Identifying a New Biological Target for Breast Cancer Therapy That Contributes to Disparities for African-American Women

确定乳腺癌治疗的新生物学目标，这会导致非裔美国女性的差异

基本信息

批准号：
10436911
负责人：
Runhua Runa Liu
金额：
$ 33.29万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10436911
关键词：
4T1 Address African American American Animal Model Antibody-drug conjugates Automobile Driving Basic Science Biodistribution Bioinformatics Biological Biological Factors Breast Cancer Cell Breast Cancer Patient Breast Cancer cell line Breast Cancer therapy Breast Epithelial Cells Cancer Etiology Cell Line Cell Surface Proteins Cell membrane Cell surface Cells Cessation of life Clinical Data Set Diagnosis Distant Dose Drug Kinetics Drug Modelings ERBB2 gene Endocytosis Epigenetic Process Evaluation Extracellular Domain Fc Receptor Genetic Goals Growth High Prevalence Human Immunohistochemistry In Vitro Investigation Lipids Lipolysis Lipoprotein Receptor Lipoproteins Malignant - descriptor Mammary Gland Parenchyma Maximum Tolerated Dose Mediating Membrane Membrane Proteins Messenger RNA Methods Modeling Monoclonal Antibodies Nature Non-Malignant Normal tissue morphology Operative Surgical Procedures Outcome Patients Pharmaceutical Preparations Play Pre-Clinical Model Procedures Proteomics Protocols documentation Quality of life Race Role Safety Sampling Societal Factors Specificity Stains Surface Survival Rate Testing The Cancer Genome Atlas Therapeutic Time Tissue Sample Tissues Toxic effect Treatment Efficacy Tumor stage Woman Work Xenograft Model Xenograft procedure aggressive breast cancer anti-cancer antitumor effect base cancer diagnosis cancer health disparity caucasian American chemotherapy comparative curative treatments cytotoxic cytotoxicity design differential expression dosage early onset effective therapy epidemiology study experimental study gemcitabine improved in vivo in vivo Model lipid metabolism malignant breast neoplasm mortality mouse model neoplastic cell new therapeutic target novel therapeutic intervention overexpression patient derived xenograft model pre-clinical protein expression racial disparity receptor receptor expression side effect small molecule synergism systemic toxicity targeted treatment translational applications translational therapeutics treatment strategy triple-negative invasive breast carcinoma tumor uptake

项目摘要

PROJECT SUMMARY Breast cancer (BC) is the second most common cancer diagnosed in American women and the second leading cause of cancer death for women in general. Compared to Caucasian American (CA) women, African American (AA) women display an earlier onset of BC and have a significantly higher mortality rate. While the role of societal factors for the poorer outcome of AA women with BC is well-established, the biological factors that mediate BC racial disparities remain largely unknown. In our preliminary studies, we identified that lipolysis-stimulated lipoprotein receptor (LSR) was expressed at the highest levels in African American BC cells, especially in triple negative BC (TNBC). We also developed a tumor specific anti-LSR antibody, tested multiple small molecules showing high toxicity, and established LSR targeting antibody-drug conjugates (ADCs) construction and evaluation procedures. Our central hypothesis is that the anti-LSR ADCs-based therapy can effectively inhibit TNBC growth with a limited side effect, especially in AA patients. In this study, we propose to develop targeted therapies for curative treatment of AA TNBC. Aim 1, we will examine the expression profile and genetic/epigenetic alterations of LSR in BC tissues between AA and CA patients. We will also assess the differences among the localized, regional and distant tumor stages and the correlation between LSR expression and genetic/epigenetic alteration. Aim 2, we aim to build an effective platform of ADC-based targeted therapies to treat TNBC, and to identify the most efficient anti-LSR ADC strategy by investigating the targeting specificity, anti-TNBC efficacy, anti-LSR mAb-induced suppression of lipid metabolism, and various ADCs-mediated anti- tumor effects. Aim 3, we aim to use our established protocols of maximal tolerated dose, pharmacokinetics, biodistribution and anti-tumor toxicity to evaluate the therapeutic value of our LSR targeting ADCs in syngeneic 4T1 TNBC xenograft models and preclinical patient-derived xenograft TNBC models after surgery and/or chemotherapy. If the anti-cancer efficacy is confirmed in the preclinical models, then it will enhance cytotoxicity to tumor cells with low dose and limit systemic toxicities. Importantly, our proposed work will improve life quality and the survival rate of TNBC patients, especially AA patients, by combining with surgery and/or chemotherapy.

项目概要乳腺癌 (BC) 是美国女性第二大常见癌症，也是第二大癌症一般女性癌症死亡的原因。与白人美国 (CA) 女性相比，非裔美国人 (AA) 女性 BC 发病较早，死亡率明显较高。虽然社会的作用 AA 女性 BC 预后较差的因素已明确，介导 BC 的生物学因素种族差异在很大程度上仍不为人所知。在我们的初步研究中，我们发现脂肪分解刺激脂蛋白受体 (LSR) 在非裔美国人 BC 细胞中表达水平最高，尤其是在三重细胞中 BC 阴性 (TNBC)。我们还开发了肿瘤特异性抗LSR抗体，测试了多种小分子显示出高毒性，并建立了 LSR 靶向抗体药物偶联物 (ADC) 构建和评估程序。我们的中心假设是基于抗 LSR ADC 的疗法可以有效抑制 TNBC 生长的副作用有限，特别是在 AA 患者中。在本研究中，我们建议开发有针对性的 AA TNBC 的治疗方法。目标 1，我们将检查表达谱并 AA 和 CA 患者之间 BC 组织中 LSR 的遗传/表观遗传改变。我们还将评估局部、区域和远处肿瘤分期的差异及LSR表达的相关性和遗传/表观遗传改变。目标2，我们的目标是建立一个有效的基于ADC的靶向治疗平台治疗 TNBC，并通过研究靶向特异性来确定最有效的抗 LSR ADC 策略，抗 TNBC 功效、抗 LSR mAb 诱导的脂质代谢抑制以及各种 ADC 介导的抗肿瘤作用。目标 3，我们的目标是使用我们既定的最大耐受剂量、药代动力学、生物分布和抗肿瘤毒性，以评估我们的 LSR 靶向 ADC 在同基因中的治疗价值手术后和/或4T1 TNBC异种移植模型和临床前患者衍生的异种移植TNBC模型化疗。如果在临床前模型中证实其抗癌功效，那么它将增强细胞毒性以低剂量作用于肿瘤细胞并限制全身毒性。重要的是，我们提出的工作将改善生活质量以及联合手术和/或化疗对TNBC患者，尤其是AA患者的生存率。