Investigating How a Balance of Negative and Positive ETS Factors Controls Prostate Oncogenesis

研究负性和正性 ETS 因素的平衡如何控制前列腺肿瘤发生

基本信息

批准号：
10229585
负责人：
Rohit Bose
金额：
$ 26.03万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-15 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10229585
关键词：
Affect Androgen Receptor Androgens Automobile Driving Binding Binding Sites Bioinformatics Cancer Biology Cancer Etiology Cancer Patient Cancerous Cells ChIP-seq Chromatin Clinical Consensus DNA Binding Data Dependence Detection Development Disease ERG gene ETV1 gene ETV3 gene ETV6 gene Environment Equilibrium Event Funding Gene Fusion Genes Genetic Genetic Transcription Genitourinary system Genomics Growth Human International Investigation Laboratories Lead Light Malignant Neoplasms Malignant neoplasm of prostate Manuscripts Maps Mass Spectrum Analysis Mediating Medical Oncology Memorial Sloan-Kettering Cancer Center Mentors Mentorship Modeling Molecular Morphology Mus Mutation Nature Oncogenic Organoids Output PTEN gene Pathogenesis Phenotype Physicians Point Mutation Positioning Attribute Prostate Prostatic Neoplasms Protein Family Proteins Receptor Signaling Recurrence Reporting Research Research Personnel Role Scientist Services Site TMPRSS2 gene Testing Testosterone Training Tumor Suppressor Proteins Work base career career development cell growth clinical biomarkers experience instructor knock-down leukemia loss of function mutation mouse model overexpression programs prostate cancer cell receptor sarcoma targeted treatment therapy development transcription factor tumor tumor growth tumorigenesis

项目摘要

Preliminary Data: Half of all prostate cancers are caused by a gene-fusion that enables androgens to drive expression of the normally silent ETS transcription factor ERG in prostate cells. Recent genomic landscape studies of such cancers have reported rare but recurrent point mutations and narrow focal deletions in the ETS repressor ERF. Here we show these ERF mutations cause decreased protein stability and are mostly exclusive from those with ERG fusions. ERF loss recapitulates the morphologic and phenotypic features of ERG gain in normal mouse prostate cells, including expansion of the androgen receptor (AR) transcriptional repertoire, and ERF has tumor suppressor activity in the same genetic background of PTEN loss that yields oncogenic activity by ERG. In the more common situation of a tumor possessing wild-type ERF, ChIP-seq studies indicate that ERG inhibits the ability of ERF to bind DNA at consensus ETS sites in both normal and cancerous prostate cells. Consistent with a competition model, ERF overexpression blocks ERG-dependent tumor growth and ERF loss rescues ERG-positive prostate cancer cells from ERG dependency. This preliminary data is described in the applicant's first author manuscript in press at Nature. Rationale and Aims: We have now discovered that loss of function mutations and copy number deletions in `negative' ETS factors are commonplace in prostate cancer. I) We aim to determine the collective importance of negative ETS factor (ETV3 and ETV6) mutations in prostate cancer. II) We aim to determine whether ERF negative regulates AR by affecting AR's ability to bind DNA or by actively repressing its function. III) We believe that negative ETS factors are continually outcompeting positive ETS factors, even in normal prostate. We seek to identify these endogenous positive ETS factors. Impact: The results of these studies will describe how ETS factors coordinate within normal prostate cells. They may also shed light on why TMPRSS2-ERG is a poor clinical biomarker. Thirdly, they may explain the pathogenesis of the half of prostate cancers that lack TMPRSS2-ERG. And finally, they may shed light on the oncogenesis of other ETS-dependent cancers such as leukemias and sarcomas. Applicant and career development: The applicant, Dr. Rohit Bose, is performing his postdoctoral work in Charles Sawyers laboratory and is also an Instructor in the Genitourinary Service at Memorial Sloan Kettering Cancer Center (MSKCC). He has outlined a 5-year career plan that builds upon his research background studying molecular mechanisms of prostate oncogenesis and his clinical training in medical oncology. Dr. Bose will conduct the proposed research under the mentorship of Dr. Charles Sawyers, an internationally recognized expert in prostate cancer biology and targeted therapy development, with a strong track record of training successful physician scientists. MSKCC provides the ideal institutional environment for Dr. Bose to embark on the proposed research program and transition to a position as an independent academic investigator with his own laboratory and R01 funding.

初步数据：一半的前列腺癌是由雄激素驱动的基因融合引起的前列腺细胞中通常沉默的 ETS 转录因子 ERG 的表达。最近的基因组景观对此类癌症的研究报告了 ETS 中罕见但反复发生的点突变和狭窄局灶性缺失阻遏物ERF。在这里，我们展示了这些 ERF 突变导致蛋白质稳定性下降，并且大部分是与 ERG 融合的患者不同。 ERF 损失概括了形态学和表型特征正常小鼠前列腺细胞中的 ERG 增益，包括雄激素受体 (AR) 转录的扩展库，并且 ERF 在 PTEN 缺失的相同遗传背景下具有肿瘤抑制活性，从而产生 ERG 的致癌活性。在更常见的情况下，肿瘤具有野生型 ERF，ChIP-seq 研究表明，ERG 抑制 ERF 在正常和正常组织中 ETS 共有位点结合 DNA 的能力。癌性前列腺细胞。与竞争模型一致，ERF 过表达会阻断 ERG 依赖性肿瘤生长和 ERF 损失将 ERG 阳性前列腺癌细胞从 ERG 依赖性中拯救出来。这初步数据在《自然》杂志上发表的申请人的第一作者手稿中进行了描述。基本原理和目的：我们现在发现“阴性”ETS 中存在功能缺失突变和拷贝数缺失因素在前列腺癌中很常见。 I) 我们的目标是确定负面影响的集体重要性前列腺癌中的 ETS 因子（ETV3 和 ETV6）突变。 II) 我们的目的是确定 ERF 是否为阴性通过影响 AR 结合 DNA 的能力或主动抑制其功能来调节 AR。三）我们相信即使在正常前列腺中，阴性 ETS 因素也不断地胜过阳性 ETS 因素。我们力求识别这些内源性积极的 ETS 因素。影响：这些研究的结果将描述 ETS 如何因素在正常前列腺细胞内协调。他们还可能解释为什么 TMPRSS2-ERG 是一个可怜的临床生物标志物。第三，他们可以解释一半缺乏前列腺癌的发病机制。 TMPRSS2-ERG。最后，它们可能揭示其他 ETS 依赖性癌症的肿瘤发生，例如如白血病和肉瘤。申请人和职业发展：申请人 Rohit Bose 博士是在 Charles Sawyers 实验室进行博士后工作，同时也是泌尿生殖系统的讲师在纪念斯隆凯特琳癌症中心 (MSKCC) 提供服务。他制定了 5 年职业规划建立在他研究前列腺癌发生的分子机制及其临床研究背景的基础上肿瘤内科培训。 Bose 博士将在 Charles 博士的指导下进行拟议的研究 Sawyers 是国际公认的前列腺癌生物学和靶向治疗开发专家，拥有培养成功医师科学家的良好记录。 MSKCC 提供理想的机构为 Bose 博士着手拟议的研究计划并过渡到担任独立学术研究者，拥有自己的实验室和 R01 资助。