Evaluation of molecular determinants of racial disparity in triple-negative breast cancer

三阴性乳腺癌种族差异的分子决定因素评估

• 批准号: 9765173
• 负责人: Dipali Sharma
• 金额: $ 36.33万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-17 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9765173
• 关键词: African American; American; Automobile Driving; Biological; Biological Assay; Biological Markers; Breast Cancer Cell; Breast Cancer Detection; Breast Cancer Patient; Clinical; Collection; Computer Simulation; Dasatinib; Data; Dichloroacetate; Drug Screening; Drug Targeting; EP300 gene; ERBB2 gene; Epoxy Compounds; Esters; Estrogen Receptors; European; Evaluation; Exhibits; Growth; Half-Life; Health Services Accessibility; In Vitro; Label; Lead; Libraries; Luciferases; Magnolia grandiflora; Mammary Neoplasms; Methane; Microarray Analysis; Modeling; Molecular; Nature; Neoplasm Metastasis; Oncogenes; Oncogenic; Oncoproteins; Oral Administration; Outcome; Patient-derived xenograft models of breast cancer; Patients; Pharmaceutical Preparations; Pharmacology; Phase II Clinical Trials; Progesterone Receptors; Prognostic Marker; Proteins; Regimen; Regulation; Role; STK11 gene; Sampling; Signal Transduction; Socioeconomic Status; Stage at Diagnosis; Testing; Therapeutic; Therapeutic Intervention; Transcriptional Coactivator with PDZ-Binding Motif; Treatment Efficacy; Tumor Bank; Tumor Suppressor Proteins; United States Food and Drug Administration; Up-Regulation; Verteporfin; Woman; Xenograft Model; addiction; analog; base; breast cancer progression; clinical predictors; cohort; disparity reduction; epithelial to mesenchymal transition; honokiol; improved; in vivo; in vivo evaluation; insight; lipophilicity; malignant breast neoplasm; migration; mortality; novel; oncogene addiction; pre-clinical; preclinical study; racial disparity; receptor expression; triple-negative invasive breast carcinoma; tumor; tumor progression; tumor xenograft; upstream kinase

PROJECT SUMMARY/ABSTRACT Triple negative breast cancer (TNBC) is a very aggressive subtype with limited therapeutic options. Intriguingly, women of African American (AA) origin have much higher TNBC-related mortality rates compared to European American (EA) women. This difference is evident even after adjusting for socioeconomic status and access to care, indicating a biological basis. TNBC tumors in AA women exhibit higher rate of growth and metastasis in comparison to TNBC in EA women. There is an urgent need to understand the molecular mechanisms involved in aggressive progression and increased metastatic potential of AA-TNBC. In our preliminary studies, we observed that AA-TNBC cells have higher invasion and migration potential in comparison to EA-TNBC cells showing inherently aggressive nature of AA-TNBC. In a preliminary screen, we found that a large percentage of AA-TNBC tumors exhibit loss-of-tumor suppressor Liver Kinase B1 (LKB1) in comparison to EA-TNBC tumors. Our preliminary microarray studies also found that LKB1-loss in AA-TNBC results in activation of oncoproteins- YAP and TAZ. Our data suggest that with inherent loss of LKB1, AA-TNBC gain `an oncogenic input' in the form of activated YAP-TAZ signaling. Using in vitro studies, clinical AA-TNBC and EA-TNBC samples and patient-derived xenograft (PDX) models, we will test our hypothesis that inherent LKB1-loss in AA-TNBC results in activation of oncogenic YAP-TAZ signaling leading to aggressive progression and increased metastatic potential of AA-TNBC. Our novel findings also suggest that AA-TNBC tumors may be vulnerable to therapeutic strategies directed at YAP-TAZ inhibition. Based on our strong preliminary data, we will investigate how loss of LKB1 in AA-TNBC might lead to acquisition of higher YAP-TAZ, and drive growth and metastasis of AA-TNBC cells. We will also analyze AA-TNBC and EA-TNBC tumors to establish LKB1-loss and elevated YAP-TAZ as biomarkers of aggressive progression of AA-TNBC. We will utilize these biological insights to test and propose safe and effective therapeutic strategies to target AA-TNBC. Using patient-derived xenograft (PDX) models, we propose to investigate whether AA-TNBCs are particularly susceptible to YAP-TAZ inhibition strategies and whether currently clinically available drugs (screened from a drug library) can be repurposed to target YAP-TAZ in AA-TNBC. Secondly, we plan to examine whether Honokiol, a natural compound from Magnolia grandiflora, (selected from a screen of known bioactive compounds) and its novel analogs have the potential to inhibit YAP-TAZ in AA-TNBC. Our studies will provide new understanding how loss-of-LKB1 and gain-of-YAP-TAZ in AA-TNBC form a relentless axis that drives AA-TNBC. These studies will provide novel insight into molecular mechanisms underlying racial disparity in TNBC and provide a novel set of biomarkers and potential drug-targets to develop novel ways to reduce the disparity in clinical outcome of AA and EA TNBC patients.

项目概要/摘要 三阴性乳腺癌（TNBC）是一种侵袭性非常强的亚型，治疗选择有限。有趣的是， 与欧洲人相比，非裔美国人 (AA) 女性的 TNBC 相关死亡率要高得多 美国（EA）女性。即使在调整了社会经济地位和获得资源的机会之后，这种差异仍然很明显 护理，表明生物学基础。 AA 女性中的 TNBC 肿瘤在 与 EA 女性中的 TNBC 进行比较。迫切需要了解相关的分子机制 AA-TNBC 的侵袭性进展和转移潜力增加。在我们的初步研究中，我们观察到 与 EA-TNBC 细胞相比，AA-TNBC 细胞具有更高的侵袭和迁移潜力 AA-TNBC 固有的攻击性。在初步筛选中，我们发现很大一部分 AA-TNBC 与 EA-TNBC 肿瘤相比，肿瘤表现出肿瘤抑制因子肝激酶 B1 (LKB1) 的缺失。我们的 初步的微阵列研究还发现，AA-TNBC 中 LKB1 缺失会导致癌蛋白 - YAP 的激活 和塔兹。我们的数据表明，随着 LKB1 的固有损失，AA-TNBC 以以下形式获得“致癌输入”： 激活 YAP-TAZ 信号传导。使用体外研究、临床 AA-TNBC 和 EA-TNBC 样本以及源自患者的样本 异种移植 (PDX) 模型中，我们将测试我们的假设，即 AA-TNBC 中固有的 LKB1 丢失导致激活 致癌 YAP-TAZ 信号传导导致 AA-TNBC 的侵袭性进展并增加转移潜力。 我们的新发现还表明，AA-TNBC 肿瘤可能容易受到针对以下治疗策略的影响： YAP-TAZ 抑制。基于我们强有力的初步数据，我们将研究 AA-TNBC 中 LKB1 的丢失如何影响 导致获得更高的 YAP-TAZ，并驱动 AA-TNBC 细胞的生长和转移。我们还将分析 AA-TNBC 和 EA-TNBC 肿瘤将 LKB1 缺失和 YAP-TAZ 升高作为侵袭性生物标志物 AA-TNBC 的进展。我们将利用这些生物学见解来测试并提出安全有效的治疗方案 针对 AA-TNBC 的策略。我们建议使用患者来源的异种移植（PDX）模型来研究是否 AA-TNBC 特别容易受到 YAP-TAZ 抑制策略的影响，以及目前临床上是否可用 药物（从药物库中筛选）可以重新用于靶向 AA-TNBC 中的 YAP-TAZ。其次，我们计划 检查和厚朴酚（Honokiol）是否是来自广玉兰的天然化合物（从已知的筛选中选择） 生物活性化合物）及其新型类似物具有抑制 AA-TNBC 中 YAP-TAZ 的潜力。我们的研究将 提供新的理解 AA-TNBC 中 LKB1 的丢失和 YAP-TAZ 的增益如何形成驱动的无情轴 AA-TNBC。这些研究将为 TNBC 种族差异背后的分子机制提供新的见解 并提供一套新颖的生物标志物和潜在的药物靶点，以开发减少差异的新方法 AA 和 EA TNBC 患者的临床结果。