Targeting CXCR4 and microRNA as Therapy for Chondrosarcoma

靶向 CXCR4 和 microRNA 治疗软骨肉瘤

• 批准号: 9315708
• 负责人: RICHARD M TEREK
• 金额: $ 28万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-25 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9315708
• 关键词: AMD3100; Adult; Animal Model; Attenuated; Biological; Bone neoplasms; CXC Chemokines; Cell Culture Techniques; Cell Line; Cell model; Cells; Chondrosarcoma; Clinical Data; Combined Modality Therapy; Cytotoxic Chemotherapy; Data; Effectiveness; Fibrinogen; G-Protein-Coupled Receptors; GTP-Binding Protein Regulators; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Genetic Techniques; Genetic Transcription; Goals; Growth; HIF1A gene; Hand; Hypoxia; In Vitro; Interstitial Collagenase; Laboratories; Lead; Link; Luciferases; Malignant Bone Neoplasm; Malignant Neoplasms; Measurement; Mediating; Metalloproteases; Metastatic Neoplasm to the Lung; MicroRNAs; Mission; Modeling; Molecular; Molecular Target; Monitor; Mus; National Cancer Institute; Neoplasm Metastasis; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Physiology; Public Health; RGS Proteins; Reporter; Research; Signal Pathway; Signal Transduction; Signaling Protein; Solid; Subfamily lentivirinae; Survival Rate; Testing; Tissues; Treatment Efficacy; Tumor Angiogenesis; Tumor Volume; Up-Regulation; Vascular Endothelial Growth Factors; Xenograft Model; angiogenesis; animal data; base; bioimaging; cancer therapy; chemokine receptor; driving force; experimental study; extracellular; in vivo; inhibitor/antagonist; innovation; knock-down; lung metastatic; molecular targeted therapies; mouse model; novel; novel strategies; overexpression; pre-clinical; public health relevance; receptor; targeted treatment; therapeutic target; transcription factor; translational approach; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：软骨肉瘤是唯一缺乏有效全身治疗的原发性骨癌。它是成人中最常见的原发性骨肿瘤，生存率仅为10-25%，大多数患者死于肺转移。然而，转移的机制，一个强大的潜在靶点治疗，是未知的。长期目标是确定治疗的分子靶点。在软骨肉瘤中，CXCR4的表达是内源性上调的，其信号传导增加了促转移因子的表达。特定的microrna也在软骨肉瘤中过表达，特别是miR-181a通过增强CXCR4信号传导而作为肿瘤细胞起作用。缺氧也会增加CXCR4信号通路和miR-181a的表达。这个应用程序的目标是同时使用蜂窝