Project 1

项目1

• 批准号: 10006537
• 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/10006537
• 关键词: Accounting; Acetyl Coenzyme A; Acetylation; African; African American; Automobile Driving; Biological; Biological Markers; Biological Response Modifier Therapy; Biology; California; 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; Modeling; Mus; Native Americans; Neoadjuvant Therapy; Not Hispanic or Latino; Oncogenic; Outcome; Pharmaceutical Preparations; Pilot Projects; Play; Predictive Factor; Production; Prospective Studies; Research Personnel; Resistance; Resources; Retrospective Studies; Role; Signal Transduction; Socioeconomic Factors; Testing; Translating; Woman; c-myc Genes; cancer cell; cancer subtypes; chemotherapy; drug development; ethnic diversity; high throughput screening; histone acetyltransferase; improved; malignant breast neoplasm; metaplastic cell transformation; mortality; non-histone protein; outcome forecast; overexpression; 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好和预后差的B型乳腺癌。穷 只有在女性对新辅助治疗无效后才能确定B型乳腺癌的预后 治愈的选择是有限的。虽然最近的努力集中在开发针对三重病毒的靶向药物 阴性乳腺癌，腔B型乳腺癌研究不足，特别是在拉丁裔/西班牙裔妇女中。 这里, 我们的目标是研究拉丁裔/西班牙裔女性侵袭性腔B乳腺癌的生物学特征。 提高早期发现和存活率的总体目标。致癌转录因子的过表达 C-myc(Myc)促进B型乳腺腔患者恶变并预测不良预后 癌症。最近的研究表明，相对于北欧白人，乳房有流明B的黑人女性 癌症有很高的MYC过度表达频率[5]。初步研究提供了MYC是 在拉丁语中也经常过度表达。加州大学河滨分校(UCR)P20 PI欧内斯特·马丁内斯博士研究 MYC乙酰化在促进糖酵解和细胞转化中的机制作用。希望之城(CoH) 研究人员Dustin Schones研究了糖酵解在驱动染色质乙酰化异常和 异常转录。在这项试验中，我们的目标是利用这些发现来针对药物的myc-乙酰化。 发展。在这项早期的药物管道初步研究中，我们的目标是检验MYC驱动的假说 腔型B型乳腺癌线粒体乙酰-辅酶A过度产生1)促进染色质异常开放 并增强MYC的致癌功能，2)预测较差的存活率。调查结果将转化为测试 MYC乙酰化是否是早期发现和/或治疗腔性B型乳腺癌的有前景的靶点 拉丁语。Aim 1将检测染色质乙酰化和/或MYC癌基因转录的乙酰化 因子预测南加州拉丁裔乳癌B腔患者预后不良。目标2的目标是 MYC在高通量筛选和小鼠PDX模型中的乙酰化/代谢功能 洛杉矶拉丁裔妇女的MYC+腔B乳腺癌。