Characterization of metastasis models derived from breast cancer patients of African descent

非洲裔乳腺癌患者转移模型的表征

• 批准号: 10510244
• 负责人: Joshua (Chuck) Harrell
• 金额: $ 18.14万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10510244
• 关键词: Address; African; African ancestry; Basic Science; Biological; Biological Models; Breast Cancer Patient; Breast Cancer Treatment; Cells; Cessation of life; Clinic; Clinical; Collection; Communities; Cytotoxic agent; DNA Methylation; DNA copy number; Data; Development; Diagnosis; Disease; Drug Targeting; ERBB2 gene; Estrogen Antagonists; Estrogen Receptors; European; Exhibits; Feasibility Studies; Generations; Genes; Genetic; Genetic Predisposition to Disease; Genomics; Goals; Green Fluorescent Proteins; Growth; Health; Human; In Vitro; Incidence; Institution; Knowledge; Laboratory Study; Lead; Luciferases; Mammary Neoplasms; Methodology; Mission; Modeling; Molecular; Mutation; Neoplasm Metastasis; Oncogenes; Organ; Organism; Organoids; Outcome; Pathway interactions; Patient-derived xenograft models of breast cancer; Patients; Persons; Predisposition; Progesterone Receptors; Prognosis; Proteins; Protocols documentation; Research; Research Design; Resources; Susceptibility Gene; Suspensions; TP53 gene; Testing; Therapeutic; Time; Translating; Tropism; Tumor-Derived; United States; United States National Institutes of Health; Variant; Woman; cancer health disparity; cancer subtypes; chemotherapeutic agent; cytotoxic; cytotoxicity; data acquisition; experience; in vivo Model; information model; innovation; insight; interest; malignant breast neoplasm; model development; mortality; neoplastic cell; novel therapeutics; patient derived xenograft model; proteogenomics; research study; response; standard of care; targeted agent; therapeutic evaluation; transcriptome sequencing; triple-negative invasive breast carcinoma; tumor

Project Summary: Breast cancers arise in one out of eight women and account for ~40,000 deaths each year in the United States. There are different types of breast tumors with varied treatment options and outcomes. Triple-negative breast cancers (TNBC) lack estrogen and progesterone receptors (ER and PR), do not express the HER2 oncogene, and are known to be highly metastatic. Since they lack ER, they cannot be targeted with antiestrogens, and by not having amplified HER2, the drugs that target this protein are ineffective. People that are of African ancestry (AA) are two-to-three times as likely to be diagnosed with basal-like TNBC than people of European ancestry, which is a major disparity and contributes to a significantly poor prognosis. Given that genetic factors have been identified which portend poor outcomes in AA patients, we hypothesize that AA derived tumor cells have unique susceptibilities which can be exploited for therapeutic benefit. The goal of this R21 project is to refine metastasis models systems derived from people of AA as they are currently lacking in abundance and determine novel therapeutic options that may best benefit them. The proposal will (1) develop trackable metastasis models from AA TNBC patient-derived xenografts, (2) define their organ tropism, (3) genomically characterize them at the single-cell level, and (4) identify and test therapeutics which may be beneficial in addition to standard of care chemotherapeutics. The study is innovative through its multifaceted approach and significant as it will directly address a major disparity and provide options for expanded testing of therapeutics that could be utilized in the clinic immediately. The expected outcome of these efforts is that we will develop model systems that can be shared with the broader research community and identify genomic features that are activated in metastases and can be targeted. Achieving these goals will have a positive impact on disparities research and breast cancer treatment.

项目摘要：每八名女性中就有一人罹患乳腺癌，每年约有40,000人死于乳腺癌 在美国。有不同类型的乳腺肿瘤，有不同的治疗选择和结果。 三阴性乳腺癌缺乏雌激素和孕激素受体(ER和PR)，不表达 HER2癌基因，已知具有高度转移性。由于他们缺乏ER，他们不能成为目标 抗雌激素，由于没有扩增HER2，针对这种蛋白的药物是无效的。那些认为 具有非洲血统(AA)的人被诊断为基底细胞样TNBC的可能性是正常人的两到三倍 欧洲血统，这是一个很大的差异，也是导致预后极差的原因之一。考虑到 已经确定了预示再生障碍性贫血患者预后不良的遗传因素，我们假设再生障碍性贫血 衍生的肿瘤细胞具有独特的敏感性，可以利用这些敏感性来治疗。这样做的目的是 R21项目是完善从再生障碍性贫血患者衍生的转移模型系统，因为他们目前缺乏 并确定可能对他们最有利的新的治疗选择。这项建议将(1)发展 来自AA TNBC患者来源的异种移植物的可追踪转移模型，(2)确定其器官趋向性，(3) 在单细胞水平上对它们进行基因组学表征，以及(4)识别和测试可能是 除了标准护理外，化疗药物也是有益的。这项研究通过其多方面的研究具有创新性 方法和意义重大，因为它将直接解决主要差异，并为扩展测试提供选择 可以立即应用于临床的治疗方法。这些努力的预期结果是，我们 将开发可与更广泛的研究社区共享的模型系统并识别基因组 在转移中被激活并可以成为靶点的特征。实现这些目标将产生积极影响 关于差异研究和乳腺癌治疗。