ROLE OF IGF SIGNALING UPON EWINGS SARCOMA PATIENT

描述：尤文肉瘤肿瘤家族(ESFT)影响患者 年龄在3岁到40岁之间，大多数病例发生在第二个 十年的生命。出现局限性肿瘤的患者大约有 70%的无病存活率，而那些存在转移性ESFT的人 尽管大剂量化疗，预后也很差。出现了两个挑战。这个 首先是将局部或转移性肿瘤患者分成 谁能通过目前的治疗存活下来，谁需要更多的治疗 强化治疗。第二是开发治疗这些疾病的新策略。 尽管接受了强化治疗，但目前仍未存活的ESFT患者 作为骨髓移植。胰岛素样生长因子1(IGF-I) 已知其受体(IGF-IR)在ESFT的生长中起重要作用 和转型。申请人最近的研究表明，IGF-I信号 参与ESFT化疗耐药。ESFT包含一种肿瘤特异性 易位，t(11；22)，具有各种外显子组合可能性 在个体肿瘤之间。其中一种易位类型，L，一直是 与局部疾病患者存活率的增加和与 IGF-IR表达降低。因此，申请人假设 ESFT患者中IGF信号的增加预示着存活率的下降。 因此，了解改变的IGF信号可以提供患者分层 和治疗靶点。为了定义IGF信令在 对于ESFT患者，需要分析IGF信号系统的组件。 这一提议试图理解配基、结合的数量变化 蛋白质或受体预测临床病程 临床试验。申请人提出三个目标：(1)测量IGF-I和 即将进行的本地化和非本地化治疗的所有患者的血清IGFBP-3水平 转移性ESFT方案。血清IGF-I、IGFBP-3和IGFBP-3：IGF-I将 分析以确定这些指标是否预测临床上的差异 介绍化疗反应性和无事件生存，(2)测量 所有患者确诊时ESFT肿瘤的IGF-IR水平 同时注册本地和转移性ESFT方案，并关联 IGF-IR数量和肿瘤IGF-I水平与临床表现、疗效的关系 化疗和预后，以及(3)将这些发现与ESFT相关联 易位类型。这项建议的优点是，拟议的 儿科临床试验提供了比较相似治疗的机会 患者对IGF信号成分的影响。申请人的调查结果 可以用于未来的患者分层，并开发了方法 这里可以应用于任何IGF信号可能起关键作用的恶性肿瘤 角色，包括乳房、前列腺和结肠。 此应用程序建议测量所有人的IGF-I、IGFBP-3和IGF-IR水平 参加即将进行的尤因肉瘤家族临床试验的患者 肿瘤[ESFT]，由儿童癌症小组/儿科肿瘤学进行 组，评估指标与治疗反应和生存的相关性， 并将结果与ESFT易位亚型相关联。

DESCRIPTION: The Ewing's sarcoma family of tumors (ESFT) affects patients between the ages of 3 and 40 years, with most cases occurring in the second decade of life. Patients who present with localized tumors have approximately 70 percent disease-free survival, while those who present with metastatic ESFT have a poor prognosis despite high dose chemotherapy. Two challenges arise. The first is to stratify patients with localized or metastatic tumors into those who will survive with current therapies and those who will require more intensive therapy. The second is to develop novel strategies for treating those ESFT patients who are not currently surviving despite intensive therapies such as bone marrow transplantation. The insulin-like growth factor type 1 (IGF-I) and its receptor (IGF-IR) are known to play a significant role in ESFT growth and transformation. The applicant's recent work shows that IGF-I signaling participates in ESFT chemoresistance. ESFT contain a tumor specific translocation, t(11;22), with various exonal combinatorial possibilities between individual tumors. One of these translocation types, type l, has been associated with increased survival of patients with localized disease and with decreased expression of the IGF-IR. Therefore, the applicant hypothesizes that increased IGF signaling in patients with ESFT predicts for decreased survival. Understanding altered IGF signaling could thus provide patient stratification and therapeutic targets. In order to define the relevance of IGF signaling in ESFT patients, the components of the IGF signaling system need to be analyzed. This proposal seeks to understand if quantitative changes in ligand, binding proteins, or receptor predict clinical course by utilizing a prospective clinical trial. The applicant proposes three aims: (1) To measure the IGF-I and IGFBP-3 serum levels in all patients enrolled in the upcoming localized and metastatic ESFT protocols. Serum IGF-I, IGFBP-3 and IGFBP-3:IGF-I will be analyzed to identify if these indices predict differences in clinical presentation chemo-responsiveness and event-free survival, (2) To measure the IGF-IR levels in ESFT tumors at the time of diagnosis from all patients enrolled in both the localized and metastatic ESFT protocols and correlate IGF-IR number and tumor IGF-I levels with clinical presentation, response to chemotherapy, and prognosis, and (3) To correlate the findings with the ESFT translocation types. The strengths of this proposal are that the proposed pediatric clinical trials offer an opportunity to compare similarly treated patients for effects of IGF signaling components. The applicant's findings could be utilized for future patient stratification, and the methods developed here can be applied to any malignancy in which IGF signaling may play a key role, including breast, prostate, and colon. This application proposes to measure IGF-I, IGFBP-3, and IGF-IR levels in all patients enrolled in upcoming clinical trials for Ewing's sarcoma family of tumors [ESFT] conducted by the Children's Cancer Group/Pediatric Oncology Group, evaluate correlation of indices with response to therapy and survival, and correlated findings with ESFT translocation subtypes.