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

项目总结 乳腺癌是美国女性诊断的第二大常见癌症，也是第二大癌症。 女性癌症死亡的一般原因。与高加索美国人(CA)女性相比，非裔美国人 (Aa)妇女罹患BC的时间较早，死亡率明显较高。而社会社会的作用 AA女性BC患者预后较差的因素是公认的，这是调节BC的生物因素 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，我们发现脂解刺激 脂蛋白受体(LSR)在非裔美国人BC细胞中的表达水平最高，尤其是在 阴性BC(TNBC)。我们还开发了一种肿瘤特异性的抗LSR抗体，测试了多种小分子 显示出高毒性，并建立了靶向抗体-药物结合物(ADC)的LSR构建和 评估程序。我们的中心假设是，基于抗LSR ADC的治疗可以有效地抑制 TNBC生长，副作用有限，尤其是在AA患者中。在这项研究中，我们建议制定有针对性的 再障TNBC的根治性治疗方法。目标1，我们将检查表达谱并 再生障碍性贫血和尖锐湿疣患者BC组织LSR的遗传/表观遗传学改变我们亦会评估 局部、区域和远处肿瘤分期的差异及其与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基于ADC的靶向治疗的有效平台 为了治疗TNBC，并通过研究靶向性来确定最有效的抗LSR ADC策略， 抗TNBC效应，抗LSR单抗诱导的脂代谢抑制，以及各种ADDC介导的抗 肿瘤效应。目标3，我们的目标是使用我们建立的最大耐受量、药代动力学、 靶向ADC的LSR在同基因小鼠体内的生物分布和抗肿瘤毒性研究 4T1TNBC异种移植模型及术后和/或临床前患者来源的异种移植模型 化疗。如果抗癌效果在临床前模型中得到证实，那么它将增强细胞毒性。 对肿瘤细胞具有低剂量和有限的全身毒性。重要的是，我们建议的工作将提高生活质量 并结合手术和/或化疗，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.