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

项目摘要 乳腺癌（BC）是美国女性中诊断出的第二大常见癌症， 是女性癌症死亡的主要原因。与高加索美国（CA）女性相比，非洲裔美国人 (AA)妇女表现出较早的BC发病，并且具有显著较高的死亡率。虽然社会的作用 AA妇女与BC的结果较差的因素是公认的，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 阴性BC（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，并且建立了靶向LSR的抗体-药物缀合物（ADC）构建， 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，副作用有限，特别是在AA患者中。在这项研究中，我们建议制定有针对性的 用于AA TNBC的治愈性治疗的疗法。目的1，我们将检查表达谱， AA和CA患者之间BC组织中LSR的遗传/表观遗传改变。我们亦会评估 局部、区域和远处肿瘤分期之间的差异以及LSR表达与肿瘤分化程度之间的相关性。 和遗传/表观遗传改变。目标二，构建有效的ADC靶向治疗平台 治疗TNBC，并通过研究靶向特异性来鉴定最有效的抗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TNBC功效。 肿瘤效应目的3，我们的目标是使用我们建立的最大耐受剂量，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在同基因小鼠中的治疗价值。 手术后的4 T1 TNBC异种移植物模型和临床前患者来源的异种移植物TNBC模型，和/或 化疗如果抗癌功效在临床前模型中得到证实，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，我们提出的工作将提高生活质量 联合手术和/或化疗可提高TNBC患者尤其是AA患者的生存率。

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.