Telomere Maintenance Mechanisms in Human Osteosarcoma

人类骨肉瘤的端粒维持机制

• 批准号: 7370817
• 负责人: JEFFREY S DOME
• 金额: $ 12.23万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7370817
• 关键词: biomarker; clinical research; enzyme activity; enzyme induction /repression; human subject; immunocytochemistry; messenger RNA; microarray technology; neoplasm /cancer genetics; osteosarcoma; polymerase chain reaction; prognosis; serial analysis of gene expression; telomerase; telomere

DESCRIPTION (provided by applicant): Osteosarcoma is the most common primary bone tumor of children and adolescents. Despite significant treatment advances over the past 30 years, approximately 30% of patients with localized disease and 60% of patients with metastatic disease do not survive. Novel prognostic markers and therapeutic targets are needed to improve the outcomes of patients with osteosarcoma. Telomeres are nucleoprotein structures that cap chromosome ends. With each round of replication, telomeres erode due to the inability of DNA polymerases to replicate the very ends of DNA. When telomeres become critically short, cellular senescence or apoptosis are induced. A hallmark of cancer cells is that they have unlimited proliferative potential. To achieve this, they must develop mechanisms to counteract telomere shortening. Most human cancers activate the enzyme telomerase to maintain telomeres, but a minority of cancers use a poorly defined mechanism called "alternative lengthening of telomeres," or "ALT." Osteosarcoma is dissimilar from most human cancers in that osteosarcomas commonly use the ALT mechanism. Laboratory studies have shown that compared to ALT, telomerase expression is associated with increased tumorigenicity and metastasis. This raises the possibility that the telomerase-dependent osteosarcomas are more clinically aggressive than their ALT-dependent counterparts. In collaboration with the Children's Oncology Group (COG), this study will evaluate the prognostic significance of telomerase expression in patients with non-metastatic osteosarcoma. In addition, this study will take advantage of the heterogeneity of telomere maintenance mechanisms in human osteosarcoma to identify novel biomarkers for ALT.

描述（由申请人提供）：骨肉瘤是儿童和青少年最常见的原发性骨肿瘤。尽管过去 30 年治疗取得了重大进展，但约 30% 的局部疾病患者和 60% 的转移性疾病患者无法存活。需要新的预后标志物和治疗靶点来改善骨肉瘤患者的预后。端粒是覆盖染色体末端的核蛋白结构。在每轮复制中，由于 DNA 聚合酶无法复制 DNA 的最末端，端粒都会受到侵蚀。当端粒变得非常短时，就会诱导细胞衰老或凋亡。癌细胞的一个特点是它们具有无限的增殖潜力。为了实现这一目标，他们必须开发出抵消端粒缩短的机制。大多数人类癌症会激活端粒酶来维持端粒，但少数癌症使用一种定义不明确的机制，称为“端粒替代延长”或“ALT”。骨肉瘤与大多数人类癌症的不同之处在于骨肉瘤通常使用 ALT 机制。实验室研究表明，与 ALT 相比，端粒酶表达与致瘤性和转移增加相关。这提出了端粒酶依赖性骨肉瘤比 ALT 依赖性骨肉瘤在临床上更具侵袭性的可能性。本研究将与儿童肿瘤学组 (COG) 合作，评估端粒酶表达对非转移性骨肉瘤患者的预后意义。此外，本研究将利用人类骨肉瘤端粒维持机制的异质性来鉴定 ALT 的新型生物标志物。