Discovery of HSPG2 (Perlecan) as a Therapeutic Target in Triple Negative Breast Cancer.,Scientific Reports

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Discovery of HSPG2 (Perlecan) as a Therapeutic Target in Triple Negative Breast Cancer.
Scientific Reports ( IF 3.8 ) Pub Date : 2019-08-28 , DOI: 10.1038/s41598-019-48993-6
Stephen Kalscheuer ₁ , Vidhi Khanna ₁ , Hyunjoon Kim _{1,

2} , Sihan Li ₃ , Deepali Sachdev _{4,

5} , Arthur DeCarlo ₆ , Da Yang ₃ , Jayanth Panyam _{1,

5}

Affiliation

In recent years, there have been significant advances in the treatment of breast cancer resulting in remarkably high survival rates. However, treatment options for metastatic triple negative breast cancer (TNBC) are quite limited due to a lack of identifiable, unique markers. Using a phage display-based whole cell biopanning procedure, we developed two human antibodies that bind to tumor cells with a metastatic TNBC phenotype. Our studies further identified domain 1 of HSPG2 (perlecan) protein as the cognate cell surface antigen bound by the antibody. Immunohistochemistry studies utilizing patient tissue samples revealed significant cell surface expression of HSPG2 in both primary tumors and metastatic lesions. Further, higher HSPG2 expression correlated with poor survival in TNBC. The affinity-matured antibody inhibited the growth of triple negative MDA-MB-231 tumors to a greater extent in nude mice than in NSG mice, pointing to the potential role of natural killer cell-mediated antibody-dependent cell cytotoxicity. This mechanism of action was confirmed through in vitro assays using mouse splenocytes and human peripheral blood mononuclear cells (PBMCs). These results suggest that HSPG2 is a promising target in metastatic TNBC and HSPG2-targeted antibodies could represent a potentially novel class of targeted therapeutics for TNBC.

中文翻译：

HSPG2（Perlecan）作为三阴性乳腺癌的治疗靶标的发现。

近年来，乳腺癌的治疗取得了显着进展，导致了很高的存活率。但是，由于缺乏可识别的独特标志物，转移性三阴性乳腺癌（TNBC）的治疗选择非常有限。使用基于噬菌体展示的全细胞生物淘选程序，我们开发了两种人抗体，它们与具有转移性TNBC表型的肿瘤细胞结合。我们的研究进一步确定了HSPG2（perlecan）蛋白的结构域1是与抗体结合的同源细胞表面抗原。利用患者组织样本进行的免疫组织化学研究表明，HSPG2在原发性肿瘤和转移性病变中均具有明显的细胞表面表达。此外，较高的HSPG2表达与TNBC中较差的生存率相关。与NSG小鼠相比，亲和力成熟的抗体在裸鼠中对三阴性MDA-MB-231肿瘤的抑制作用更大，这表明自然杀伤细胞介导的抗体依赖性细胞的细胞毒性具有潜在的作用。通过使用小鼠脾细胞和人外周血单核细胞（PBMC）的体外分析，证实了这种作用机制。这些结果表明，HSPG2是转移性TNBC中有希望的靶标，而靶向HSPG2的抗体可能代表TNBC的潜在新型靶向治疗剂。通过使用小鼠脾细胞和人外周血单核细胞（PBMC）的体外分析，证实了这种作用机制。这些结果表明，HSPG2是转移性TNBC中有希望的靶标，而靶向HSPG2的抗体可能代表TNBC的潜在新型靶向治疗剂。通过使用小鼠脾细胞和人外周血单核细胞（PBMC）的体外分析，证实了这种作用机制。这些结果表明，HSPG2是转移性TNBC中有希望的靶标，而靶向HSPG2的抗体可能代表TNBC的潜在新型靶向治疗剂。

更新日期：2019-08-28

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