Genomic and Functional Identification of Chemotherapy Resistance Mechanisms in Small Cell Lung Cancer

小细胞肺癌化疗耐药机制的基因组和功能鉴定

• 批准号: 10241343
• 负责人: Ramaswamy Govindan
• 金额: $ 56.11万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10241343
• 关键词: Address; Automobile Driving; Biological Markers; CSNK1A1 gene; Cancer Patient; Cancer cell line; Candidate Disease Gene; Cessation of life; Chemoresistance; Clinic; Clinical Trials; Combination Drug Therapy; Critical Pathways; DNA Repair; DNA Sequence Alteration; Data; Development; Disease; Disease Resistance; Disease model; Excision; Exhibits; Genes; Genetically Engineered Mouse; Genomics; Goals; Histopathology; Human; Immunocompetent; In Vitro; Knock-out; Light; Malignant Neoplasms; Malignant neoplasm of lung; Medical; Mission; Modeling; Mus; Mutation; Neurosecretory Systems; Operative Surgical Procedures; Pathway interactions; Patients; Pharmacology; Public Health; Quality of life; Recurrence; Relapse; Research; Resistance; Resistance development; Resources; Sampling; Signal Transduction; Survival Rate; TP53 gene; Testing; Tissues; United States; United States National Institutes of Health; WNT Signaling Pathway; Work; base; beta catenin; cancer cell; chemotherapy; combat; epigenome; epigenomics; exome; exome sequencing; human disease; human model; improved; in vitro testing; in vivo; inhibitor/antagonist; innovation; lung small cell carcinoma; mortality; mouse model; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; overexpression; prevent; resistance mechanism; response; standard of care; targeted treatment; therapeutic target; tool; transcriptome; transcriptomics; treatment strategy; tumor; whole genome

Project Summary Small cell lung cancer (SCLC) is responsible for over 30,000 deaths each year in the United States alone. SCLC has a two-year survival rate of ~6% and unlike the other major subtypes of lung cancer, there are currently no targeted therapies approved for SCLC. SCLC is initially highly responsive to chemotherapy, but rapidly develops resistance leading to mortality in ~10 months. Clearly, a major unmet need for the treatment of SCLC is the identification of new therapeutic targets and treatment strategies to combat chemo-resistant disease. Our understanding of chemotherapy resistance mechanisms has been hampered by a lack of relapsed human SCLC tissue due to rare surgical resections. In addition, there have been few mouse models of the disease that exhibit short latencies and chemo-sensitivity. To address these challenges, we performed whole exome sequencing on relapsed SCLC from 30 patients. Relapse-specific genomic alterations in the WNT/APC/β-catenin pathway were identified in ~66% of relapsed SCLC suggesting that this pathway promotes chemo-resistance. Second, we developed a novel mouse model of SCLC driven by loss of Rb1, Trp53 and overexpression of Myc—three of the most common genetic alterations in the human disease. Mice develop SCLC within weeks that highly resembles the human disease at the level of histopathology, biomarker expression and chemo-sensitivity followed by relapse. This model will be a useful tool to test candidate chemotherapy resistance mechanisms and identify novel therapeutic targets that inhibit chemo-resistance. The objective of this study is to use this novel mouse model and comprehensive genomic analyses of primary and relapsed human SCLC to identify mechanisms of chemotherapy resistance and novel therapeutic targets to combat chemo-resistant disease. We hypothesize that activation of the WNT/β-catenin pathway promotes chemo-resistance in SCLC and that targeted inhibition of the pathway will inhibit chemo-resistant disease. We predict that expansion of our genomic and transcriptomic profiling will identify additional novel pathways involved in chemo-resistance. To test these hypotheses, we will: 1) identify recurrent pathway alterations in relapsed human and mouse SCLC using whole genome, exome, transcriptome and epigenome sequencing and 2) functionally determine whether canonical WNT/β-catenin signaling and other candidate pathways are necessary and sufficient for chemo-resistance in SCLC in vivo. This approach is innovative because we will employ unbiased comprehensive genomic and epigenomic analyses on relapsed human SCLC and a novel immune-competent mouse model of SCLC that recapitulates key features of the human disease. The WNT/β- catenin pathway is largely unexplored in SCLC. This research is significant because there are currently no targeted therapies approved for SCLC. A better understanding of the critical pathways driving chemo- resistance in SCLC will impact the treatment and survival of patients with this intractable disease.

项目摘要 仅在美国，每年就有超过3万人死于小细胞肺癌(SCLC)。 小细胞肺癌的两年存活率约为6%，与其他主要肺癌亚型不同，小细胞肺癌有 目前还没有针对小细胞肺癌的靶向治疗被批准。小细胞肺癌最初对化疗高度敏感，但 迅速产生抗药性，导致约10个月内死亡。显然，治疗的主要未得到满足的需求 小细胞肺癌的关键是确定新的治疗靶点和治疗策略，以对抗化疗耐药 疾病。我们对化疗耐药机制的理解因缺乏 因罕见的手术切除而复发的人小细胞肺癌组织。此外，几乎没有老鼠模型。 表现出短潜伏期和化疗敏感性的疾病。为了应对这些挑战，我们进行了 30例复发性小细胞肺癌患者外显子组全序列测定。慢性粒细胞白血病复发特异的基因组改变 在66%的复发性小细胞肺癌中检测到WnT/APC/β-连环蛋白通路，提示该通路在小细胞肺癌复发中起重要作用。 促进抗药性。第二，我们建立了一种新的Rb1缺失驱动的小鼠小细胞肺癌模型， Trp53和Myc的过度表达--这是人类疾病中最常见的三种基因改变。老鼠 在几周内发展成在组织病理学、生物标记物水平上与人类疾病高度相似的小细胞肺癌 表达和化疗敏感性继而复发。该模型将是测试应聘者的有用工具 化疗耐药机制，并确定抑制化疗耐药的新治疗靶点。这个 本研究的目的是利用这一新的小鼠模型和全面的基因组分析的初级和 复发性人小细胞肺癌化疗耐药机制及新的治疗靶点 与抗药性疾病作斗争。我们假设Wnt/β-连环蛋白通路的激活促进了 在小细胞肺癌中存在化疗耐药，靶向抑制该途径将抑制耐药疾病。我们 预测我们的基因组和转录图谱的扩展将发现更多的新途径 与化疗耐药有关。为了验证这些假说，我们将：1)确定反复发生的通路改变 应用全基因组、外显子组、转录组和表观基因组测序研究复发性人和小鼠小细胞肺癌 2)从功能上确定规范的Wnt/β-连环蛋白信号通路和其他候选通路是否 小细胞肺癌体内化疗耐药的充分必要条件。这种方法是创新的，因为我们将 对复发性人小细胞肺癌和一个新的小细胞肺癌进行无偏全面的基因组和表观基因组分析 具有免疫能力的小鼠小鼠模型，概括了人类疾病的主要特征。WNT/β- 在小细胞肺癌中，连环蛋白通路在很大程度上是未知的。这项研究意义重大，因为目前还没有 被批准用于小细胞肺癌的靶向治疗。更好地了解推动化疗的关键途径- 小细胞肺癌的耐药性将影响这种顽固性疾病患者的治疗和生存。