Clinical Protocols in the Cancer Signaling Networks Section

癌症信号网络部分的临床方案

• 批准号: 10262393
• 负责人: Udayan Guha
• 金额: $ 55.43万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10262393
• 关键词: Aftercare; Appearance; Autopsy; Biological Markers; Biopsy; Cell Line; Clinic; Clinical; Clinical Protocols; Collaborations; Correlative Study; Country; Data; Data Analyses; Detection; Disease; Enrollment; Epidermal Growth Factor Receptor; Family; Generations; Genes; Genetic; Genomics; Germ-Line Mutation; Glass; Goals; Heterogeneity; High Resolution Computed Tomography; Histologic; Histology; Infrastructure; Inpatients; Inter-tumoral heterogeneity; Intervention; Intramural Research Program; Laboratories; Life; Lung Adenocarcinoma; Lung Neuroendocrine Neoplasm; Lung nodule; Malignant Neoplasms; Malignant neoplasm of thorax; Manuscripts; Mass Spectrum Analysis; Mesothelioma; Molecular Abnormality; Molecular Profiling; Mutate; Mutation; Mutation Detection; Natural History; Non-Small-Cell Lung Carcinoma; Nurses; Oncology; Pain; Palliative Care; Pathologist; Pathology; Patients; Phase; Pilot Projects; Predisposition; Preparation; Procedures; Proteins; Proteomics; Protocol Treatment Arm; Protocols documentation; Recruitment Activity; Research; Resistance; Resources; Safety; Sampling; Scanning; Signal Pathway; Signal Transduction; Site; Small Cell Carcinoma; Social Workers; Specialist; Technology; Testing; Thoracic Oncology; Thymus Epithelial Neoplasm; Thymus Gland; Tissue Banks; Tissue Procurements; Tissue Viability; Treatment Protocols; Tumor Tissue; United States National Institutes of Health; Validation; Visit; X-Ray Computed Tomography; Xenograft procedure; arm; base; clinical center; design; exome; exome sequencing; expiration; follow-up; genomic data; hospice environment; lung small cell carcinoma; member; molecular targeted therapies; mutant; next generation sequencing; novel; patient subsets; pilot trial; potential biomarker; pre-clinical; proteogenomics; recruit; research study; resistance mechanism; sample fixation; targeted agent; targeted sequencing; targeted treatment; therapy resistant; transcriptome; transcriptome sequencing; treatment arm; treatment group; treatment response; trial design; tumor heterogeneity; tumor progression

Protocol 1: A Pilot Study of Local Ablative Therapy for Treatment of Oligoprogressive, EGFR-Mutated, Non-Small Cell Lung Cancer (NSCLC) After Treatment with Osimertinib (AZD9291, Tagrisso) Project summary: We have enrolled 34 patients in this protocol. 16 patients underwent LAT procedure. Since we have mandatory biopsies during PFS1 pre- and post-resistance to osimertinib, we have developed a proteo-genomics analysis plan to identify key mechanisms of resistance.We have conducted whole exome sequencing (WES) and transcriptome sequencing (RNAseq) on pre-treatment and post-progression tumor samples of 14 patients. We have analyzed this data and uncovered novel mechanisms of resistance to osimertinib. We have identified MET amplification, C797S mutation, SCLC transformation among the mechanisms of resistance to osimertinib. Interestingly, significant heterogeneity in MET amplification was uncovered by multi-region sequencing. A manuscript on the data from these 14 patients is in preparation. Protocol 2: Tissue Procurement and Natural History Study of Patients with Non-Small Cell Lung Cancer, Small Cell Lung Cancer, Extrapulmonary Small Cell Cancer, Pulmonary Neuroendocrine Tumors, and Thymic Epithelial Tumors. Project summary: This protocol is actively recruiting. 296 patients have been recruited. This is the only study for tissue procurement in our thoracic oncology clinic for patients of all histologies except mesothelioma in which patients can get enrolled even if they are not enrolled in any treatment protocol at the NIH. There is a separate such protocol for mesothelioma (PI- Dr. Hassan). The tumor tissue acquired from this protocol will be used for validation of potential biomarkers of treatment response and resistance. Candidates will primarily be from the basic and pre-clinical proteomics studies performed in our laboratory. This protocol will also allow correlative studies for all other treatment protocols conducted in our clinic. Protocol 3: A pilot study of inpatient hospice with procurement of tissue on expiration in thoracic malignancies. Project summary: We have performed six autopsies on this protocol. It is quite challenging to acquire tumor tissue from various sites of metastatic disease in patients. However, such a tissue bank is a unique resource for various research studies. A rapid autopsy protocol enables viable tissue procurement for generation of cell lines, creation of patient-derived xenografts (PDX), and proper storage and fixation for research studies. This requires a close collaboration with pathologists, pain and palliative care specialists, nurses and social workers. The NIH Clinical Center has all the resources needed to conduct such a study. The patients who visit the Clinical Center are also very motivated and often want to contribute to research in oncology at the end of their life. The overall goal of this protocol is to examine the extent of tumor heterogeneity in various thoracic malignancies and how it influences targeted treatment response. The proteo-genomic studies proposed are actively being conducted in our and in our collaborators' laboratories within the intramural program. We have performed sequencing of 52 exomes and 30 transcriptomes to interrogate both intra-tumor and inter-tumor heterogeneity in these patients. We are currently analyzing the genomics data. The same sites of disease that underwent next-generation sequencing will undergo mass spectrometry-based proteomics to examine the heterogeneity at the protein level and in signaling pathways. The genomics and the proteomics studies on these rapid autopsy samples will be correlated to get a comprehensive analysis of the extent of heterogeneity and how it may have influenced treatment response in these patients. We have successfully conducted autopsies in 18 patients. 1 more patient is enrolled in this study and being followed. Protocol 4: Pilot trial of molecular profiling and targeted therapy for advanced Non-Small Cell Lung Cancer, Small Cell Lung Cancer, and Thymic malignancies. Project summary: Currently this is closed to accrual for new patients on all treatment arms, except for patients with potential EGFR germline mutations. Such patients are enrolled and tested for EGFR germline mutations. We are following several members of two families harboring the EGFR germline mutation, T790M. The detection of germline EGFR mutation and follow up of families with the mutation will soon be a stand-alone protocol. This is a biomarker derived multi-arm, multi-histology phase II "basket" trial. The feasibility of this "basket" trial design was not assessed properly when this trial was started. This design assesses the effects of a targeted agent against a specific molecular aberration while agnostic of the histologic context. Mutations or amplifications in 11 genes were used to assign patients to 1 of 5 biomarker matched treatment groups. In addition, around 200 genes were tested for mutations by next generation sequencing (NGS) technology. The infrastructure for such targeted sequencing analysis is available in the intramural program. The sequencing studies were performed in the Laboratory of Pathology (Dr. Mark Raffeld) and the Genetics Branch (Dr. Paul Meltzer). Germline EGFR mutant patients in this protocol constitute a unique subset of patients with germline predisposition of lung adenocarcinoma. There are few clinical protocols of this subset of patients in this country. Unlike other protocols elsewhere for germline EGFR mutation detection, our protocol allows clinical follow up of these patients with annual high resolution CT scan, including all interventions necessary to follow abnormal scans.

方案1：Osimertinib(AZD9291，Tagrisso)治疗后局部消融治疗寡进性、EGFR突变的非小细胞肺癌(NSCLC)的试点研究项目总结：我们在该方案中招募了34名患者。16例行LAT手术。由于我们在对奥西美替尼耐药前后的PFS1期间进行了强制性的活检，我们制定了一项蛋白质基因组学分析计划来确定关键的耐药机制。我们对14名患者的治疗前和进展后的肿瘤样本进行了完整的外显子组测序(WES)和转录组测序(RNAseq)。我们分析了这些数据，发现了对奥西美替尼耐药的新机制。我们已经确定MET扩增、C797S突变、SCLC转化是奥西美替尼耐药的机制。有趣的是，通过多区域测序发现MET扩增具有显著的异质性。一份关于这14名患者数据的手稿正在准备中。方案2：非小细胞肺癌、小细胞肺癌、肺外小细胞癌、肺神经内分泌肿瘤和胸腺上皮肿瘤患者的组织获取和自然病史研究。项目简介：该协议正在积极招聘中。共招募了296名患者。这是我们胸腔肿瘤诊所唯一一项针对除间皮瘤以外的所有组织学患者的组织采购研究。间皮瘤患者即使没有参加美国国立卫生研究院的任何治疗方案，也可以登记参加。对于间皮瘤有一个单独的这样的方案(Pi-Dr.Hassan)。通过该方案获得的肿瘤组织将用于验证潜在的治疗反应和耐药性生物标记物。候选人将主要来自我们实验室进行的基础和临床前蛋白质组学研究。该方案还将允许对我们临床进行的所有其他治疗方案进行相关研究。方案3：胸部恶性肿瘤住院患者临终关怀与过期组织采集的初步研究。项目概述：我们已经对该方案进行了六次尸检。从患者转移的不同部位获取肿瘤组织是非常具有挑战性的。然而，这样的组织库对于各种研究来说是一个独特的资源。快速尸检方案使可行的组织获取能够用于细胞系的生成、患者来源的异种移植(PDX)的创建以及研究研究的适当存储和固定。这需要与病理学家、疼痛和姑息治疗专家、护士和社会工作者密切合作。美国国立卫生研究院临床中心拥有进行这项研究所需的所有资源。参观临床中心的患者也非常有动力，往往希望在生命结束时为肿瘤学研究做出贡献。该方案的总体目标是检查各种胸部恶性肿瘤中肿瘤异质性的程度，以及它如何影响靶向治疗反应。建议的蛋白质基因组研究正在我们和我们的合作者的实验室内的内部计划中积极进行。我们进行了52个外显子组和30个转录体的测序，以询问这些患者的肿瘤内和肿瘤间的异质性。我们目前正在分析基因组学数据。接受下一代测序的相同疾病部位将接受基于质谱学的蛋白质组学研究，以检查蛋白质水平和信号通路的异质性。对这些快速尸检样本的基因组学和蛋白质组学研究将相互关联，以全面分析这些患者的异质性程度及其可能如何影响治疗反应。我们已经成功地对18名患者进行了尸检。另有1名患者进入本研究并接受随访。方案4：晚期非小细胞肺癌、小细胞肺癌和胸腺恶性肿瘤的分子图谱和靶向治疗的试点试验。项目摘要：目前，除了具有潜在EGFR种系突变的患者外，所有治疗组的新患者的这一比例接近应计。这些患者被登记并进行EGFR种系突变检测。我们正在跟踪携带EGFR胚系突变T790M的两个家族的几名成员。对生殖系EGFR突变的检测和对突变家庭的随访将很快成为一项独立的方案。这是一项生物标记物衍生的多臂、多组织学II期“篮子”试验。这一“篮子”试验设计的可行性在试验开始时没有得到适当的评估。该设计评估靶向制剂对特定分子畸变的效果，而不受组织学背景的影响。11个基因的突变或扩增被用来将患者分配到5个生物标记物匹配的治疗组中的1个。此外，约200个基因通过下一代测序(NGS)技术进行了突变测试。这种定向测序分析的基础设施在内部计划中可用。测序研究在病理学实验室(Mark Raffeld博士)和遗传学分部(Paul Meltzer博士)进行。该方案中的胚系EGFR突变患者构成了肺腺癌胚系易感性患者的独特亚群。在这个国家，这类患者的临床方案很少。与其他用于生殖系EGFR突变检测的其他协议不同，我们的协议允许通过每年高分辨率CT扫描对这些患者进行临床随访，包括跟踪异常扫描所需的所有干预措施。