypoxia and chondrosarcoma metastasis;2) Evaluate pharmacologic, anti-microRNA, and combined therapy in a chondrosarcoma mouse model.
In Aim #1, overexpression of miR-181a in chondro- sarcoma cells will be inhibited using a lentivirus based expression construct for anti-miR-181a which has been proven feasible in the applicant's hands. The effects of such inhibition on expression of RGS16 and CXCR4 signaling will be analyzed. 3'-UTR luciferase reporters will be used to validate RGS16 as a target of miR-181a.
In Aim #2, CXCR4 inhibition with anti-miR-181a, the drug AMD3100, and both will be evaluated in a mouse chondrosarcoma model for their effects on tumor growth, angiogenesis, and metastasis. In vivo bioimaging will be used to monitor matrix metalproteinase activity and angiogenesis in the tumors. The contribution of the pro- posed research is expected to be a detailed understanding of how microRNA and CXCR4 signaling regulate expression of MMPs, VEGF, and chondrosarcoma metastasis. This project is innovative because it utilizes anti-microRNA to inhibit CXCR4 signaling which may cause a shift from cytotoxic chemotherapy to biologic based therapy. The proposed research is significant because inhibition of CXCR4 signaling will provide the first biologically targeted therapy for chondrosarcoma.
The proposed research is relevant to public health because chondrosarcoma is the most common bone cancer in adults, with a very low survival rate and no effective therapeutics. The proposed research is expected to lead to new understanding of the mechanisms of chondrosarcoma metastasis and to new biologically targeted therapies, which is relevant to the the National Cancer Institute's mission pertaining to the cause and treatment of cancer.
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