Predictive biomarker development in lung cancer: ROS1 chromosomal rearrangements

肺癌预测生物标志物的发展：ROS1染色体重排

• 批准号: 8166470
• 负责人: Anthony John Iafrate
• 金额: $ 22.63万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-07 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8166470
• 关键词: ALK gene; Adenocarcinoma; Adoption; Age; Archives; BRAF gene; Biological Assay; Biological Markers; Brain Neoplasms; Cancer Diagnostics; Cancer Patient; Cell Line; Chromosomal Rearrangement; Clinical; Clinical Trials; Community Clinical Oncology Program; DNA Sequence Rearrangement; Data; Development; Diagnosis; Diagnostic; ERBB2 gene; Enrollment; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Erlotinib; Fluorescent in Situ Hybridization; Future; General Hospitals; Genetic; Genotype; Glioblastoma; Home environment; Imatinib; Immunohistochemistry; In Vitro; Individual; Institution; Knowledge; Laboratories; Learning; Lung Adenocarcinoma; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of lung; Massachusetts; Methods; Molecular Analysis; Mutation; Non-Small-Cell Lung Carcinoma; Pathology; Patient Care; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Phase III Clinical Trials; Phosphotransferases; Population; ROS1 gene; Receptor Tyrosine Kinase Gene; Relative (related person); Reverse Transcriptase Polymerase Chain Reaction; Sensitivity and Specificity; Somatic Mutation; Specimen; Staging; Standardization; Technical Expertise; Technology; Testing; Therapeutic; Time; Trastuzumab; Tumor Tissue; Work; base; bcr-abl Fusion Proteins; beneficiary; cancer diagnosis; cancer genetics; cancer therapy; clinical application; cohort; cost; cost effective; design; drug development; experience; genetic profiling; improved; inhibitor/antagonist; interest; kinase inhibitor; malignant breast neoplasm; melanoma; model development; mutant; next generation; non-smoker; novel; open source; patient population; prospective; research study; response; small molecule; tumor

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.

描述（由申请人提供）：在过去的两年中，马萨诸塞州综合医院诊断出患有癌症的患者是成功实施临床，高通量肿瘤基因分型平台的受益者。这有助于将癌症诊断从纯粹的形态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，实验疗法与最有可能反应的患者的匹配可以加速采用新颖的疗法，并进步患者护理。 该提案的总体目的是设计和开发强大的临床测定法，以检测肺癌中的ROS1重排。在我们从成功实施诊断方面汲取的教训以检测涉及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分析平台。我们将测试使用多种测定平台的可行性，包括原位杂交，免疫组织化学和PCR进行临床应用。这一目标将在两个目的中实现：（1）建立评估非小细胞肺癌中ROS1重排的测定法，（2）在较大的NSCLC队列中进行ROS1测定比较。 该提案将允许及时实施新型ROS1诊断，这将使可以有效鉴定肺癌患者的一部分，这些肺癌患者可能受益于靶向ROS1激酶的新的小分子抑制剂。该项目将作为诊断诊断的开发和临床实施的模型，以使患者受益，并将用于将知识和专业知识传播到一般而言的临床肺癌诊断学术领域。 公共卫生相关性：有关癌症患者肿瘤遗传变化的详细知识现在对患者护理很重要。在个性化的癌症治疗时代，靶向药物或“智能药物”通常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测定法，以鉴定涉及ROS1基因的肺癌中新描述的遗传改变。该测定法将增强靶向ROS1抑制剂的临床试验成功的机会，并可以提高ROS1改变患者获得最佳治疗的机会。