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

• 批准号: 10471816
• 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
• 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/10471816
• 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

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基因融合引起的，这种融合使雄激素能够驱动 正常沉默的Ets转录因子ERG在前列腺细胞中的表达现代基因组图景 对这类癌症的研究已经报道了在ETS中罕见但复发的点突变和狭窄的局灶性缺失。 抑制因子ERF。在这里，我们展示了这些ERF突变导致蛋白质稳定性降低，并且主要是 仅限ERG融合者使用。ERF Lost概括了细胞的形态和表型特征 正常小鼠前列腺细胞ERG的获得，包括雄激素受体(AR)转录的扩增 和ERF在相同的PTEN缺失的遗传背景下具有肿瘤抑制活性 ERG法检测致癌活性。在更常见的肿瘤具有野生型ERF的情况下，CHIP-SEQ 研究表明，ERG抑制ERF结合DNA的能力在正常和 癌变的前列腺细胞。与竞争模型一致，ERF过表达阻断ERG依赖 肿瘤生长和ERF缺失将ERG阳性的前列腺癌细胞从ERG依赖中拯救出来。这 申请人在《自然》杂志上发表的第一篇作者手稿中描述了初步数据。基本原理和 目的：我们现在发现‘阴性’ETS中功能突变和拷贝数缺失的丢失 前列腺癌的发病因素很常见。一)我们的目标是确定消极的集体重要性 前列腺癌中ETS因子(ETV3和ETV6)突变的研究Ii)我们的目标是确定ERF是否为负值 通过影响AR结合DNA的能力或主动抑制其功能来调节AR。三)我们认为 即使在正常的前列腺中，负面的ETS因素也持续胜过正面的ETS因素。我们寻求 找出这些内生的积极ETS因素。影响：这些研究的结果将描述ETS如何 在正常的前列腺细胞中，各种因子相互协调。他们还可能解释为什么TMPRSS2-ERG是一个糟糕的 临床生物标志物。第三，它们可以解释一半前列腺癌缺乏的发病机制。 TMPRSS2-ERG。最后，他们可能会揭示其他依赖ETS的癌症的致癌机制 白血病和肉瘤。申请人和职业发展：申请人罗希特·博斯博士是 在Charles Sawyers实验室从事博士后工作，同时也是生殖泌尿外科的讲师 纪念斯隆·凯特琳癌症中心(MSKCC)的服务。他勾勒出了一个5年的职业计划， 以他研究前列腺癌发生的分子机制和他的临床的研究背景为基础 内科肿瘤学培训。博斯博士将在查尔斯博士的指导下进行拟议中的研究 索耶斯是国际公认的前列腺癌生物学和靶向治疗开发专家， 在培养成功的内科科学家方面有着良好的记录。MSKCC提供了理想的机构 为Bose博士开始拟议的研究计划并过渡到一个职位的环境 独立的学术研究人员，拥有自己的实验室和R01资金。