EWS/FLI-1: TARGET FOR RADIOSENSITIZATION & GROWTH INHIBITION OF EWING TUMORS

EWS/FLI-1：放射增敏目标

• 批准号: 6651743
• 负责人: VICENTE NOTARIO
• 金额: $ 34.88万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6651743
• 关键词: DNA damage; Ewing's tumor; antisense nucleic acid; apoptosis; cell growth regulation; cell line; cellular pathology; genetic transcription; ionizing radiation; molecular pathology; neoplasm /cancer pharmacology; neoplastic cell; oligonucleotides; oncoproteins; radiation sensitivity; transcription factor; transfection

DESCRIPTION (provided by applicant): Ewing's sarcoma (ES) is a solid highly malignant neoplasm of the bone and soft tissues. Most often it affects children and young adolescents, being the second most common malignant bone tumor in young adults. ES is formed by poorly differentiated round cells of neuroectodermal origin. Current ES treatment includes a combined modality with radiotherapy and chemotherapy. Clinically, ES tumors are generally responsive to such treatment, but the overall cure rate is low because ES is an aggressive osteolytic tumor that frequently presents with metastatic disease. ES cells are characterized for having, in nearly 100 percent of the cases a reciprocal translocation between chromosomes 11 and 22 or, much less frequently, 21 and 22. This translocation results in the synthesis in these cells of fusion proteins with their N-terminus encoded by EWS gene sequences and their C- terminus encoded by sequences of either the FLI-1 gene, most frequently, or the ERG gene, both members of the ETS family of transcription factors. There is a limited repertoire of fusion types, with those involving EWS/FLI-1 being most frequently detected in ES patients. We have found that down-regulation of EWS/FLI-1 in ES cells caused both growth inhibition and sensitization to apoptosis by ionizing radiation and chemotherapeutic agents. Our overall objective is to define antisense oligonucleotides targeted to the EWS/FLI-1 (or EWS/ERG) junction as highly specific therapeutic tools for ES management, because there are no target fusion sequences in normal cells. Our central hypothesis is that antisense EWS/FLI-1 oligonucleotides targeted to the translocation junction will specifically render ES cells sensitive to DNA-damaging agents and, in addition, will prevent the oncogenic activity of the EWS/FLI-1 protein product. Treatment with antisense EWS/FLI-1 oligonucleotides will have a dual effect, enhancing ES cell killing and down-regulating cellular neoplastic properties. Two specific aims are proposed, which include experiments designed to study the effects of antisense EWS/FLI-1 oligonucleotides in vitro, on cultures ES cell lines, and in vivo, on tumors induced in mice by injection of ES cells. These studies should advance technological and scientific understanding for the translational application of antisense EWS/FLI-1 oligonucleotides to ES treatment in the future.

描述(申请人提供)：尤文肉瘤(ES)是一种高度恶性的实性肿瘤 骨骼和软组织。它最常影响儿童和青少年，是年轻人中第二常见的恶性骨肿瘤。ES由神经外胚层来源的低分化圆形细胞形成。目前ES的治疗方法包括放射治疗和化疗相结合。临床上，ES肿瘤一般对这种治疗有反应，但总体治愈率很低，因为ES是一种侵袭性溶骨肿瘤，经常表现为转移性疾病。ES细胞的特征是，在近100%的情况下，在第11和22号染色体之间存在相互易位，或者在更少的情况下，21和22号染色体之间存在易位。这种易位导致在这些细胞中合成融合蛋白，其N端由EWS基因序列编码，其C端由ETS转录因子家族成员FLI-1基因或ERG基因的序列编码。融合类型的谱系有限，涉及EWS/FLI-1的融合类型在ES患者中最常见。我们发现，ES细胞中EWS/FLI-1的下调既能抑制生长，又能增敏 电离辐射和化疗药物引起的细胞凋亡。我们的总体目标是定义 针对EWS/Fli-1(或EWS/ERG)连接的高度特异的反义寡核苷酸 ES治疗的治疗工具，因为在正常细胞中没有靶向融合序列。我们的中心假设是，针对易位连接的反义EWS/FLI-1寡核苷酸将特异性地使ES细胞对DNA损伤剂敏感，此外，还将阻止EWS/FLI-1蛋白产物的致癌活性。用反义EWS/FLI-1寡核苷酸治疗将具有双重效果，增强ES细胞杀伤和下调细胞肿瘤特性。我们提出了两个特定的目标，包括在体外研究反义EWS/FLI-1寡核苷酸对培养的ES细胞系的影响，以及在体内对ES细胞注射诱发的小鼠肿瘤的影响。这些研究将促进对反义EWS/FLI-1寡核苷酸在未来ES治疗中的翻译应用的技术和科学理解。