Pilot Research Project: Evaluating Black and African American Breast Cancer Populations for Therapeutic Targeting of Aberrant p53, MDM2, MDMX, and PARP signaling

试点研究项目：评估黑人和非裔美国人乳腺癌人群的异常 p53、MDM2、MDMX 和 PARP 信号传导靶向治疗

• 批准号: 10757595
• 负责人: Jill E. Bargonetti
• 金额: $ 11.22万
• 依托单位: HUNTER COLLEGE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-18 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10757595
• 关键词: Address; Affect; African American; African American population; African ancestry; American; Animals; BRCA mutations; BRCA1 gene; Basic Research Breast Cancer; Bioinformatics; Biological; Biological Markers; Biological Specimen Banks; Biology; Biometry; Black American; Black race; Breast Cancer Cell; Breast Cancer Patient; Cancer Biology; Cancer health equity; Cell Culture Techniques; Cell Line; Cells; Chromosomes; Clinical; Collaborations; Communities; Community Outreach; Complex; DNA Damage; DNA Repair Pathway; DNA biosynthesis; Data Analyses; Detection; Diagnosis; Disparity; Doctor of Philosophy; Educational workshop; Eligibility Determination; Ethics; Ethnic Origin; European; Exposure to; Fox Chase Cancer Center; Gene Amplification; Genetic Engineering; Genetic Screening; Goals; Health Fairs; Human; Imaging technology; Immunohistochemistry; Informed Consent; Institution; Learning; MDM2 gene; Malignant Neoplasms; Mentors; Microarray Analysis; Molecular Biology; Morbidity - disease rate; Mutation; Neoplasm Circulating Cells; Outcome; Participant; Pathology; Pathway interactions; Patients; Pilot Projects; Play; Poly(ADP-ribose) Polymerase Inhibitor; Poly(ADP-ribose) Polymerases; Population; Probability; Proliferating; Proteins; Race; Research; Research Personnel; Research Project Grants; Resources; Risk; Role; Sampling; Scientist; Signal Transduction; Specimen; Stains; Students; TP53 gene; Testing; Tissue Microarray; Tissues; Training; Tumor Tissue; Underrepresented Minority; Underrepresented Students; Universities; Woman; Work; Xenograft procedure; aggressive breast cancer; animal imaging; biological research; cancer biomarkers; cancer health disparity; cancer subtypes; cohort; college; data acquisition; education research; empowerment; follower of religion Jewish; health disparity; improved; inhibitor therapy; insight; malignant breast neoplasm; minority engagement; minority trainee; mortality; mouse model; mutant; mutation carrier; next generation; novel; patient derived xenograft model; protein expression; replication stress; reverse genetics; screening; systemic barrier; targeted treatment; temozolomide; therapeutic target; triple-negative invasive breast carcinoma; tumor; university student

Project Summary Evaluating Black and African American Breast Cancer Populations for Therapeutic Targeting of Aberrant p53, MDM2, MDMX, and PARP signaling HC: Jill Bargonetti, PhD (Co-Leader) TUFCCC: Denise Connolly, PhD (Co-Leader) Partnerships are needed to break the systemic barriers that have limited systematic and ethical biological research on the underpinnings of aggressive triple negative breast cancer (TNBC) in Black Americans of African Ancestry (AA). Our U54 partnership increases the ability to study understudied biomarkers in order to improve screening and treatment options. This U54 pilot project brings together teams of established scientists at Hunter College (HC) and Temple University Fox Chase Cancer Center (TUFCCC) to analyze already available AA patient breast cancer samples for screening highly probable aggressive breast cancer biomarkers that may facilitate targeted treatments for AA TNBCs. Moreover, the team will mentor underrepresented students from HC with cross-institutional exposure to different state of the art scientific platform to Address Cancer Health Equity in training as well as research objectives. The primary goal of this project is to determine if PARP inhibitor (PARPi) therapeutics can be expanded, beyond the mutant BRCA1 cohorts, to Black/AA cohorts with mtp53/MDM2/MDMX/PARP biomarkers. We will educate the Black/AA community about breast cancer biomarkers and will empower them to ask biomarker-based questions during diagnosis and treatment. The aims are the following. 1) To compare the expression of MDM2, MDMX, mtp53 and PARP in breast cancer (BC) tumors from AA and EA patients. We will construct (BC) tissue microarrays (TMAs) from retrospectively collected tumors from 125 AA and 125 EA patients. TMAs will be stained for MDM2, MDMX, p53 and PARP. 2) We will test the driver roles of the MDM2/MDMX-mtp53-PARP for targeting BCs with PARPi therapies in cell culture and xenograft mouse models. We will work with the Community Outreach Core to educate community about breast cancer biomarkers Break Systemic Barriers to Inclusion: This study directly addresses systemic barriers of AA women as an understudied cohort for biological determinants of TNBC. We are collating TUFCCC BC AA samples, with the goal of identifying potential targeted therapeutic options to reduce breast cancer disparities. Completion of this work will provide insights on critical breast cancer biomarkers mtp53/MDM2/MDMX/PARP in Black/AAs and will educate the next generation of under-represented scientists.

项目概要 评估黑人和非裔美国人乳腺癌人群的治疗 异常 p53、MDM2、MDMX 和 PARP 信号传导的靶向 HC：Jill Bargonetti 博士（联合负责人） TUFCCC：Denise Connolly 博士（联合负责人） 需要建立伙伴关系来打破限制系统性和道德性的系统性障碍 侵袭性三阴性乳腺癌 (TNBC) 基础的生物学研究 非洲裔美国黑人 (AA)。我们的 U54 合作伙伴关系提高了学习能力 对生物标志物进行充分研究，以改善筛查和治疗选择。这位U54飞行员 该项目汇集了亨特学院 (HC) 和坦普尔的知名科学家团队 福克斯蔡斯大学癌症中心 (TUFCCC) 将分析现有的 AA 患者乳房 用于筛查极有可能的侵袭性乳腺癌生物标志物的癌症样本 促进 AA TNBC 的靶向治疗。此外，该团队将指导代表性不足的人 HC 的学生跨机构接触不同最先进的科学平台 解决培训和研究目标中的癌症健康公平问题。主要目标是 该项目旨在确定 PARP 抑制剂 (PARPi) 疗法是否可以扩展， 除了突变 BRCA1 队列之外，还有带有 mtp53/MDM2/MDMX/PARP 的 Black/AA 队列 生物标志物。我们将为黑人/AA 社区提供有关乳腺癌生物标志物的教育，并将 使他们能够在诊断和治疗期间提出基于生物标记的问题。目标是 下列。 1)比较乳腺癌中MDM2、MDMX、mtp53和PARP的表达 (BC) AA 和 EA 患者的肿瘤。我们将构建 (BC) 组织微阵列 (TMA) 回顾性收集了 125 名 AA 和 125 名 EA 患者的肿瘤。 TMA 将被染色 MDM2、MDMX、p53 和 PARP。 2）我们将测试MDM2/MDMX-mtp53-PARP的驱动程序角色 用于在细胞培养和异种移植小鼠模型中使用 PARPi 疗法靶向 BC。我们将工作 与社区外展核心一起向社区提供有关乳腺癌生物标志物的教育 打破包容性的系统性障碍：这项研究直接解决了 AA 的系统性障碍 女性作为 TNBC 生物决定因素的待研究群体。我们正在整理TUFCCC BC AA 样本，目的是确定潜在的靶向治疗方案，以减少乳房 癌症差异。完成这项工作将为危重乳腺癌提供见解 生物标志物 mtp53/MDM2/MDMX/PARP 为黑色/AA，并将教育下一代 代表性不足的科学家。