Research Project 1

总结/摘要 该提案的主要焦点是开发聚异戊二烯化半胱氨酰酰胺抑制剂（PCAIs）， 一种新型的靶向治疗，以解决有效药物的空白，用于治疗三重 阴性乳腺癌（TNBC）困扰着显着更高比例的非裔美国人。 聚异戊二烯化途径蛋白及其调节因子的高活性是目前研究的热点。 最难治疗的癌症，如TNBC的主要驱动因素。事实上，Cdc 42和EGFR/HER 1是 分别在95%和91%的乳腺癌中过度表达。RASA 1功能缺失突变 乳腺癌和TNBC分别有61%和72%在功能上等同于Ras过度活跃 因为它的角色是一个拉斯-哥特人开发治疗Ras和Ras过度活化的癌症的有效药物 相关蛋白质的研究非常具有挑战性。尽管做出了许多努力，但仍没有有效的治疗方法。 有这些畸变的癌症这项建议采用了一种迄今为止尚未探索过的方法来解决这一问题 使用靶向聚异戊二烯化蛋白质代谢的全新化合物的问题， 功能这是基于以前的研究表明，聚异戊二烯化途径的修饰是 对于聚异戊二烯化蛋白控制细胞增殖、分化、凋亡和 细胞骨架组织这些研究将解决PCAIs扰乱信号通路的假设 促进癌细胞增殖和肿瘤生长以及细胞迁移和侵袭， 推广商业TNBC。科学文献中的大量证据表明， 单体G蛋白的过度活跃导致了大量的TNBC病例， 初步结果清楚地显示了PCAIs阻断3D球体侵入的有效性， 细胞凋亡、血管生成和TNBC异种移植肿瘤体积的抑制。此外，我们的其他发现 表明非细胞毒性浓度破坏F-肌动蛋白组织并降低关键蛋白的水平 介导F-肌动蛋白组织。因此，拟议的研究旨在扩大这些研究 通过（1）合成新的PCAIs类似物并确定它们对以下的详细抑制作用： 基础和EGF和VEGF诱导的3D球状体TNBC细胞生长和侵袭，（2）确定 PCAIs的抗癌机制（3）确定PCAIs在3D患者中的体内作用- 衍生的TNBC类器官和TNBC异种移植物中。预计在完成 研究，这是持续开发这类全新药物治疗TNBC的明确理由 对少数群体造成不成比例影响的原则将得到牢固确立。

Summary/Abstract The principal focus of this proposal is to develop polyisoprenylated cysteinyl amide inhibitors (PCAIs) as a novel class of targeted therapies to address the void of effective drugs for the treatment of triple negative breast cancer (TNBC) that afflicts a significantly higher proportion of African Americans. Hyperactivities of polyisoprenylated pathway proteins and their modulating factors are currently the principal drivers of the most difficult-to-treat cancers such as TNBC. In fact, Cdc42 and EGFR/HER1 are overexpressed in 95% and 91% of breast cancers, respectively. RASA1 loss-of-function mutations in 61% and 72% of breast cancers and TNBC, respectively, is functionally equivalent to Ras hyperactivity given its role as a Ras-GTPase. Developing effective drugs for cancers with hyperactivities of Ras and related proteins has been very challenging. Despite numerous efforts, there are no effective therapies for cancers with these aberrations. This proposal adopts a hitherto unexplored approach to address this problem using an entirely novel class of compounds targeting polyisoprenylated protein metabolism and function. This is based on previous studies showing that polyisoprenylation pathway modifications are essential for polyisoprenylated protein control on cell proliferation, differentiation, apoptosis and cytoskeletal organization. The studies will address the hypothesis that PCAIs disrupt signaling pathways that promote cancer cell proliferation and tumor growth as well as the cell migration and invasion that promote metastastic TNBC. This is rationalized by the vast evidence in the scientific literature showing that hyperactivities of monomeric G-proteins drive a large number of TNBC cases and our own preliminary results clearly showing the effectiveness of the PCAIs to block 3D spheroid invasion, apoptosis, angiogenesis and inhibition of TNBC xenograft tumor volume. Furthermore, our other findings reveal that non-cytotoxic concentrations disrupt F-actin organization and lower the levels of key proteins that mediate F-actin organization. The proposed studies are therefore aimed at broadening these studies by (1) Synthesizing new PCAIs analogs and determining their detailed inhibitory effects against basal and EGF- and VEGF-induced 3 D spheroid TNBC cell growth and invasion, (2) Determining the anticancer mechanisms of PCAIs (3) Determining the in vivo effects of the PCAIs in 3D patient- derived TNBC organoids and in TNBC xenografts. It is anticipated that upon the completion of the studies, a clear rationale for the continuous development of this entirely new class of drugs to treat TNBC that disproportionately affects minorities will be firmly established.