Project 1

项目1

• 批准号: 10246846
• 负责人: Dustin Edward Schones
• 金额: $ 9万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-02 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10246846
• 关键词: Accounting; Acetyl Coenzyme A; Acetylation; African; African American; Automobile Driving; Biological; Biological Markers; Biological Response Modifier Therapy; Biology; California; Chemoresistance; Chromatin; Chromatin Structure; Cities; ERBB2 gene; Early Diagnosis; Early treatment; Estrogen receptor positive; Ethnic group; European; Frequencies; Fresh Tissue; Genetic; Genetic Transcription; Glycolysis; Goals; Hispanics; Histones; Incidence; Indigenous American; Latina; Los Angeles; Low income; Malignant - descriptor; Metabolic; Metabolism; Mexico; Mitochondria; Mus; Native American Ancestry; Neoadjuvant Therapy; Not Hispanic or Latino; Oncogenic; Outcome; Pharmaceutical Preparations; Pilot Projects; Play; Predictive Factor; Production; Prognosis; Prospective Studies; Research Personnel; Resources; Retrospective Studies; Role; Signal Transduction; Socioeconomic Factors; Testing; Translating; Woman; black women; c-myc Genes; cancer cell; cancer subtypes; drug development; ethnic diversity; high throughput screening; histone acetyltransferase; improved; malignant breast neoplasm; metaplastic cell transformation; mortality; non-histone protein; overexpression; patient derived xenograft model; targeted agent; transcription factor; triple-negative invasive breast carcinoma

Abstract: Currently there are no biomarkers to separate good from poor prognosis luminal B breast cancers. Poor prognosis luminal B breast cancers are only identified after a woman fails to respond to neo-adjuvant therapy and options for cure are limited. While recent efforts have focused on developing targeted agents for triple- negative breast cancer, luminal B breast cancer has been understudied, particularly in Latina/Hispanic women. Here, we aim to investigate the biology of aggressive luminal B breast cancers in Latina/Hispanic women with the overall goal of improving early detection and survival. Overexpression of the oncogenic transcription factor c-MYC (MYC) promotes malignant transformation and predicts poor prognosis in women with luminal B breast cancers. Recent studies show that, relative to Northern European Whites, Black women with luminal B breast cancers have a high-frequency of MYC-overexpression[5]. Preliminary studies provide evidence that MYC is also frequently overexpressed in Latinas. UC Riverside (UCR) P20 PI Dr. Ernest Martinez studies the mechanistic role of MYC-acetylation in promoting glycolysis and cellular transformation. City of Hope (CoH) investigator, Dustin Schones studies the role of glycolysis in driving abnormal chromatin acetylation and aberrant transcription. In this pilot, we aim to leverage these discoveries to target MYC-acetylation for drug development. In this Early Drug Pipeline Pilot study, we aim to test the hypothesis that MYC-driven mitochondrial Acetyl-CoA overproduction in luminal B breast cancer 1) promotes abnormal chromatin opening and enhances the oncogenic functions of MYC and 2) predicts poor survival. Findings will be translated to test whether MYC-acetylation is a promising target for early detection and/or treatment of luminal B breast cancer in Latinas. Aim 1 will test whether chromatin acetylation and/or acetylation of the MYC oncogenic transcription factor predicts poor prognosis in Southern California Latinas with luminal B breast cancer. Aim 2 will target the acetylation/metabolic functions of MYC in high-throughput screening and mouse PDX models derived from MYC+ luminal B breast cancers from Los Angeles Latina women.

摘要： 目前还没有生物标志物来区分预后良好和预后不良的腔型B乳腺癌。贫困 只有在女性对新辅助治疗无效后，才能发现腔型B乳腺癌 治愈的方法也很有限虽然最近的努力集中在开发三重靶向药物， 阴性乳腺癌，管腔型B乳腺癌研究不足，特别是在拉丁裔/西班牙裔妇女中。 在这里， 我们的目的是研究拉丁裔/西班牙裔女性侵袭性管腔型B乳腺癌的生物学， 提高早期发现率和生存率的总体目标。致癌转录因子的过表达 c-MYC（MYC）促进腔型B乳腺女性的恶性转化并预测不良预后 癌的最近的研究表明，相对于北方欧洲白人，黑人女性的腔B乳房 癌症具有高频率的MYC过表达[5]。初步研究表明，MYC是 在拉丁美洲人中也经常过度表达。加州大学滨江（UCR）P20 PI博士欧内斯特马丁内斯研究 MYC-乙酰化在促进糖酵解和细胞转化中的机制作用。City of Hope（英语：City of Hope） 研究人员Dustin Schones研究了糖酵解在驱动异常染色质乙酰化中的作用， 异常转录在这项试验中，我们的目标是利用这些发现来靶向MYC-乙酰化， 发展在这项早期药物管道试点研究中，我们的目标是测试MYC驱动的假设， 管腔型B乳腺癌中线粒体乙酰辅酶A的过度产生1）促进异常染色质开放 并增强MYC的致癌功能; 2）预测较差的存活率。将结果转换为测试 MYC-乙酰化是否是早期检测和/或治疗管腔型B乳腺癌的有希望的靶点 拉丁语目的1将测试MYC致癌转录的染色质乙酰化和/或乙酰化是否与MYC的表达相关。 在南加州拉丁人中，一个预测管腔型B乳腺癌预后不良的因子。目标2将瞄准 MYC在高通量筛选中的乙酰化/代谢功能和源自 来自洛杉矶拉丁裔女性的MYC+腔型B乳腺癌。