Predictive biomarker development in lung cancer: ROS1 chromosomal rearrangements

描述（由申请人提供）：在过去两年中，马萨诸塞州总医院（MGH）诊断为癌症的患者是临床高通量肿瘤基因分型平台成功实施的受益者。这有助于将癌症诊断从纯粹的形态学评估转变为前瞻性分子分析。了解单个肿瘤的突变状态意味着临床医生可以决定最适合该患者的治疗方法。此外，将实验性疗法与最有可能产生反应的患者相匹配，加速了新疗法的采用，并促进了患者护理。 该提案的总体目标是设计和开发一种稳健的临床检测方法，以检测肺癌中的ROS1重排。基于我们成功实施诊断以检测涉及ALK基因的染色体重排的经验教训，我们将识别、测试、验证和实施最佳的ROS1检测平台。我们将测试使用各种检测平台的可行性，包括荧光原位杂交，免疫组织化学和PCR的临床应用。这一目标将通过两个目标实现：（1）建立用于评估非小细胞肺癌中ROS1重排的检测方法，以及（2）在更大的NSCLC队列中进行ROS1检测灵敏度和特异性比较。 该提案将允许及时实施新型ROS 1诊断，从而能够有效识别可能受益于靶向ROS 1激酶的新型小分子抑制剂的肺癌患者子集。该项目将作为诊断的开发和临床实施的模式，以造福患者，并将用于传播知识和专业知识，以学术领域的临床肺癌诊断一般。 公共卫生相关性：详细了解癌症患者肿瘤中的遗传变化对患者护理非常重要。在个性化癌症治疗的时代，靶向药物或“智能药物”通常主要基于其肿瘤的遗传特征与患者相匹配。我们建议开发一种临床生物标志物检测方法，以确定一个新描述的肺癌涉及ROS 1基因的遗传改变。该检测将提高靶向ROS1抑制剂临床试验成功的机会，并将提高ROS1改变患者接受最佳治疗的机会。

DESCRIPTION (provided by applicant): Over the last two years, patients diagnosed with cancer at the Massachusetts General Hospital (MGH) have been the beneficiaries of the successful implementation of a clinical, high-throughput tumor genotyping platform. This has helped transform cancer diagnosis from a purely morphologic assessment to a prospective molecular analysis. Knowledge of the mutational status of an individual tumor means that clinicians can decide on the treatment that is best for that patient. Furthermore, the matching of experimental therapeutics to the patients most likely to respond accelerates the adoption novel therapies and advances patient care. The overall objective of this proposal is to design and develop a robust clinical assay to detect ROS1 rearrangements in lung cancer. Building on the lessons learned from our successful implementation of diagnostics to detect chromosomal rearrangements involving the ALK gene, we will identify, test, validate, and implement the optimal ROS1 assay platform. We will test the feasibility of using a variety of assay platforms including fluorescence in situ hybridization, immunohistochemistry and PCR for clinical application. This objective will be achieved in two aims: (1) To establish assays for assessing ROS1 rearrangements in non-small cell lung carcinoma and (2) to perform ROS1 assay comparisons of sensitivity and specificity in a larger NSCLC cohort. This proposal will allow the timely implementation of novel ROS1 diagnostics that will enable the efficient identification of a subset of lung cancer patients that may benefit from new small molecule inhibitors that target the ROS1 kinase. This project will serve as a model for development and clinical implementation of diagnostics for the benefit of patients, and will be used to disseminate knowledge and expertise to the academic field of clinical lung cancer diagnostics in general. PUBLIC HEALTH RELEVANCE: Detailed knowledge of the genetic changes in a cancer patient's tumor is now important for patient care. In the era of personalized cancer therapy, targeted agents or "smart drugs" are routinely matched to a patient based largely on the genetic profile of their tumor. We propose to develop a clinical biomarker assay to identify a newly-described genetic alteration in lung cancer involving the ROS1 gene. This assay will enhance the chances that clinical trials of targeted ROS1 inhibitors will be successful, and will improve the chances that the patients with ROS1 alterations will receive optimal therapy.