Predicting Metastasis in Melanoma

预测黑色素瘤的转移

• 批准号: 7992775
• 负责人: DAVID L RIMM
• 金额: $ 26.44万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-17 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7992775
• 关键词: Adjuvant Therapy; Adoption; Algorithms; Biological Assay; Biological Markers; Biopsy; Biopsy Specimen; Case Series; Clinical; Clinical Oncology; Clinical Trials; Collection; Country; Data; Development; Diagnostic; Disease; Disease-Free Survival; Funding; Future; Goals; Grant; Incidence; Individual; Institution; Journals; Malignant Neoplasms; Metastatic Neoplasm to Lymph Nodes; Modeling; Multi-Institutional Clinical Trial; Neoplasm Metastasis; Outcome; Pathologic; Patients; Procedures; Prognostic Marker; Proteins; Publishing; Recurrence; Recurrent disease; Risk; Sentinel Lymph Node; Sentinel Lymph Node Biopsy; Series; Site; Specimen; Staging; Testing; Thick; Tissues; Toxic effect; Training; Translating; United States; Validation; Work; base; cohort; experience; hazard; high risk; improved; interest; melanoma; metastatic process; molecular marker; novel marker; prognostic; prospective; protein expression; public health relevance; standard of care; tool; tumor

DESCRIPTION (provided by applicant): In 2005, we embarked on an RO-1 funded project to build a quantitative multi-parameter protein-based model to predict recurrence in melanoma. The effort culminated in a Melanoma Recurrence Risk (MRR) test that was published in JCO in November 2009. The MRR test was based on 5 markers (two of which required subcellular localization) that could distinguish sentinel node negative patients with a 40% chance of recurrence from those with a 10% chance of recurrence in 8 years. Although this result is quite promising, was validated on 250 sentinel node patients, and has caught the interest of two diagnostic companies, the MMR has not been tested prospectively. Thus we are faced with a choice of "locking" this test and beginning a prospective clinical trial or trying to improve the test, to get better separation between low risk and high risk disease. We have opted to let potential licensees (if there are any) test MMR version 1 while we move on to the development of version 2. Careful review of our work and the melanoma biomarker field has revealed about 75 very promising markers that we have not yet tested for potential inclusion into our MRR assay. Furthermore, our original assay was validated on a single cohort and has not been converted for use on standard melanoma biopsy tissue, since it was constructed and validated on TMAs. Here we propose construction and validation of a second version of the MMR. We will achieve this goal in three aims. The first aim is to construct a new training set and then test a series of new markers on this cohort. These new markers were either lost due to technical issues in our original version, or overlooked in the first round selections. A new model will be constructed based on the new marker data and internally validated. Then in aim 2 we will validate the cohort on two or three independent melanoma cohorts from at least one other institution. In aim 3, working in parallel to the validation in aim 2, we will develop and standardize the MMR version 2 assay for use on whole sections typical of routine melanoma specimens. At the completion of this grant, we anticipate a MMR version 2 assay will be ready for application to patients and for a prospective diagnostic clinical trial. PUBLIC HEALTH RELEVANCE: A key clinical problem in melanoma is the management of patients with melanoma greater than 0.8mm thick and no evidence of tumor in their sentinel nodes. Here we propose to build a model, based on multi-parameter, standardized protein expression in the primary melanoma, that can predict which of these patients have a high likelihood of recurrence and can subsequently be managed more aggressively.

描述（由申请人提供）：2005年，我们开始了一个由RO-1资助的项目，以建立一个基于多参数蛋白的定量蛋白质模型，以预测黑色素瘤的复发。这项努力最终导致了2009年11月在JCO上发表的黑色素瘤复发风险（MRR）测试。MRR测试基于5个标记（其中两个需要亚细胞定位），这些标记可以区分8年后有40％复发机会的前哨淋巴结阴性患者。尽管这一结果非常有前途，但已对250名Sentinel Node患者进行了验证，并引起了两家诊断公司的兴趣，但MMR尚未预期进行测试。因此，我们面临“锁定”这项测试的选择，并开始一项前瞻性临床试验或试图改善测试，以在低风险和高风险疾病之间获得更好的分离。我们选择让潜在的被许可人（如果有的话）测试MMR版本1时，我们继续进行2版的开发。对我们的工作和黑色素瘤生物标志物领域进行仔细的审查显示，大约有75个非常有前途的标记，我们尚未测试潜在的纳入MRR分析。此外，我们的原始测定在单个队列上得到了验证，并且尚未转换为标准黑色素瘤活检组织，因为它是在TMAS上构建和验证的。在这里，我们建议对MMR的第二版进行构建和验证。我们将以三个目标实现这一目标。第一个目的是构建一个新的训练集，然后在该队列上测试一系列新标记。这些新标记要么因我们的原始版本中的技术问题而丢失，要么在第一轮选择中被忽略。将根据新的标记数据构建一个新模型并在内部验证。然后，在AIM 2中，我们将在至少一个其他机构的两个或三个独立黑色素瘤队列上验证队列。在AIM 3中，与AIM 2中的验证并行工作，我们将开发并标准化MMR版本2分析，以在整个典型的常规黑色素瘤标本的典型部分中使用。该赠款完成后，我们预计MMR版本2分析将准备好适用于患者并进行前瞻性诊断临床试验。 公共卫生相关性：黑色素瘤的关键临床问题是黑色素瘤患者厚度大于0.8毫米，其前哨淋巴结中没有肿瘤的证据。在这里，我们建议建立一个基于原发性黑色素瘤中多参数，标准化蛋白质表达的模型，该模型可以预测这些患者的复发可能性很高，随后可以更积极地管理。