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 美国国家癌症研究所 (NCI) 的癌症基因组学中心 (CCG) 成立于 2011 年，其使命是领导 NCI 生成编目人类肿瘤变化所需的关键数据集、协调数据统一和共享工作，以及支持分析工具和计算方法的开发，以提高我们对大规模多维数据的理解。 CCG 的目标还包括开发和应用尖端基因组科学来预防癌症并更好地治疗癌症患者，例如在 NCI 支持的临床试验中。目前，CCG 旗下有多个大型癌症基因组研究项目，包括由癌症基因组图谱 (TCGA) 项目办公室和癌症基因组学办公室 (OCG) 管理的项目。此外，CCG 还支持与其他 NCI 部门合作项目中的基因组学分析。其中一项合作是与 DCTD 赞助的 Alchemist 临床试验。生物样本核心存储库 (BCR) 为 CCG 提供癌症活检样本的采集、核酸分析物的推导以及与 CCG 资助的基因组研究相关的临床数据管理的支持。 癌症临床试验当前的目标是采用精准医学范例，其中患者的治疗反应根据所治疗肿瘤的个体分子和细胞特征进行定制。 NCI 已开展多项精准医疗举措，其中一些举措详情如下。 杰出响应者计划 该计划的主要重点是探索分子基础，解释为什么 1% 至 10% 参加单一靶向药物治疗临床试验的患者（否则被认为“失败”）对这些药物做出反应，使疾病完全或部分缓解。目标是破译可以解释这些“异常反应”的分子因素。试点工作的短期目标是确定如何有效地从这种方法中产生假设，从而产生新的治疗策略。 大多数进入 I 期和 II 期临床试验的单药抗癌药物未能表现出足够的肿瘤反应，无法继续开发。然而，在许多此类试验中，有少数（1% 至 10%）患者对治疗有显着反应。这些“失败”的试验可能会提供非常丰富的分子标志物信息，这些分子标志物可以预测一小部分患者对这些单药疗法的阳性反应，从而使这些“无效”药物变得有用。即使是后期临床试验，也可能有少数患者出现异常反应，例如完全缓解，这种情况发生在 10% 或更少的患者中。这种方法的实用性例子已经存在（例如，预测对依维莫司和 EGFR 酪氨酸激酶抑制剂敏感性的突变）。特殊反应者计划设想这种了解治疗反应的基因组方法可能广泛适用于癌症。分子技术对肿瘤类型进行分层的能力使许多常见癌症被分为特定的亚型，这些亚型对治疗药物的反应方式截然不同。识别能够预测患者亚群临床反应的其他分子标记将使未来的癌症治疗更加精确。在这组接受“失败”试验的患者中观察到的完全或部分“异常反应”应该为未来的肿瘤治疗提供新的线索。 杰出反应者范式的可行性将在 100 名患者中进行评估，这些患者的可靠结果数据来自接受靶向单一疗法或靶向组合疗法临床试验的患者。将从这些患者以及种系组织（如果有）中获取肿瘤活检材料。该组织将进行下一代全外显子组重测序，如果可行的话，还将进行全转录组重测序。如果这被证明是可行的，该项目可以扩展到包括其他治疗方案。这项努力的成功取决于是否有足够的组织进行分析、强大的分析技术/平台以及接受明确且一致的药物治疗方案治疗的患者的可靠结果数据。组织和临床数据可以从 NCI 支持的试验或制药行业试验中获得，这些试验有可靠的结果数据，也可能从其他来源获得。此外，“特殊反应者”计划将从具有特殊治疗反应的患者那里收集公开的测序和临床数据。 炼金术士临床试验 Alchemist 试验旨在利用一系列已发生的事件，为辅助性肺癌治疗的重大临床进展创造机会，并在国家层面上进一步研究肺癌的生物学特征。最近，两个 NCI 支持的美国合作临床试验小组向 NCI 胸部恶性肿瘤指导委员会提交了研究提案以供评估。每项提案都将根据在转移环境中验证的生物标志物选择可切除的患者，并测试大型临床效果。 EGFR 突变和 ALK 阳性这两个标志物在一般肺腺癌人群中的发病率约为 5%-10%，因此每个研究设计都需要对约 8000 名患者进行筛查。这两种标记物是相互排斥的，因此筛选一组患者以识别一种标记物或另一种标记物呈阳性的患者特别有效。该试验将提供手术标本，为广泛分析提供足够的组织。虽然从合作小组临床试验中获得的大多数肿瘤组织都是福尔马林固定的，但技术进步现在允许对这种材料进行广泛的序列表征。 尽管该项目将基于 EGFR 和 ALK 生物标志物启动，但 Alchemist 作为一个开放平台，如果基础设施到位，其他研究很可能可以利用生物标志物分类的患者流。特别是，所有接受 Alchemist 试验筛选的患者的组织都将可用于全面的基因组分析，并获得患者的同意。 EGFR 和 ALK 生物标志物检测呈阴性的患者将接受标准治疗，并作为前瞻性队列进行随访，并在肿瘤复发时进行重复活检。 生物样本核心资源 (BCR) CCG BCR 作为一个集中的组织处理中心，并为该中心提供生物分子。此外，BCR 还收集临床注释并对其进行标准化。标准操作协议 (SOP) 管理临床数据收集、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向癌症基因组表征中心和基因组测序中心分发生物分子。 BCR 确保在适当的人类受试者审查和知情同意下收到样本和数据，并且材料转让协议代表 NIH 对于该项目的政策。 CCG 基因组学项目的一个主要先决条件是获取高质量的生物样本。为了满足这一需求，NCI 建立了一个临床站点网络，为集中的质量控制和处理设施提供高质量、有临床注释的生物样本。该设施是 CCG 和提供样本的组织源站点之间的主要接口。必须指出的是，“高质量”一词不仅指组织的组织学和分子特性，还指临床注释的程度和质量、生物分子和数据的预期用途是否存在适当的知情同意条款、根据机构审查委员会 (IRB) 审查的协议进行收集和随后分发以及研究用途的不受阻碍的访问（例如知识产权）等特征。 限制）。 CCG 管理层选择建立集中式组织处理模型，以确保最小化过程变量，直到充分了解它们对分子分析结果的影响。这种集中化具体意味着处理 CCG 研究的任何单一癌症的组织和数据的所有操作都在 BCR 上进行，并利用 SOP。这种差异最小化是指生物样本接收、后勤和物理管理、加工成分析物（从组织中提取的分子提取物，如 DNA 和 RNA）、组织细分以及最终将组织或分析物分配到研究地点的过程，并对整个工作流程中的所有中间产品和最终产品进行严格的质量控制。