BCR Support for Precision Medicine

BCR 对精准医疗的支持

• 批准号: 8757475
• 负责人: DAVID HEIMBROOK
• 金额: $ 310万
• 依托单位: LEIDOS BIOMEDICAL RESEARCH, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-26 至 2018-09-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8757475
• 关键词: Adjuvant; Amendment; Animals; Antineoplastic Agents; Archives; Area; Biological; Biological Markers; Biopsy; Biopsy Specimen; Cancer Patient; Cataloging; Catalogs; Characteristics; Chest; Clinical; Clinical Data; Clinical Trials; Clinical Trials Cooperative Group; Collaborations; Collection; Computer software; Consent; Contracts; Core Biopsy; DNA; DNA Resequencing; Data; Data Collection; Data Coordinating Center; Data Set; Derivation procedure; Development; Diagnostic; Disease; Documentation; Drug Industry; Drug or chemical Tissue Distribution; Enrollment; Ensure; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Evaluation; Event; Failure; Formalin; Funding; Future; Gene Expression Profile; Genomics; Goals; Guidelines; Histology; Human; In complete remission; Incidence; Individual; Informatics; Informed Consent; Institutional Review Boards; Intellectual Property; Investigation; Laboratories; Lead; Logistics; Lung Adenocarcinoma; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Medicine; Methods; Microscopy; Mission; Modeling; Molecular; Monitor; Mutation; National Cancer Institute; Nucleic Acids; Office of Cancer Genomics; Operative Surgical Procedures; Outcome; Paraffin Embedding; Partial Remission; Pathology; Patients; Performance; Pharmaceutical Preparations; Phase; Policies; Population; Preparation; Procedures; Process; Property; Protocols documentation; Quality Control; RNA; Regimen; Relapse; Reporting; Research; Research Design; Research Infrastructure; Research Project Grants; Resectable; Resources; SDZ RAD; Sample Size; Sampling; Scanning; Science; Shipping; Ships; Site; Slide; Source; Specimen; Stream; Task Performances; Techniques; Technology; Testing; The Cancer Genome Atlas; Therapeutic; Therapeutic Agents; Time; Tissue Banking; Tissue Banks; Tissue Extracts; Tissues; Tumor Tissue; United States National Institutes of Health; Vendor; Work; analytical tool; base; cancer genome; cancer genomics; cancer therapy; clinical effect; clinical research site; cohort; data acquisition; exome; experience; falls; genome sequencing; human subject; improved; material transfer agreement; meetings; molecular marker; next generation; novel therapeutics; operation; outreach; prevent; programs; prospective; response; sample collection; screening; standard care; success; tissue processing; tumor; virtual; working group

Background The Center for Cancer Genomics (CCG) at the National Cancer Institute (NCI) was established in 2011 with a mission to lead the NCI efforts in generating critical datasets required to catalog the alterations seen in human tumors, coordinating data unification and sharing efforts, and supporting development of analytical tools and computational approaches aimed at improving our understanding of the large-scale, multidimensional data. CCG also has the goal of developing and applying cutting-edge genomic science to prevent cancer and better treat cancer patients, for example in the context of NCI-supported clinical trials. Currently, several large-scale cancer genome research projects fall under the CCG umbrella including those managed by The Cancer Genome Atlas (TCGA) Program Office and the Office of Cancer Genomics (OCG). In addition, the CCG support genomics analyses in collaborative projects with other NCI Divisions. One such collaboration is with the Alchemist clinical trial sponsored by DCTD. The Biospecimen Core Respository (BCR) provides CCG with support for the acquisition of cancer biopsy samples, the derivation of nucleic acid analytes, and the curation of clinical data associated with CCG-sponsored genomic studies. The current goal of cancer clinical trials is to embrace the precision medicine paradigm in which the therapeutic response of patients is tailored to the individual molecular and cellular features of the tumors being treated. The NCI has embarked on a number of precision medicine initiatives, some of which are detailed below. Exceptional Responders Initiative The main focus of this initiative is to explore the molecular basis for why 1% to 10% of patients enrolled in clinical trials of single targeted agent therapies that are otherwise deemed ¿failures¿ respond to these agents with a complete or partial remission of their disease. The goals are to decipher the molecular factors that may explain these ¿exceptional responses¿. The short term goal of a pilot effort will be to determine how effectively hypotheses can be generated from this approach that lead to new therapeutic strategies. The majority of single agent cancer drugs that enter Phase I and II clinical trials fail to show adequate tumor response for continued development. However, in many of these trials there are a few (1% to 10%) patients that have a significant response to the therapy. These ¿failed¿ trials could be very informative with regard to molecular markers that predict a positive response to these single agent therapies in a small subset of patients, thus making these ¿inactive¿ agents useful. Even later phase clinical trials may have a few patients that experience an exceptional response, such as a complete response, that occurs in 10% or less of patients. Examples of the utility of this approach exist already (e.g., mutations predicting sensitivity to everolimus and EGFR tyrosine kinase inhibitors). The Exceptional Responders initiative envisions that this genomic approach to understanding therapeutic responses may be broadly applicable in cancer. The ability of molecular technologies to stratify tumor types has resulted in many common cancers being separated into specific subtypes that respond to therapeutic agents in very different ways. Identifying additional molecular markers that are able to predict a clinical response in subsets of patients will render future cancer treatments more precise. The complete or partial ¿exceptional responses¿ observed in this cohort of patients treated on ¿failed¿ trials should provide new leads for future oncologic therapies. The feasibility of the Exceptional Responders paradigm will be assessed in 100 patients for whom reliable outcome data from patients treated on clinical trials with targeted monotherapies or targeted combinations. Tumor biopsy material will be obtained from these patients as well as germline tissue, if available. The tissue will undergo next generation whole exome resequencing and, if practical, whole transcriptome resequencing. If this proves feasible, the project can be expanded to include other therapy regimens. The success of the endeavor depends on having adequate tissue for analysis, robust analytical techniques/platforms, and reliable outcome data for patients who have been treated on defined and consistent drug regimens. Tissue and clinical data could be obtained from either NCI-supported or pharmaceutical industry trials where there is reliable outcome data, and perhaps from other sources. In addition, the Exceptional Responders initiative will collect publically available sequencing and clinical data from patients with exceptional therapeutic responses. Alchemist clinical trial The Alchemist trial seeks to capitalize on a number of events have converged to create an opportunity for significant clinical advances in the treatment of subsets of adjuvant lung cancer and to take the next step in biological characterization of lung cancer on a national level. Recently, two of the NCI-supported US Cooperative Clinical Trials groups have brought study proposals forward for evaluation in the NCI Thoracic Malignancy Steering Committee. Each proposal would select resectable patients according to a biomarker validated in the metastatic setting and test for a large clinical effect. The two markers, EGFR mutation and ALK-positivity, each have an incidence of about 5%-10% in the general lung adenocarcinoma population, so each study design would require screening of about 8000 patients. These two markers are mutually exclusive, so there is particular efficiency in screening one set of patients to identify those positive for one marker or the other. Surgical specimens will be available from this trial, providing adequate tissue for extensive analysis. While most of this tumor tissue obtained from a cooperative group clinical trial would be formalin-fixed, technical advances now allow extensive sequence characterization of this material. Although this project would launch based on the EGFR and ALK biomarkers, Alchemist serves as an open platform, and it is likely that if the infrastructure were put in place, additional studies could tap into the stream of biomarker-classified patients. In particular, tissues from all patients screened for the Alchemist trial would be available for comprehensive genomic analyses, for which the patients would be consented. Patients testing negative for the EGFR and ALK biomarkers will be given standard treatment and followed as a prospective cohort, with repeat biopsies obtained upon tumor relapse. Biospecimen Core Resource (BCR) The CCG BCR serves as a centralized tissue processing center and provides the biomolecules for the Center. In addition, the BCR collects and standardizes clinical annotations. Standard Operating Protocols (SOP) governed clinical data collection, sample collection, pathological examination, biomolecule (e.g., DNA and RNA) extractions, quality control, laboratory data collection, and biomolecule distribution to the Cancer Genome Characterization Centers and the Genome Sequencing Centers. The BCR ensures that samples and data are received under appropriate human subjects review and informed consent, and also that Material Transfer Agreements represented the policies of the NIH for this project. A major prerequisite of the genomics projects within CCG was the acquisition of high quality biospecimens. To meet this need, NCI established a network of clinical sites providing high quality, clinically annotated biospecimens to a centralized quality control and processing facility. This facility is the primary interface between CCG and the Tissue Source Sites that provide samples. It must be noted that the term ¿high quality¿ refers not only to the histological and molecular properties of the tissue, but also to characteristics such as degree and quality of clinical annotation, the existence of appropriate informed consent provisions for the intended use of the biomolecules and data, collection and subsequent distribution under an Institutional Review Board (IRB) reviewed protocol, as well as unencumbered access for research use (e.g., intellectual property restrictions). CCG management chose to establish a centralized tissue processing model to ensure that process variables are minimized until their effects on the results of molecular analyses become well understood. This centralization specifically means that all operations to process tissue and data for any single cancer studied by CCG occur at the BCR, utilizing SOPs. This minimization of variance refers to the processes of biospecimen receipt, logistical and physical management, processing into analytes (the molecular extracts from tissue such as DNA and RNA), the subdivision of tissue, and finally distribution of tissue or analytes to the research sites with rigorous QC of all intermediate and final products along the workflow.

背景 National Cancer Institute（NCI）的癌症基因组学中心（CCG）成立于2011年，其使命是领导NCI的努力，以生成对人类肿瘤中所见的重要数据集，协调数据统一和共享努力的改动，并支持我们对大型数据的理解，并支持分析工具和计算方法的开发，旨在提高我们对大型数据的理解。 CCG还具有开发和应用尖端的基因组科学以预防癌症和更好地治疗癌症患者的目标，例如在NCI支持的临床试验的背景下。目前，一些大规模的癌症基因组研究项目属于CCG伞，其中包括由癌症基因组图集（TCGA）计划办公室和癌症基因组学办公室（OCG）管理的伞。此外，CCG支持基因组学分析与其他NCI部门的协作项目。这样的合作是与DCTD赞助的炼金术士临床试验。 Biospecimen核心呼吸道（BCR）提供了CCG，并支持癌症活检样本，核酸分析物的推导以及与CCG赞助的基因组研究相关的临床数据的策划。 癌症临床试验的当前目标是包含精度医学范式，其中患者的治疗反应是针对正在治疗的肿瘤的单个分子和细胞特征量身定制的。 NCI已经着手进行了许多精确的医学计划，其中一些详细介绍了下面的详细信息。 杰出的响应者倡议 该计划的主要重点是探索为什么1％至10％的分子基础参加了单个靶向药物疗法的临床试验患者，这些疗法被认为是失败的。目标是破译可以解释这些异常反应的分子因素。试点努力的短期目标是确定如何从这种导致新的治疗策略的方法中产生如何有效地假设的。 进入I和II期临床试验的大多数单药癌药物都无法显示出足够的肿瘤反应以进行持续发展。但是，在许多此类试验中，有几个（1％至10％）对治疗有重大反应的患者。这些失败的试验对于在一小部分患者中预测对这些单一药物疗法的积极反应的分子标记可能非常有用，因此使这些非活性药物有用。即使以后的临床试验，也可能有一些患者出现出色反应的患者，例如完全反应，在10％或更少的患者中发生。这种方法的实用性的例子已经存在（例如，突变预测对依维莫司和EGFR酪氨酸激酶抑制剂的敏感性）。杰出的响应者计划设想，这种理解治疗反应的基因组方法可能广泛地适用于癌症。分子技术对肿瘤类型进行分层的能力导致许多常见的癌症分离成特定的亚型，这些亚型以截然不同的方式对治疗剂反应。识别能够预测患者子集的临床反应的其他分子标记将使未来的癌症治疗更加精确。完全或部分的反应`在接受失败试验治疗的患者中观察到的特殊反应应为未来的肿瘤疗法提供新的潜在客户。 在100名患者中，将评估特殊响应者范式的可行性，这些患者的可靠结果数据是在具有靶向单层或有针对性组合的临床试验中接受治疗的患者。如果有的话，将从这些患者以及种系组织中获得肿瘤活检材料。该组织将经历下一代外显子组重新陈述，如果实用，则整个转录组重新陈述。如果证明这是可行的，则可以扩展该项目以包括其他治疗方案。努力的成功取决于具有足够的组织进行分析，可靠的分析技术/平台以及可靠的结果数据，可用于在定义且一致的药物方案中接受治疗的患者。组织和临床数据可以从NCI支持或药物行业试验中获得，其中有可靠的结果数据，也许是从其他来源获得的。此外，杰出的响应者计划将从具有特殊治疗反应的患者中收集公开可用的测序和临床数据。 炼金术士临床试验 炼金术士试图利用许多事件的资本化，为在可调肺癌亚群治疗的治疗方面带来重大临床进步的机会，并在全国范围内迈出了肺癌生物学表征的下一步。最近，两个NCI支持的美国合作临床试验小组提出了研究建议，以在NCI胸腔恶性转向委员会中进行评估。每个建议将根据在转移性环境中验证的生物标志物选择可切除的患者，并测试具有较大的临床效果。 EGFR突变和ALK积极性的两个标记在一般的肺腺癌人群中，每个标记的事件约为5％-10％，因此每个研究设计都需要筛查约8000名患者。这两个标记是互斥的，因此筛查一组患者以识别一个标记或另一个标记阳性的患者有特殊效率。该试验将获得手术标本，提供足够的组织进行广泛的分析。虽然从教练组临床试验中获得的大多数肿瘤组织将是福尔马林固定的，但技术进步现在允许对该材料进行广泛的序列表征。 尽管该项目将根据EGFR和ALK生物标志物启动，但炼金术士可以用作开放式平台，并且如果实施基础设施，则可能会进行更多的研究，但可以利用生物标志物分类的患者的流。特别是，所有受筛查炼金术症试验的患者的组织将用于全面的基因组分析，并同意患者。测试EGFR和ALK生物标志物阴性的患者将获得标准治疗，并作为前瞻性队列，并在肿瘤缓解后重复活检。 Biospecimen Core Resources（BCR） CCG BCR充当集中组织加工中心，并为中心提供生物分子。此外，BCR还收集并标准化临床注释。标准运营方案（SOP）控制了临床数据收集，样本收集，病理检查，生物分子（例如DNA和RNA）提取，质量控制，实验室数据收集以及对癌症基因组表征中心和基因组测序中心的生物分子分布。 BCR确保在适当的人类受试者审查和知情同意下收到样品和数据，还确保物质转移协议代表了该项目的NIH政策。 CCG中基因组学项目的主要先决条件是获得高质量的生物测量。为了满足这一需求，NCI建立了一个临床站点网络，为集中质量控制和加工设施提供了高质量的临床注释生物测量。该设施是CCG与提供样品的组织源位点之间的主要接口。 It must be noted that the term ¿ High quality¿ refers not only to the histological and molecular properties of the tissue, but also to characteristics such as degree and quality of clinical annotation, the existence of appropriate informed consent provisions for the intended use of the biomolecules and data, collection and subsequent distribution under an Institutional Review Board (IRB) reviewed protocol, as well as unencumbered access for research use (e.g., intellectual property 限制）。 CCG管理选择建立集中式组织加工模型，以确保将过程变量最小化，直到它们对分子分析结果的影响得到充分了解。该集中化特别意味着使用SOP在BCR处进行任何CCG研究的组织和数据的所有操作。方差的最小化是指生物测量收据，后勤和物理管理的过程，处理分析物（来自组织等组织的分子提取物，例如DNA和RNA），组织的细分，最终的组织或分析物或分析物在所有中间和最终产物的QC的研究地点分布到研究地点。