TRIM37 is a genetic determinant of racial disparity in metastatic TNBC patients

TRIM37 是转移性 TNBC 患者种族差异的遗传决定因素

基本信息

批准号：
10610351
负责人：
Sanchita Bhatnagar
金额：
$ 46.76万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10610351
关键词：
Address Affect African American Alleles Anoikis Antibodies Antisense Oligonucleotides Artificial nanoparticles Biological Brain Breast Breast Cancer Cell Breast Cancer Patient Breast Cancer Risk Factor Breast Cancer Treatment Breast Cancer cell line Breast Epithelial Cells Breast cancer metastasis CRISPR screen Caucasians Cell Line Circulation Clinical Data Data Set Dependence Development Disease Disparity Distant Engineering Epigenetic Process Ethnic Origin FOLR1 gene Gene Expression Profile Genes Genetic Genetic Determinism Genetic Polymorphism Genetic Risk Genetic Transcription Genome Genotype Goals Growth Head Start Program In Vitro Incidence Infiltration Legal patent Link Liver Mammary Gland Parenchyma Metastatic Neoplasm to the Lung Metastatic breast cancer Molecular Target Neoplasm Metastasis Oncogenic Oncoproteins Outcome Pathway interactions Patients Phase I Clinical Trials Phenotype Predisposition Prognosis Prognostic Marker Proteins Quantitative Trait Loci Race Racial Segregation Relapse Resistance Risk Single Nucleotide Polymorphism Site Survival Rate Susceptibility Gene TRIM Motif Technology Testing Therapeutic Therapeutic Intervention Tissues Tumor Burden Tumor Tissue Variant Woman cancer cell cancer health disparity cancer predisposition cancer subtypes causal variant clinically relevant comorbidity disparity reduction efficacy evaluation ethnic diversity experience folate-binding protein genetic variant health care availability health care disparity high risk in vivo in vivo Model innovation malignant breast neoplasm mortality mouse model nanoparticle novel overexpression patient derived xenograft model programs prospective racial disparity rational design survival outcome targeted treatment transcriptomics treatment disparity triple-negative invasive breast carcinoma tumor tumor growth

项目摘要

African American (AA) women presents with aggressive metastatic subtype of triple negative breast cancer (TNBC) compared to other ethnicities and experience greater mortality rates. Although health care disparities contribute to poor prognosis in AA women but a race-specific genetic component to TNBC disparity cannot be ruled out. Thus, racially-segregated genetic determinant underlying TNBC disparity remains an unmet clinical need. This project is built upon our novel findings suggesting that an oncogenic tripartite motif-containing protein 37 (TRIM37) protein predisposes AA women to highly aggressive TNBC. We demonstrate that 1) TRIM37 associates with metastatic phenotype and overall survival in TNBC patients, 2) TRIM37 is expressed at higher level in the breast and TNBC tumor tissue of AA women relative to other races, 3) TRIM37- associated single nucleotide polymorphism correlates with high TRIM37 expression in AA women, 4) TRIM37 regulates genes and pathways involved in metastasis cascade, such as promoting survival in circulation, 5) AA TNBC cells showed increased dependency on oncogenic TRIM37 compared to non-AA TNBC cell lines in vitro and in vivo, 6) TRIM37 depletion reduces distant infiltration and growth in metastasis murine model 7) TRIM37 inhibition using targeted nanoparticles-based delivery of TRIM37-specific antisense oligonucleotides reduces TNBC tumor growth. Based on these findings, we hypothesize that higher TRIM37 levels in AA women gives a would-be cancer cell a “head start” by creating a pre-metastatic niche. This hypothesis will be tested in three specific aims. In aim 1, we will evaluate TRIM37-allelic variants, that we have already identified, through small- scale phenotypic screen based on anoikis resistance. We will also determine the mechanism of TRIM37-allelic variants by comparing the biological activity of TRIM37 risk and reference alleles. In aim 2, we will compare and contrast the relative contribution of TRIM37 to TNBC metastatic potential in race-dependent manner. We will also track association between TRIM37 and its transcriptional signatures with race, metastasis incidence, and patient's survival using disease-free and tumor tissue from TNBC patients. In aim 3, we will compare the metastatic potential of TRIM37-depleted and TRIM37 overexpressing race-specific breast and TNBC cells using spontaneous metastasis murine models. Finally, we will test newly engineered TNBC selective therapeutic platform to inhibit TRIM37 using spontaneous metastasis, race-specific patient-derived xenografts and humanized murine models. Together, the proposed studies will demonstrate that TRIM37 is a genetic variant associated with high TNBC risk in AA women and proof-of-concept results will establish the clinical relevance of inhibiting TRIM37 for TNBC treatment.

非裔美国人（AA）妇女以三重阴性乳腺癌的侵略性转移性亚型呈现（TNBC）与其他种族相比，并经历了更高的死亡率。尽管医疗保健分销在AA妇女的预后不良，但针对TNBC差异的特定种族遗传成分不能是排除了。这是大致分离的遗传决定因素TNBC差异仍然是未经临床的需要。该项目建立在我们的新发现基础上，表明含有致癌的三方图案蛋白37（TRIM37）蛋白质使AA女性易于攻击性TNBC。我们证明了1） TRIM37与TNBC患者的转移表型和整体存活相关，2）TRIM37表示 AA妇女相对于其他种族的乳房和TNBC肿瘤组织的较高水平，3）Trim37- 相关的单核苷酸多态性与AA女性中高的TRIM37表达相关，4）TRIM37 调节涉及转移级联反应的基因和途径，例如促进循环中的生存，5）AA 与非AA TNBC细胞系相比，TNBC细胞显示出对致癌TRIM37的依赖性增加在体内，6）TRIM37耗尽可减少转移鼠的远处浸润和生长7）TRIM37 使用靶向纳米颗粒的抑制作用基于TRIM37特异性反义寡核苷酸的递送减少 TNBC肿瘤生长。根据这些发现，我们假设AA妇女的TRIM37水平较高可能会通过创建一种前转移的利基市场来成为癌细胞的“头开始”。该假设将在三个具体目标。在AIM 1中，我们将评估我们已经通过小型 - 基于Anoikis抗性的比例表型屏幕。我们还将确定Trim37-allectric的机制通过比较TRIM37风险和参考等位基因的生物学活性来变体。在AIM 2中，我们将比较并以种族依赖性方式对比TRIM37对TNBC转移潜力的相对贡献。我们还将跟踪Trim37及其转录签名与种族，转移事件的关联，以及使用TNBC患者的无病和肿瘤组织的患者生存。在AIM 3中，我们将比较 TRIM37耗尽和TRIM37过表达种族特异性乳房和TNBC细胞的转移潜力使用赞助转移鼠模型。最后，我们将测试新设计的TNBC选择性使用赞助转移，特定于种族的患者衍生的Xenographictics抑制TRIM37的治疗平台和人源化的鼠模型。共同的研究将证明TRIM37是一种遗传与AA妇女的高TNBC风险相关的变体和概念证明结果将建立临床抑制TRIM37进行TNBC治疗的相关性。