Research Project 1

摘要/摘要 这项建议的主要重点是开发聚异戊二烯基半胱氨酰胺抑制剂(PCAIs)作为 一类新的靶向治疗方法，以解决治疗三联症有效药物的空白 阴性乳腺癌(TNBC)，困扰非裔美国人比例明显更高的疾病。 聚异戊二烯途径蛋白及其调节因子的超活性是目前研究的热点 像TNBC这样最难治疗的癌症的主要驱动力。事实上，CDC42和EGFR/HER1是 分别在95%和91%的乳腺癌中过表达。RASA1功能缺失突变 61%的乳腺癌和72%的TNBC在功能上等同于RAS过度活跃 鉴于其作为RAS-GTP酶的作用。开发治疗RAS和RAS高活性肿瘤的有效药物 相关蛋白质一直是非常具有挑战性的。尽管付出了许多努力，但目前还没有有效的治疗方法 有这些像差的癌症。这项提案采用了一种迄今未被探索的方法来解决这个问题。 问题是使用一类全新的化合物靶向多异戊二烯基化的蛋白质代谢和 功能。这是基于之前的研究表明，多异戊二烯基化途径的修饰是 多异戊二烯基化蛋白对细胞增殖、分化、凋亡和 细胞骨架组织。这些研究将解决PCAI扰乱信号通路的假设 促进癌细胞增殖和肿瘤生长，以及促进细胞迁移和侵袭 促进转移性TNBC。科学文献中的大量证据表明，这是合理的 单体G蛋白的过度活跃导致了大量的TNBC病例和我们自己的病例 初步结果清楚地显示了PCAI对阻止3D球体入侵的有效性， 细胞凋亡、血管生成与抑制TNBC移植瘤体积此外，我们的其他发现 揭示了非细胞毒性浓度会破坏F-肌动蛋白的组织，并降低关键蛋白的水平 调解F-肌动蛋白组织。因此，拟议的研究旨在扩大这些研究的范围。 通过(1)合成新的PCAIs类似物并测定其具体的抑制作用 基础、EGF和VEGF诱导的三维球形TNBC细胞的生长和侵袭，(2)测定 PCAIs的抗癌机制(3)测定PCAIs在3D患者体内的作用 衍生的TNBC有机体和TNBC异种移植物中。预计在完成后， 研究表明，继续开发这类治疗TNBC的全新药物有明确的理由 对少数群体造成不成比例影响的政策将得到稳固的确立。

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.