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)是一种恶性肿瘤，在美国每年约有24,000人死于癌症。在降低小细胞肺癌死亡率方面进展甚微。在小细胞肺癌中识别驱动突变、基因扩增或具有临床实用价值的特征的基因表达和突变图谱的努力一直是有限的，到目前为止还没有取得成果。我们的初步数据表明存在SCLC亚类和新的治疗靶点。基于这些初步数据，我们假设，发现与肿瘤进展相关的原发和继发突变的时间性、频率和性质，表征少数亚群及其对药物的反应，将在肺癌的诊断、预后和治疗方面带来显著改善。我们建议在原发肿瘤中验证小细胞肺癌的两种不同的表型--神经内分泌和间质。我们将以新鲜标本为基础，通过单细胞质量细胞术研究肿瘤的异质性，因为它与肿瘤的行为有关。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 小细胞肺癌在原发肿瘤和化疗耐药肿瘤发生中的暂时性。将对这些样本进行全基因组测序和RNAseq分析，以分析肿瘤的异质性，比较治疗前后的差异，并确定特殊应答者的变化。最后，我们将询问患者在化疗后复发的SCLC中衍生异种移植瘤的异质性，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。这项转化性研究的最终目标是为表现为小细胞肺癌的患者开发个性化管理。即使在单个肿瘤中也能观察到癌细胞的表型异质性，这对开发“最佳”靶向治疗计划提出了巨大的挑战。我们希望揭示小细胞肺癌的异质性及其对化疗的影响。我们希望确定与肿瘤进展唯一相关的驱动因素突变和突变，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别患者量身定制治疗方案。

 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.