A novel set of molecular markers to measure metastatic neuroblastoma

一套用于测量转移性神经母细胞瘤的新型分子标记物

• 批准号: 7023377
• 负责人: NAI-KONG V CHEUNG
• 金额: $ 13.79万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-24 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7023377
• 关键词: antibody; archives; clinical research; model; neoplasm /cancer; neuroblastoma; stem cells

DESCRIPTION (provided by applicant): Cancer patients are often told that they have "no evidence of disease" after initial therapy. Yet, it is crucial for these "cured" patients (pts) to have careful follow-up and monitoring for recurrence. Unfortunately, by the time such recurrence is detected by scan or symptoms, it is often too late for curative intervention. Here we propose to use molecular markers to detect minimal residual disease (MRD) immediately after completion of therapy. We use as our model metastatic neuroblastoma (NB), an orphan childhood cancer that is difficult to cure because of its tendency to relapse after near complete remission. We propose to target subclinical NB as an alternative to the traditional approach of waiting for signs or symptoms of gross disease. Doing so requires an accurate quantification of MRD in order to: (1) detect recurrence much earlier than the conventional clinicopathological methods and (2) use early response indicators for timely treatment interventions. Development of MRD measurement will also facilitate (3) assessment of the efficacy of novel therapies. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) is a highly sensitive method for measuring transcripts from viable tumor cells circulating in bone marrow (BM), peripheral blood (PB), and stem cell harvests. We have demonstrated that GD2 synthase and tyrosine hydroxylase (TH) are useful MRD markers. Nevertheless, given the heterogeneity among and within NB, studying multiple markers will enhance detection. Using tumor expression-arrays, we discovered cyclin D1 (CCND1) as a highly promising MRD marker. We propose to test the clinical utility of a core marker set (GD2synthase,TH, CCND1) for measuring MRD in 136 pts undergoing adjuvant therapy by using archived samples in the R21 phase, and prospectively collected fresh samples in 129 pts for the R33 phase. We will also complete the analysis and validation of the remaining 10 novel markers discovered by expression array analysis. Besides proving their utility as accurate measures of MRD, this application tests the hypothesis of using early MRD response for prognostication, potentially providing a guide for choosing therapies. We also aim to accelerate technology transfer to the clinic by validating one-step BM and PB sampling methods. Armed with the tools to collect samples expeditiously and to measure MRD accurately, the paradigm of treating subclinical NB can then be tested in multicenter randomized studies.

描述（由申请人提供）：癌症患者经常被告知，在最初的治疗后，他们“没有疾病的迹象”。然而，对这些“治愈”的患者进行仔细的随访和监测复发是至关重要的。不幸的是，当通过扫描或症状发现这种复发时，通常为时已晚，无法进行治疗干预。在这里，我们建议在完成治疗后立即使用分子标记来检测最小残留病（MRD）。我们使用转移性神经母细胞瘤（NB）作为我们的模型，这是一种难以治愈的孤儿儿童癌症，因为它在接近完全缓解后有复发的倾向。我们建议以亚临床NB为目标，作为等待肉眼疾病体征或症状的传统方法的替代方法。这样做需要准确量化MRD，以便：(1)比传统的临床病理学方法更早地发现复发；(2)使用早期反应指标及时进行治疗干预。MRD测量的发展也将促进(3)对新疗法疗效的评估。定量逆转录聚合酶链反应（qRT-PCR）是一种高度敏感的方法，用于测量骨髓（BM）、外周血（PB）和干细胞收获中循环的活肿瘤细胞的转录本。我们已经证明GD2合成酶和酪氨酸羟化酶（TH）是有用的MRD标记。然而，考虑到NB之间和内部的异质性，研究多个标记将提高检测。使用肿瘤表达阵列，我们发现cyclin D1 （CCND1）是一个非常有前途的MRD标记物。我们建议通过使用R21期的存档样本来测试核心标记集（GD2synthase，TH, CCND1）用于测量136名接受辅助治疗的患者的MRD的临床效用，并前瞻性地收集129名患者的R33期的新样本。我们还将完成通过表达阵列分析发现的剩余10个新标记的分析和验证。除了证明它们作为MRD准确测量的效用外，该应用还验证了使用早期MRD反应进行预测的假设，可能为选择治疗方法提供指导。我们还旨在通过验证一步BM和PB采样方法来加速技术向临床的转移。有了快速收集样本和准确测量MRD的工具，治疗亚临床NB的范例就可以在多中心随机研究中进行测试。