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.

概括 小细胞肺癌（SCLC）是一种肺部神经内分泌癌，生存率很低。没有 SCLC 疗法针对含有特定驱动突变的肿瘤。最近的基因组分析和 我们自己的初步数据显示，CREBBP 突变/缺失在人类 SCLC 中很常见。 CREBBP 是一个 乙酰化组蛋白和其他蛋白质的乙酰转移酶。 CREBBP 正在成为一种频繁突变的基因 造血肿瘤和某些实体瘤中的基因，但 CREBBP 肿瘤的功能证据 实体瘤中缺乏抑制活性。我们有证据表明 CREBBP 是一种关键肿瘤 跨多种神经内分泌肿瘤类型（包括 SCLC）的抑制基因。我们的目标是确定 CREBBP 抑制 SCLC 的机制并测试针对 CREBBP 突变型 SCLC。具体目标 1：表征 CREBBP 缺失对小鼠模型的影响 小细胞肺癌和人类细胞系。我们将使用致敏小鼠模型灭活 Crebbp SCLC 是由 Rb 和 p53 中肺部特异性缺失驱动的。在这个小鼠模型中，肿瘤的产生需要很长时间 延迟，提供了一个理想的系统来测试潜在的 SCLC 驱动突变加速的能力 肿瘤发生。具体目标 2：确定 CREBBP 缺失与 Rb 协作的机制 p53 缺失促进 SCLC。我们假设 Crebbp 损失与 Rb 和 p53 损失协同作用 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 的比较，我们将 在多个 Rb/p53 缺失的神经内分泌肿瘤中鉴定出一组常见的 Crebbp 控制基因。 专注于 SCLC，我们还将鉴定组蛋白乙酰化减少的基因组位点和具有 CREBBP 缺失后乙酰化减少。功能实验将审问候选 CREBBP 肿瘤抑制活性的效应器。具体目标 3：确定 Crebbp 突变肿瘤是否表现出 对 HDAC 抑制的敏感性。我们假设 CREBBP 缺陷会导致对组蛋白的敏感性 去乙酰化酶 (HDAC) 抑制，因为这可能会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消退 基因工程和患者衍生的异种移植模型。 CREBBP 正在成为一种频繁突变的基因 该基因存在于许多实体瘤中，是 SCLC 中最常见的突变基因之一，但其突变率较差 了解 CREBBP 如何发挥肿瘤抑制因子的作用。通过基因组综合分析 根据数据，我们将确定 Crebbp 控制的肿瘤抑制信号网络。我们还将确定是否 Crebbp 失活导致对 HDAC 抑制剂罗米地辛敏感。由于罗米地辛是 FDA 批准的 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