Determinants of acquired resistance in small cell lung cancer

 描述（由申请人提供）：小细胞肺癌（SCLC）具有极高的转移潜力，大多数患者在诊断时患有广泛期疾病。虽然大多数患者对化疗具有高度反应性，但疾病复发是普遍的，并且复发性疾病在很大程度上对治疗无反应。从诊断时的高度化学敏感性疾病到几个月后的高度化学难治性和致死性疾病的戏剧性转变的分子基础尚未确定。我们对这种肿瘤演变缺乏了解的一个关键因素是，SCLC很少在疾病进展时重新采样。 该项目将采取互补的方法，使用下一代测序来全面表征与人类SCLC获得性治疗耐药性相关的变化。第一个目的是基于对患者来源的异种移植物（PDX）模型中获得性耐药性的分析。我们已经从新诊断的、未经治疗的SCLC患者中产生了一个大型PDX细胞系库。通过将荷瘤小鼠反复暴露于标准一线化疗，我们已经产生了化学抗性衍生物，正如临床上发生的那样。我们将使用成对分析来评估与小细胞肺癌获得性耐药相关的复发性基因组和表观遗传变化。第二个目的是基于对来自SCLC患者的循环肿瘤细胞（CTC）的分析。CTC将用作肿瘤基因组DNA的来源，通过该来源，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变化，将目标1中发现的结果与临床联系起来。第三个AI将验证前2个目标中确定的SCLC获得性耐药的主要候选驱动因素。 候选物将通过一系列体外和体内互补方法进行验证，包括使用新方法靶向修饰目的1中描述的PDX模型中的基因表达。 本研究中获得的数据将定义SCLC中获得性耐药的机制，并将深入了解侵入性肿瘤活检与CTC采集作为全面肿瘤突变谱来源的相对优点。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性具有广泛的意义。

 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.