CLINICAL CORRELATIVE STUDIES OF NEUROBLASTOMA

描述（改编自申请人的摘要）：神经母细胞瘤是一种 最常见的颅外肿瘤的儿童，和案件是高度 在临床行为方面具有异质性。 虽然患者群体 不同的预期存活率可以通过临床分期来确定， 诊断，个体临床定义的风险组包括以下患者 完全不同的结果 级间和级内多样性提供了 确定分子遗传和生物学特性的机会 与治疗结果相关的肿瘤。 这种相关性可以 确定以其他方式无法识别的风险群体，从而帮助 临床研究的解释，它们可以提供新的标准 更合适的治疗分配 他们也可能提出新的方法 接受治疗 拟议研究的长期目标是开发测试 这改进了危险群体定义， 可以对每个患者进行有效的治疗。 本申请的假设是，神经母细胞瘤的亚群可以是 通过评估（1）关键参与的基因来确定 神经母细胞瘤的生长、分化和存活;（2） 肿瘤细胞在体外持续生长。 计划是建立在以前的基础上 N-myc原癌基因在神经母细胞瘤中表达的研究 神经营养因子（神经生长因子，NGF和脑源性神经营养因子） 因子，BDNF）及其受体（例如，TrkAl），以及在 体外，这证明了这些标记物在 精确化。 具体目的如下：（1）确定肿瘤表型是否定义 通过MYCN基因扩增和表达、TrkA表达、端粒酶RNA 表达和体外生长与疾病进展相关， （2）建立多变量统计模型， 基于临床表现（分期和年龄）和实验室数据的结局 （肿瘤MYCN基因扩增，TrkA表达，端粒酶RNA表达， 体外生长和组织病理学）;（3）在初步研究中确定， 其他神经营养因子及其受体的表达定义了风险组。 如果是，请将其纳入上述分析。 CCG进行III期研究，其中新诊断的患者接受 根据风险分类进行治疗，目前基于 临床分期、年龄、组织病理学和N-myc基因扩增状态。 每年约有200名患者在低， 中危和高危神经母细胞瘤 肿瘤组织包括（在一些实施例中， 患者）在诊断时前瞻性地获得具有肿瘤的骨髓。 测试肿瘤以确定其关于N-myc的表型 扩增，trk RNA表达水平和表达模式，BDNF RNA 表达，端粒酶RNA表达和活性，染色体1 p缺失， 和体外肿瘤细胞生长。 目标是确定这些 实验室检查结果可以识别临床上重要但较小的子集 可能受益于不同疗法的患者。 如果初步研究 表明特定的测试在预测中特别重要， 预后，将进行大规模研究，以更好地确定价值 在这些新测试中（例如，他们识别可能会 治疗失败）。 预计这些研究将改善统计学， 它们可能有助于开发新的和可能更有效的 高风险患者的治疗，同时降低治疗风险 低风险患者。

DESCRIPTION (Adapted from the applicant's abstract): Neuroblastoma is the most common extra cranial tumor of childhood, and cases are highly heterogenous with regard to clinical behavior. Although patient groups with different expected survivals can be identified by clinical staging at diagnosis, individual clinically defined risk groups include patients with quite different outcomes. Inter- and intra-stage diversity provides opportunities for identifying molecular genetic and biologic properties of tumors that are associated with treatment outcome. Such correlations can identify risk groups that otherwise are not recognizable, thus aiding in the interpretation of clinical studies, and they can provide new criteria for more appropriate therapy assignment. They may also suggest new approaches to therapy. The long-term goal of the proposed studies is to develop tests that improve definition of risk groups so that the most appropriate and effective therapy can be given to each patient. The hypothesis of this application is that subsets of neuroblastomas can be identified by evaluating (1) genes that are critically involved in neuroblastoma growth, differentiation, and survival and (2) the ability of tumor cells to grow continuously in vitro. Plans are to build upon previous studies of N-myc proto-oncogene expression in neuroblastoma and of the neurotrophins (nerve growth factor, NGF, and brain derived neurotrophic factor, BDNF) and their receptors (e.g., TrkAl), and of tumor cell growth in vitro, which demonstrated the potential importance of these markers in prognostication. The specific aims are as follows: (1) determine if tumor phenotype defined by MYCN gene amplification and expression, TrkA expression, telomerase RNA expression, and growth in vitro correlates with disease progression during or after therapy; (2) develop multivariate statistical models for predicting outcome based upon clinical presentation (stage and age) and laboratory data (tumor MYCN gene amplification, TrkA expression, telomerase RNA expression, growth in vitro, and histopathology); (3) determine in a pilot study if expression of other neurotrophins and their receptors defines risk groups. If so, include these in the above analyses. The CCG performs phase III studies in which newly diagnosed patients receive therapy according to risk classification, which is currently based upon clinical stage, age, histopathology, and N-myc gene amplification status. Approximately 200 patients are registered annually in studies for low, intermediate, and high-risk neuroblastoma. Tumor tissues including (in some patients) bone marrow with tumor are obtained at diagnosis prospectively. Tumors are tested to determine their phenotype with regard to N-myc amplification, trk RNA expression level and pattern of expression, BDNF RNA expression, telomerase RNA expression and activity, chromosome 1p deletions, and tumor cell growth in vitro. The goal is to determine if these laboratory test results can identify clinically important but small subsets of patients who may benefit from different therapy. If preliminary studies indicate that specific tests are particularly important in predicting prognosis, large-scale studies will be conducted to better define the value of these new tests (e.g., their ability to identify patients who will likely fail treatment). It is anticipated that these studies will improve prognostication and that they may contribute to development of novel and possibly more effective therapies for high-risk patients, while diminishing the risks of treatment for low risk patients.