2/2 Drug Development and Capacity Building: A UCR/CoH-CCC Partnership (Pilot Project 1)

2/2 药物开发和能力建设：UCR/CoH-CCC 合作伙伴关系（试点项目 1）

• 批准号: 10249139
• 负责人: ERNEST MARTINEZ
• 金额: $ 10.2万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 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/10249139
• 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，没有生物标志物可以将好处与较差的预后腔乳房癌分开。贫穷的 仅在妇女未能对新辅助治疗反应后，才能确定预后B乳腺癌的乳腺癌 治愈的选项受到限制。尽管最近的努力集中在开发目标代理以进行三重目标 乳腺癌阴性B乳腺癌已经研究了，特别是在拉丁裔/西班牙裔女性中。 这里， 我们旨在调查拉丁裔/西班牙裔女性的侵略性腔内B乳腺癌的生物学 改善早期检测和生存的总体目标。致癌转录因子的过表达 C-Myc（MYC）促进了恶性转化，并预测了腔内B乳房女性的预后不良 癌症。最近的研究表明，相对于北欧白人，腔内B乳房的黑人妇女 癌症具有高频的Myc-Over表达[5]。初步研究提供了MYC是的证据 也经常在拉丁裔中过表达。 UC Riverside（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械作用。希望之城（COH） Dustin Schones研究者研究糖酵解在驱动异常染色质乙酰化和 异常转录。在此飞行员中，我们旨在利用这些发现来靶向Myc-乙酰化药物 发展。在这项早期的药物管道试验研究中，我们旨在检验以MYC驱动的假设 线粒体乙酰-COA在腔内B乳腺癌中产生过量1）促进异常染色质开口 并增强了MYC的致癌功能，2）预测存活率不佳。调查结果将转换为测试 Myc-乙酰化是否是早期检测和/或腔内B乳腺癌治疗的有希望的靶标 在拉丁裔。 AIM 1将测试MYC致癌转录的染色质乙酰化和/或乙酰化是否 因素预测南加州拉丁裔的预后不良患有腔内乳腺癌。 AIM 2将针对 MYC在高通量筛选和鼠标PDX模型中的乙酰化/代谢功能 来自洛杉矶拉丁女性的Myc+ Luminal B乳腺癌。