Investigating CREBBP as a tumor suppressor in small cell lung cancer

研究 CREBBP 作为小细胞肺癌的肿瘤抑制因子

• 批准号: 10049235
• 负责人: David MacPherson
• 金额: $ 44.2万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-15 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10049235
• 关键词: Acetylation; Acetyltransferase; CREBBP gene; Cancer Model; Cancer cell line; Candidate Disease Gene; Cell Death; Cells; ChIP-seq; Cisplatin; Clustered Regularly Interspaced Short Palindromic Repeats; Combined Modality Therapy; Data; Deletion Mutation; Enhancers; Etoposide; Exhibits; FDA approved; Gene Expression; Gene Mutation; Genes; Genetic; Genetic Engineering; Genetic Transcription; Genomic approach; Genomics; Hematopoietic Neoplasms; Histone Acetylation; Histone Deacetylase; Histone Deacetylase Inhibitor; Histones; Human; Human Cell Line; Image; Lead; LoxP-flanked allele; Lung; Magnetic Resonance Imaging; Malignant neoplasm of lung; Molecular Analysis; Mus; Mutate; Mutation; Neuroendocrine Carcinoma; Neuroendocrine Tumors; Neurosecretory Systems; Pathway interactions; Patients; Pharmaceutical Preparations; Pituitary Gland; Pituitary Neoplasms; Proteins; Proteomics; Signal Transduction; Site; Solid Neoplasm; Survival Rate; System; TP53 gene; Testing; Therapeutic; Thyroid Gland; Time; Transcript; Translating; Tumor Suppression; Tumor Suppressor Genes; Tumor Suppressor Proteins; comparative efficacy; driver mutation; effective therapy; experimental study; genomic data; improved; in vivo; lung small cell carcinoma; mouse model; mutant; neuroendocrine cancer; non-histone protein; patient derived xenograft model; promoter; small hairpin RNA; thyroid neoplasm; transcriptome sequencing; tumor; tumor initiation; tumor progression; tumorigenesis

Summary Small cell lung cancer (SCLC) is a neuroendocrine cancer of the lung with dismal survival rates. There are no therapies for SCLC directed towards tumors harboring specific driver mutations. Recent genomic analyses and our own preliminary data revealed that CREBBP mutation/deletion is frequent in human SCLC. CREBBP is an acetyltransferase that acetylates histones and other proteins. CREBBP is emerging as a frequently mutated gene in hematopoietic tumors as well as certain solid tumors, but functional evidence of CREBBP tumor suppressor activity in solid tumors is lacking. We have evidence that CREBBP functions as a critical tumor suppressor gene across multiple neuroendocrine tumor types including SCLC. Our aims are to identify the mechanisms through which CREBBP suppresses SCLC and to test a therapeutic approach directed towards CREBBP-mutant SCLC. Specific Aim 1: To characterize effects of CREBBP deletion in a mouse model of small cell lung cancer and in human cell lines. We will inactivate Crebbp using a sensitized mouse model of SCLC that is driven by lung specific deletions in Rb and p53. In this mouse model, tumors arise with long latency, providing an ideal system to test the ability of potential SCLC driver mutations to accelerate tumorigenesis. Specific Aim 2: To identify mechanisms through which CREBBP deletion collaborates with Rb and p53 loss to promote SCLC. We hypothesize that Crebbp loss collaborates with Rb and p53 loss to promote neuroendocrine tumor types through control of gene expression. By integrating transcriptional data from Crebbp wild-type vs. mutant murine neuroendocrine pituitary tumors, thyroid tumors and SCLC, we will identify a common group of Crebbp-controlled genes across multiple Rb/p53-deleted neuroendocrine tumors. Focusing on SCLC, we will also identify genomic sites with reduced histone acetylation and proteins with reduced acetylation upon CREBBP deletion. Functional experiments will interrogate candidate CREBBP effectors for tumor suppressive activity. Specific Aim 3: To determine whether Crebbp-mutant tumors exhibit sensitivity to HDAC inhibition. We hypothesize that CREBBP deficiency will result in sensitivity to histone deacetylase (HDAC) inhibition as this could potentially restore lost histone acetylation. We will determine whether HDAC inhibition will lead to regression of Crebbp-mutant neuroendocrine tumors employing both genetically engineered and patient derived xenograft models. CREBBP is emerging as a frequently mutated gene in many solid tumors and is one of the most frequently mutated genes in SCLC, but there is a poor understanding of how CREBBP functions as a tumor suppressor. Through integrative analyses of genomic data we will identify Crebbp-controlled tumor suppressive signaling networks. We will also determine whether inactivation of Crebbp leads to sensitivity to the HDAC inhibitor romidepsin. As romidepsin is an FDA- approved drug, positive results could rapidly be translated to improving therapies for patients with CREBBP- mutated tumors.

总结 小细胞肺癌（SCLC）是一种神经内分泌肺癌，生存率很低。没有 针对携带特定驱动突变的肿瘤的SCLC治疗。最近的基因组分析和 我们自己的初步数据显示CREBBP突变/缺失在人SCLC中是常见的。CREBBP是一个 使组蛋白和其他蛋白质乙酰化的乙酰转移酶。CREBBP是一种经常突变的 CREBBP基因在造血系统肿瘤以及某些实体瘤中存在，但CREBBP肿瘤的功能证据 在实体瘤中缺乏抑制活性。我们有证据表明CREBBP是一种重要的肿瘤 在包括SCLC在内的多种神经内分泌肿瘤类型中存在抑制基因。我们的目标是确定 CREBBP抑制SCLC的机制，并测试针对SCLC的治疗方法。 CREBBP突变型SCLC。具体目的1：表征CREBBP缺失在小鼠模型中的作用， 小细胞肺癌和人类细胞系。我们将使用致敏小鼠模型来检测Crebbp， 由Rb和p53中的肺特异性缺失驱动的SCLC。在这个小鼠模型中，肿瘤随着长时间的生长而出现。 延迟，提供了一个理想的系统来测试潜在的SCLC驱动程序突变的能力，以加速 肿瘤发生具体目标2：确定CREBBP缺失与Rb协同作用的机制 和p53缺失促进SCLC。我们假设Crebbp缺失与Rb和p53缺失协同作用， 通过控制基因表达促进神经内分泌肿瘤类型。通过整合转录数据 从Crebbp野生型与突变型小鼠神经内分泌垂体肿瘤、甲状腺肿瘤和SCLC中，我们将 在多种Rb/p53缺失的神经内分泌肿瘤中鉴定一组共同的Crebbp控制基因。 聚焦于SCLC，我们还将鉴定组蛋白乙酰化减少的基因组位点和蛋白质， CREBBP缺失后乙酰化减少。功能实验将询问候选CREBBP 肿瘤抑制活性的效应物。具体目标3：确定Crebbp突变型肿瘤是否表现出 对HDAC抑制敏感。我们假设CREBBP缺乏会导致对组蛋白的敏感性， 脱乙酰酶（HDAC）抑制，因为这可能潜在地恢复丢失的组蛋白乙酰化。我们将确定 HDAC抑制是否会导致Crebbp突变型神经内分泌肿瘤的消退， 基因工程和患者来源的异种移植物模型。CREBBP是一种经常突变的 基因在许多实体瘤中，是SCLC中最常见的突变基因之一，但在许多实体瘤中， 了解CREBBP如何作为肿瘤抑制因子发挥作用。通过基因组的综合分析， 数据，我们将确定Crebbp控制的肿瘤抑制信号网络。我们还将确定 Crebbp的失活导致对HDAC抑制剂罗米地辛的敏感性。因为罗米地辛是FDA- 批准的药物，积极的结果可以迅速转化为改善CREBBP患者的治疗- 突变的肿瘤

项目成果

Small Cell Lung Cancer Exhibits Frequent Inactivating Mutations in the Histone Methyltransferase KMT2D/MLL2: CALGB 151111 (Alliance).

• DOI: 10.1016/j.jtho.2016.12.011
• 发表时间: 2017-04
• 期刊: Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
• 作者: Augert A;Zhang Q;Bates B;Cui M;Wang X;Wildey G;Dowlati A;MacPherson D
• 通讯作者: MacPherson D