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（由申请人提供）：尤因的肉瘤是一个坚实的高度恶性肿瘤 骨骼和软组织。通常，它会影响儿童和青少年，这是年轻人中第二常见的恶性骨肿瘤。 ES是由神经皮质起源的圆形细胞不分化的。当前的ES治疗包括放射疗法和化学疗法的组合方式。从临床上讲，ES肿瘤通常对这种治疗有反应，但是总体治愈率很低，因为ES是一种侵略性的骨化肿瘤，经常出现转移性疾病。 ES细胞的特征是在近100％的情况下，染色体11和22之间的相互易位，或者较少频繁的21和22。这种易位导致这些融合蛋白的细胞与ews基因序列及其c-末端编码的N-末端在这些融合蛋白中的合成，或者由FLI序列的序列，或fli serm of fli serm of Fli serm of Fli，或eRG ear of fli serm of Fli serm of Fli sere of Fli sere of Fli serm of Fli sere of Fli sere of Fli sere of Fli seme，或转录因子。融合类型的曲目有限，在ES患者中最常检测到涉及EWS/FLI-1的曲目。我们发现EWS/FLI-1在ES细胞中的下调导致生长抑制和致敏对 电离辐射和化学治疗剂的细胞凋亡。我们的总体目标是定义 针对EWS/FLI-1（或EWS/ERG）连接的反义寡核苷酸作为高度特异性 ES管理的治疗工具，因为正常细胞中没有目标融合序列。 我们的中心假设是，针对易位连接的反义EWS/FLI-1寡核苷酸将特别使ES细胞对DNA损害剂敏感，此外，还将防止EWS/FLI-1蛋白产物的致癌活性。反义EWS/FLI-1寡核苷酸的处理将具有双重作用，从而增强ES细胞杀伤和下调的细胞肿瘤特性。提出了两个具体目标，其中包括旨在研究反义EWS/FLI-1寡核苷酸在体外，培养物ES细胞系和体内对小鼠通过ES细胞诱导的肿瘤的影响。这些研究应提高技术和科学理解，以在将来对反义EWS/FLI-1寡核苷酸的翻译应用中进行转化。