Phenotypic heterogeneity in small cell lung cancer.

 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，每年在美国造成约24，000例癌症死亡。在降低SCLC死亡率方面几乎没有取得进展。基因表达和突变谱的努力，以确定驱动突变，基因扩增，或签名与临床实用性在SCLC已有限，迄今为止是徒劳的。我们的初步数据指向SCLC的亚类和新的治疗靶点的存在。基于这些初步数据，我们假设发现与肿瘤进展相关的原发性和继发性突变的时间性、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诊断、预后和治疗的显著改善。我们建议验证两种不同的表型-神经内分泌和间充质-小细胞肺癌在原发性肿瘤。我们将基于新鲜标本通过单细胞质量细胞计数法研究肿瘤的异质性，因为它与它们的行为有关。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。康贝特人将以 原发性肿瘤和耐化疗肿瘤中SCLC肿瘤发生事件的时间性。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，并在治疗前后进行比较，以及确定特殊应答者的特异性变化。最后，我们将在化疗后复发的SCLC中询问患者来源的异种移植物肿瘤异质性，以发现新的途径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患者制定个性化管理。即使在单个肿瘤中也观察到癌细胞之间的表型异质性，这对开发“最佳”靶向治疗计划提出了巨大挑战。我们希望揭示SCLC异质性及其对化疗的影响。我们希望识别与肿瘤进展唯一相关的驱动突变和突变，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，并帮助临床医生为个体患者定制治疗。

 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.