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）构成了一组恶性肿瘤，每年约有24,000例癌症死亡。在降低SCLC死亡率方面几乎没有取得进展。基因表达和突变分析工作以识别SCLC中临床实用性的驱动器突变，基因扩增或特征的努力受到限制，迄今为止尚未实现。我们的初步数据指向SCLC和新的治疗靶标的子类的存在。基于这些初步数据，我们假设发现与肿瘤进展相关的原发性和次要突变的临时性，频率和性质，少数亚群的表征及其对药物的反应将导致诊断，预后和治疗肺癌的治疗。我们建议在原发性肿瘤内验证两种不同的表型 - 神经内分泌和间质 - 我们将根据单细胞质量细胞仪与其行为相关的单细胞质量细胞仪，研究肿瘤的异质性。我们的单细胞分析将告知我们病变的克隆性和肿瘤内异质性。我们将确定 SCLC肿瘤发生的临时性在原发性肿瘤和抵抗化疗的肿瘤中。将对这些样品进行整个基因组测序和RNASEQ分析，以主张肿瘤异质性，并在治疗前后进行比较，并确定特定于特殊响应者的变化。最后，我们将在患者中询问异种移植物在SCLC中肿瘤异质性，后者在化学疗法后中继，以发现新的途径激活并测试包括SYK和EPHA2酪氨酸激酶抑制剂在内的新干预策略。这项翻译研究的最终目标是为参加SCLC的患者开发个性化管理。癌细胞之间的表型异质性，即使在单个肿瘤中也观察到，为制定“最佳”靶向治疗计划提出了巨大的挑战。我们希望发现SCLC异质性及其对化学疗法的影响。我们希望确定与肿瘤进展唯一相关的驱动突变和突变，包括治疗引起的突变。这将更好地为临床试验的设计提供信息，并协助临床医生对个别患者进行调整治疗。