Phenotypic heterogeneity in small cell lung cancer.

小细胞肺癌的表型异质性。

• 批准号: 9252982
• 负责人: PIERRE P. MASSION
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9252982
• 关键词: Aftercare; Automobile Driving; Behavior; Biological; Biological Assay; Cells; Cessation of life; Clinical; Clinical Trials Design; Clonality; Core Biopsy; Cytometry; Data; Diagnosis; Disease; EphA2 Receptor; Event; Exhibits; Experimental Designs; Frequencies; Gene Amplification; Gene Expression; Gene Mutation; Goals; Heterogeneity; High Prevalence; Human; Induced Mutation; Inter-tumoral heterogeneity; Intervention; Lesion; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Mesenchymal; Molecular; Mutation; Nature; Neurosecretory Systems; Newly Diagnosed; Pain; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Pattern; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Population; Pre-Clinical Model; Primary Neoplasm; Property; Recurrence; Relapse; Resistance; SYK gene; Sampling; Signal Pathway; Signal Transduction; Site; Specimen; Testing; Time; Translational Research; Treatment outcome; United States; Validation; Veterans; Work; Xenograft Model; Xenograft procedure; actionable mutation; base; cancer cell; cancer heterogeneity; chemotherapy; conventional therapy; data integration; design; drug sensitivity; exceptional responders; genome sequencing; improved; individual patient; individualized medicine; insight; kinase inhibitor; lung small cell carcinoma; molecular targeted therapies; mortality; neuroendocrine phenotype; new therapeutic target; novel marker; outcome forecast; personalized management; public health relevance; resistance mechanism; response; single cell analysis; targeted agent; targeted treatment; transcriptome sequencing; treatment planning; tumor; tumor heterogeneity; tumor progression; tumor xenograft; tumorigenesis; whole genome

 DESCRIPTION (provided by applicant): Phenotypic heterogeneity in small cell lung cancer. Abstract. Small cell lung cancer (SCLC) constitutes a group of malignancies responsible for the about 24,000 cancer deaths every year in the United States. Little progress has been made in decreasing SCLC mortality. Gene expression and mutation profiling efforts to identify driver mutations, gene amplifications, or signatures with clinical utility in SCLC have been limited and thus far been unfruitful. Our preliminary data point towards the existence of subclasses of SCLCs and new therapeutic targets. Based on these preliminary data we hypothesize that discovering the temporality, frequency and nature of primary and secondary mutations associated with tumor progression, the characterization of a small number of subpopulations and their responses to drugs will lead to significant improvements in the diagnosis, prognosis, and treatment of lung cancer. We propose to validate the two distinct phenotypes- neuroendocrine and mesenchymal- of SCLC within primary tumors. We will investigate the heterogeneity of the tumors based on fresh specimens by single cell mass Cytometry as it relates to their behavior. Our single cell analysis will inform us on the clonality of the lesions and intra-tumor heterogeneity. We will determine the temporality of events in tumorigenesis of SCLC in primary tumors and in tumors resisting chemotherapy. Whole genome sequencing and RNAseq analyses will be performed on these samples to assay tumor heterogeneity and compare before and after treatment as well as to identify changes specific to exceptional responders. Finally, we will interrogate in patient derive xenografts tumor heterogeneity in SCLCs who relapse after chemotherapy to discover new pathway activation and test new strategies for intervention including SYK and EPHA2 tyrosine kinase inhibitors. The ultimate goal of this translational research is to develop personalized management for patients presenting with SCLC. Phenotypic heterogeneity among cancer cells, observed even within single tumors, presents enormous challenges for developing "optimal" targeted treatment plans. We hope to uncover SCLC heterogeneity and its implications for chemotherapy. We hope to identify driver mutations and mutations that are uniquely associated with tumor progression, including therapy induced mutations. This will better inform the design of clinical trials and assist clinicians in tailoring treatment in individual patients.

 描述（由申请人提供）： 小细胞肺癌的表型异质性。抽象的。小细胞肺癌 (SCLC) 是一组恶性肿瘤，每年导致美国约 24,000 例癌症死亡。在降低 SCLC 死亡率方面进展甚微。基因表达和突变分析工作旨在识别 SCLC 中具有临床实用性的驱动突变、基因扩增或特征，但迄今为止尚未取得成果。我们的初步数据表明 SCLC 亚类和新治疗靶点的存在。基于这些初步数据，我们假设发现与肿瘤进展相关的初级和次级突变的时间性、频率和性质、少数亚群的特征及其对药物的反应将导致肺癌的诊断、预后和治疗的显着改善。我们建议验证原发性肿瘤内 SCLC 的两种不同表型——神经内分泌表型和间充质表型。我们将通过单细胞质量细胞计数法研究基于新鲜标本的肿瘤的异质性，因为它与其行为相关。我们的单细胞分析将告诉我们病变的克隆性和肿瘤内的异质性。我们将确定 原发性肿瘤和化疗耐药肿瘤中 SCLC 肿瘤发生事件的暂时性。将对这些样本进行全基因组测序和 RNAseq 分析，以测定肿瘤异质性并比较治疗前后，以及识别特殊反应者特有的变化。最后，我们将探讨化疗后复发的 SCLC 中患者来源的异种移植肿瘤异质性，以发现新的通路激活并测试新的干预策略，包括 SYK 和 EPHA2 酪氨酸激酶抑制剂。这项转化研究的最终目标是为 SCLC 患者开发个性化管理。即使在单个肿瘤内也观察到癌细胞之间的表型异质性，这对制定“最佳”靶向治疗计划提出了巨大的挑战。我们希望揭示 SCLC 异质性及其对化疗的影响。我们希望识别驱动突变和与肿瘤进展独特相关的突变，包括治疗诱导的突变。这将更好地为临床试验的设计提供信息，并帮助临床医生针对个体患者制定治疗方案。