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: 10757261
• 负责人: DENISE C CONNOLLY
• 金额: $ 34.29万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-19 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10757261
• 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.

项目摘要 评估治疗性黑人和非裔美国乳腺癌种群 靶向异常P53，MDM2，MDMX和PARP信号传导 HC：Jill Bargonetti，博士（共同领导） TUFCCC：Denise Connolly，博士（共同领导） 需要合作伙伴关系来打破有限的系统性和道德的系统性障碍 关于侵略性三重阴性乳腺癌（TNBC）基础的生物学研究 非洲血统的黑人美国人（AA）。我们的U54合作伙伴关系增加了学习的能力 研究的生物标志物是为了改善筛查和治疗选择。这个U54飞行员 项目汇集了亨特学院（HC）的成熟科学家团队和坦普尔 大学Fox Chase Cancer Center（TUFCCC）分析已经可用的AA患者乳房 癌症样品，用于筛查高度可能的侵略性乳腺癌生物标志物 促进针对AA TNBC的靶向治疗。此外，团队将指导代表人数不足 来自HC的学生跨机构暴露于不同的先进科学平台 解决培训和研究目标中的癌症健康公平。主要目标 该项目是为了确定PARP抑制剂（PARPI）是否可以扩展， 超越突变体BRCA1队列，与MTP53/MDM2/MDMX/PARP的黑色/AA队列 生物标志物。我们将教育黑人/AA社区有关乳腺癌生物标志物的教育，并将 在诊断和治疗期间，使他们能够提出基于生物标志物的问题。目的是 下列。 1）比较乳腺癌中MDM2，MDMX，MTP53和PARP的表达 （BC）来自AA和EA患者的肿瘤。我们将从 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的驱动器角色 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 凭借社区外展核心，向社区教育有关乳腺癌生物标志物 破坏包容性的全身障碍：本研究直接解决了AA的系统障碍 妇女是TNBC生物决定因素的研究研究。我们正在整理TUFCCC BC AA样品，目的是确定潜在的有针对性的治疗选择以减少乳房 癌症差异。这项工作的完成将提供有关关键乳腺癌的见解 黑色/AA的生物标志物MTP53/MDM2/MDMX/PARP，将教育下一代 代表性不足的科学家。