Determinants of acquired resistance in small cell lung cancer

 描述(申请人提供)：小细胞肺癌(SCLC)具有极高的转移潜能，大多数患者在诊断时已有广泛的分期疾病。虽然大多数患者对化疗高度敏感，但疾病复发是普遍的，复发的疾病在很大程度上对治疗没有反应。从确诊时的高度化疗敏感性疾病到几个月后的高度耐化疗和致命性疾病的戏剧性转变的分子基础尚未确定。我们对这种肿瘤进化缺乏了解的一个关键因素是，小细胞肺癌很少在疾病进展时重新取样。该项目将采取补充方法，使用下一代测序来全面表征与人类小细胞肺癌获得性治疗耐药相关的变化。第一个目标是基于对患者来源异种移植(PDX)模型获得性抵抗的分析。我们已经从新诊断的、治疗天真的小细胞肺癌患者中产生了大量的PDX谱系。随着荷瘤小鼠反复接受标准一线化疗，我们产生了化疗耐药衍生物，这与临床上发生的情况完全相同。我们将使用配对分析来评估与获得性化疗耐药相关的小细胞肺癌复发的基因组和表观遗传学变化。第二个目标是基于对小细胞肺癌患者循环肿瘤细胞(CTC)的分析。CTC将被用作肿瘤基因组DNA的来源，通过它，我们可以类似地评估与获得性耐药相关的基因组和表观遗传学变化，将AIM 1中的结果与临床联系起来。第三个人工智能将验证前两个AIMS中确定的小细胞肺癌获得性耐药的主要候选驱动因素。 候选者将在体外和体内通过一系列互补的方法得到验证，包括使用新的方法在AIM 1中描述的PDX模型中对基因表达进行靶向修饰。本研究获得的数据将确定小细胞肺癌获得性耐药的机制，并将深入了解侵袭性肿瘤活检与CTC收集作为全面肿瘤突变分析来源的相对优点。这些数据将影响小细胞肺癌治疗的临床研究策略，并对其他疾病的获得性化疗耐药具有广泛的影响。

 DESCRIPTION (provided by applicant): Small cell lung cancer (SCLC) has an exceptionally high metastatic potential, and the majority of patients have extensive stage disease at the time of diagnosis. While most patients are highly responsive to chemotherapy, disease recurrence is universal, and recurrent disease is largely unresponsive to therapy. The molecular basis for the dramatic shift from a highly chemosensitive disease at diagnosis to a highly chemorefractory and lethal disease a few months later has not been defined. A key contributor to our lack of knowledge about this tumor evolution is that SCLC is rarely re-sampled at the time of disease progression. This project will take complementary approaches, using next generation sequencing to comprehensively characterize changes associated with acquired therapeutic resistance in human SCLC. The first Aim is based on analysis of acquired resistance in patient-derived xenograft (PDX) models. We have generated a large library of PDX lines from patients with newly diagnosed, treatment-naïve SCLC. With repeated exposure of tumor-bearing mice to standard first line chemotherapy, we have generated chemoresistant derivatives, precisely as occurs in the clinic. We will use pair-wise analysis to assess recurrent genomic and epigenetic changes associated with acquired chemoresistance in SCLC. The second Aim is based on analysis of circulating tumor cells (CTC) from patients with SCLC. CTC will be used as a source of tumor genomic DNA through which we can similarly assess genomic and epigenetic changes associated with acquired resistance, linking the results found in Aim 1 to the clinic. The third Ai will validate lead candidate drivers of acquired resistance in SCLC identified in the first 2 Aims. Candidates will be validated by a series of complementary approaches both in vitro and in vivo, including use of novel approaches to targeted modification of gene expression in the PDX models described in Aim 1. Data obtained in this study will define mechanisms of acquired resistance in SCLC and will provide insight into the relative merits of invasive tumor biopsy vs. CTC collection as sources for comprehensive tumor mutational profiling. These data will influence clinical research strategies for the treatment of SCLC, and have broad-based implications for acquired chemotherapeutic resistance in other diseases.