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.

抽象的： 目前尚无生物标记物可区分预后良好和预后不良的管腔 B 型乳腺癌。贫穷的 预后 Luminal B 型乳腺癌只有在女性对新辅助治疗没有反应后才会被识别出来 并且治疗的选择是有限的。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 B 型乳腺癌尚未得到充分研究，特别是在拉丁裔/西班牙裔女性中。 这里， 我们的目标是研究拉丁裔/西班牙裔女性侵袭性管腔 B 型乳腺癌的生物学特性 提高早期发现和生存率的总体目标。致癌转录因子的过度表达 c-MYC (MYC) 促进 Luminal B 型乳房女性恶性转化并预测不良预后 癌症。最近的研究表明，相对于北欧白人，具有管腔 B 型乳房的黑人女性 癌症中 MYC 过度表达的频率很高[5]。初步研究证明 MYC 是 在拉丁裔中也经常过度表达。加州大学河滨分校 (UCR) P20 PI Ernest Martinez 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) 研究员达斯汀·舍恩斯（Dustin Schones）研究糖酵解在驱动异常染色质乙酰化中的作用和 转录异常。在此试点中，我们的目标是利用这些发现来靶向 MYC 乙酰化药物 发展。在这项早期药物管道试点研究中，我们旨在检验 MYC 驱动的假设 管腔 B 型乳腺癌中线粒体乙酰辅酶 A 过量产生 1) 促进异常染色质打开 并增强 MYC 的致癌功能，2) 预测较差的生存率。调查结果将转化为测试 MYC-乙酰化是否是早期检测和/或治疗 Luminal B 乳腺癌的有希望的靶点 在拉丁裔中。目标 1 将测试染色质乙酰化和/或 MYC 致癌转录的乙酰化 该因子预测患有管腔 B 型乳腺癌的南加州拉丁裔患者预后不良。目标 2 将针对 MYC 在高通量筛选和小鼠 PDX 模型中的乙酰化/代谢功能 来自洛杉矶拉丁裔女性的 MYC+ 管腔 B 型乳腺癌。