Genotypic Interactions in Brain Cancer Heterogeneity

脑癌异质性中的基因型相互作用

• 批准号: 10454095
• 负责人: Frank Furnari
• 金额: $ 34.56万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10454095
• 关键词: Ablation; Address; Adult; Alleles; Attenuated; Automobile Driving; Binding; Biology; Bromodomain; CRISPR/Cas technology; Candidate Disease Gene; Cell Communication; Cell Line; Cells; ChIP-seq; Chemicals; Chromatin; Chromatin Structure; Cisplatin; Clinical; Clinical Trials; Competence; Cytology; DNA Damage; DNA Polymerase II; Data Set; Engineering; Enhancers; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Epigenetic Process; Family; Fluorescence; Fostering; Ganciclovir; Gene Amplification; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Heterogeneity; Genetic Structures; Genetic Transcription; Genotype; Glioblastoma; Glioma; Goals; Grant; HSV-Tk Gene; Heterogeneity; Individual; Inflammatory; Inflammatory Response; Interleukin-6; Ionizing radiation; Label; Lead; Lesion; Lysine; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Mediator of activation protein; Modeling; Molecular; Monitor; Mus; Mutate; Mutation; Nature; Neoplasms; Neurologic; Paracrine Communication; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Population; Primary Brain Neoplasms; Process; Protein Family; Protein Kinase; Proteins; RNA; Radiation therapy; Role; Sampling; Signal Transduction; Specificity; Tertiary Protein Structure; Testing; The Cancer Genome Atlas; Therapeutic; Therapeutic Agents; Tissues; Treatment Efficacy; Triage; Tumor Stem Cells; Tumorigenicity; Variant; Vincristine; autocrine; base; cancer heterogeneity; cell type; chemical genetics; chromatin remodeling; cytokine; drug sensitivity; epidermal growth factor receptor VIII; experimental study; genome editing; improved; in vivo; inhibitor; loss of function; member; mutant; neoplastic cell; neurosurgery; novel therapeutic intervention; novel therapeutics; p65; paracrine; programs; promoter; protein expression; receptor; recruit; regional difference; response; stem cells; suicide gene; targeted treatment; temozolomide; therapy resistant; tool; transcriptome sequencing; tumor; tumor growth

Project Summary Minimal improvement in the 12-15 month average survival of patients with glioblastoma multiforme (GBM) has been achieved despite decades of advances in neurosurgery and radiation therapy, many clinical trials for novel therapeutics, and increased understanding of the driving molecular mechanisms. A central issue that confounds successful treatment is the heterogeneous nature of this aggressive tumor. This heterogeneity presents phenotypically as mixed cytological subtypes, genotypically as mutations and gene amplifications, and transcriptionally as regional differences in gene expression. As a result, multiple and spatially distinct heterotypic populations exist within a single GBM, making any lesion- or pathway-specific therapy less effective. While considerable effort has been placed on understanding cell intrinsic mechanisms conferring therapeutic resistance, much less is known about the interactions between heterogeneous tumor cells within these neoplasms that contribute to the recalcitrant nature of this cancer. In GBM, amplification of the epidermal growth factor receptor, a hallmark mutation present in 60% of cases, often occurs in a heterogeneous manner and is frequently associated with structural alterations. The most common of these alterations, EGFRvIII, (also known as ∆EGFR) results in a constitutively active mutant receptor with tumor enhancing capability. This ability is lacking from amplified wtEGFR despite its more pervasive tumor expression. By modeling this type of genetic heterogeneity in vivo, we have determined that an IL-6 paracrine signaling mechanism driven by EGFRvIII activity can not only recruit wtEGFR-expressing cells into accelerated proliferation, but also promote EGFR-targeted therapeutic resistance through activation of a pro-survival inflammatory NF-κB/BRD4 signaling axis. Given the central role of NF-κB/BRD4 in the remodeling of chromatin super enhancers we postulate that EGFRvIII/wtEGFR sub-population interactions not only enhance aggressive tumor growth, but also prompt the synchronization of aspects of gene expression in these heterotypic cells through shared enhancer remodeling. The overall goal of this renewal project is to dissect and target the mechanisms whereby GBM EGFR/EGFRvIII heterogeneity drives therapeutic resistance through orchestration of NF-κB/BRD4-mediated remodeling of the epigenetic landscape. The following lines of experimentation will be carried out: 1) genome editing to create a drug-selective BRD4 allele for mechanistic chemical biology studies; 2) use of this modified BRD4 allele as a tool for chromatin structure and functional analysis of the cytokine-stimulated NF-κB/BRD4 enhancer landscape in heterotypic and subpopulation-ablated gliomas; 3) genetic and pharmacological inhibition of identified NF-κB/BRD4-mediated genetic or epigenetic vulnerabilities shared among EGFR and EGFRvIII heterotypic cells to enhance therapeutic efficacy.

项目摘要 多形性胶质母细胞瘤(GBM)患者12-15个月平均生存期的微小改善 尽管几十年来神经外科和放射治疗取得了进展，但许多临床试验 新的治疗方法，以及对驱动分子机制的更多了解。一个核心问题是 这种侵袭性肿瘤的异质性混淆了成功的治疗。这种异质性 表现为混合细胞学亚型，基因典型为突变和基因扩增， 在转录水平上则是基因表达的区域差异。因此，多个和空间上不同的 在单个GBM中存在异型群体，使得任何病变或路径特异性治疗变得更少 有效。虽然在理解细胞内在机制方面已经付出了相当大的努力 治疗耐药，对体内异质肿瘤细胞之间的相互作用知之甚少 这些肿瘤导致了这种癌症的顽固性。在GBM中，扩增的 表皮生长因子受体是一种标志性突变，存在于60%的病例中，通常发生在 不同的方式，并经常与结构变化联系在一起。其中最常见的是 突变的EGFRvIII(也被称为∆EGFR)导致与肿瘤有关的结构性活性突变受体 增强能力。这种能力在扩增的wtEGFR中是缺乏的，尽管它的肿瘤更普遍 表情。通过在体内模拟这种类型的遗传异质性，我们已经确定了IL-6旁分泌 EGFRvIII活性驱动的信号机制不仅可以将表达wtEGFR的细胞招募到加速状态 增殖，但也促进EGFR靶向的治疗耐药通过激活一个亲生存 炎症性NF-κB/BRD4信号轴。鉴于NF-κB/BRD4在血管重构中的核心作用 染色质超级增强子我们假设EGFRvIII/wtEGFR亚群相互作用不仅增强 侵袭性肿瘤生长，但也促使这些方面的基因表达同步 通过共享增强子重塑的异型细胞。 这一更新项目的总体目标是剖析和瞄准GBM EGFR/EGFRvIII 异质性通过协调NF-κB/BRD4介导的细胞重塑来驱动治疗耐药 表观遗传景观。将进行以下实验：1)基因组编辑，以创建 用于机械化学生物学研究的药物选择性BRD4等位基因；2)将该修饰的BRD4等位基因用作 细胞因子刺激的NF-κB/BRD4增强子染色质结构和功能分析工具 异型和亚群消融的胶质瘤中的景观；3)基因和药物抑制 确定了EGFR和EGFRvIII共有的NF-κB/BRD4介导的遗传或表观遗传脆弱性 异型细胞，以提高治疗效果。

项目成果

Corrigendum to: EGFR, the Lazarus target for precision oncology in glioblastoma.

勘误表：EGFR，胶质母细胞瘤精准肿瘤学的 Lazarus 靶标。

• DOI: 10.1093/neuonc/noac254
• 发表时间: 2023
• 期刊: Neuro-oncology
• 影响因子: 15.9
• 作者: Lin,Benjamin;Ziebro,Julia;Smithberger,Erin;Skinner,KaseyR;Zhao,Eva;Cloughesy,TimothyF;Binder,ZevA;O'Rourke,DonaldM;Nathanson,DavidA;Furnari,FrankB;Miller,CRyan
• 通讯作者: Miller,CRyan

FHL2 interacts with EGFR to promote glioblastoma growth.

FHL2与EGFR相互作用促进胶质母细胞瘤生长

• DOI: 10.1038/s41388-017-0068-0
• 发表时间: 2018-03
• 期刊: Oncogene
• 影响因子: 8
• 作者: Sun L;Yu S;Xu H;Zheng Y;Lin J;Wu M;Wang J;Wang A;Lan Q;Furnari F;Cavenee W;Purow B;Li M
• 通讯作者: Li M

Fluorescence Molecular Tomography for In Vivo Imaging of Glioblastoma Xenografts.

用于胶质母细胞瘤异种移植物体内成像的荧光分子断层扫描。

• DOI: 10.3791/57448
• 发表时间: 2018
• 期刊: Journal of visualized experiments : JoVE
• 作者: Benitez,JorgeA;Zanca,Ciro;Ma,Jianhui;Cavenee,WebsterK;Furnari,FrankB
• 通讯作者: Furnari,FrankB

An LXR-Cholesterol Axis Creates a Metabolic Co-Dependency for Brain Cancers.

• DOI: 10.1016/j.ccell.2016.09.008
• 发表时间: 2016-11-14
• 期刊: Cancer cell
• 影响因子: 50.3
• 作者: Villa GR;Hulce JJ;Zanca C;Bi J;Ikegami S;Cahill GL;Gu Y;Lum KM;Masui K;Yang H;Rong X;Hong C;Turner KM;Liu F;Hon GC;Jenkins D;Martini M;Armando AM;Quehenberger O;Cloughesy TF;Furnari FB;Cavenee WK;Tontonoz P;Gahman TC;Shiau AK;Cravatt BF;Mischel PS
• 通讯作者: Mischel PS

A urokinase receptor-Bim signaling axis emerges during EGFR inhibitor resistance in mutant EGFR glioblastoma.

• DOI: 10.1158/0008-5472.can-14-2004
• 发表时间: 2015-01-15
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Wykosky J;Hu J;Gomez GG;Taylor T;Villa GR;Pizzo D;VandenBerg SR;Thorne AH;Chen CC;Mischel PS;Gonias SL;Cavenee WK;Furnari FB
• 通讯作者: Furnari FB