Research Project 1

研究项目1

基本信息

批准号：
10361206
负责人：
NAZARIUS SAAH LAMANGO
金额：
$ 23.27万
依托单位：
FLORIDA AGRICULTURAL AND MECHANICAL UNIV
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-08-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10361206
关键词：
3-Dimensional Address Adopted Affect African American African American population Amides Angiogenesis Inhibition Animals Antineoplastic Agents Apoptosis Biological Assay Black Populations Breast Cancer Cell Breast Cancer therapy Cancer Cell Growth Cell Proliferation Cells Chick Chick Embryo Clinical Cytoskeletal Modeling Development Diagnosis Drug Targeting EGF gene ERBB2 gene Effectiveness Embryo Epidermal Growth Factor Epidermal Growth Factor Receptor Estrogens F-Actin Filopodia Florida GTP-Binding Proteins Genetic Goals Growth Guanosine Triphosphate Phosphohydrolases Health Disparities Research Human Hyperactivity Incidence Latina Literature MAPK3 gene Malignant Neoplasms Mediating Mediator of activation protein Minority Mission Modification Molecular Chaperones Monomeric GTP-Binding Proteins Mus Mutation Organoids Outcome Pathway interactions Patients Personal Satisfaction Pharmacotherapy Post-Translational Protein Processing Progesterone Protein Family Proteins RAS Superfamily Proteins Research Project Grants Role Signal Pathway Signal Transduction Structure Survival Rate Therapeutic Tube Tumor Volume Universities Vascular Endothelial Growth Factors Woman Xenograft procedure Zebrafish analog angiogenesis anti-cancer base black women blood vessel development cancer cell cancer therapy cell motility disparity reduction drug candidate drug development effective therapy egg experimental study genetic regulatory protein hyperactive Ras improved in vivo inhibitor loss of function mutation malignant breast neoplasm matrigel mortality new therapeutic target novel novel drug class novel strategies novel therapeutics overexpression protein function protein metabolism rational design receptor rho targeted agent targeted treatment therapeutically effective triple-negative invasive breast carcinoma tumor tumor growth tumor progression tumor xenograft

项目摘要

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.

摘要/摘要该提案的主要重点是开发聚异戊二烯化半胱氨酰胺抑制剂（PCAI）一类新型靶向疗法，旨在解决治疗三联症的有效药物的缺乏阴性乳腺癌 (TNBC) 困扰非裔美国人的比例明显更高。聚异戊二烯化途径蛋白及其调节因子的过度活跃是目前 TNBC 等最难治疗的癌症的主要驱动因素。事实上，Cdc42 和 EGFR/HER1 是分别在 95% 和 91% 的乳腺癌中过度表达。 RASA1 功能丧失突变分别有 61% 和 72% 的乳腺癌和 TNBC 在功能上相当于 Ras 过度活跃鉴于其作为 Ras-GTPase 的作用。开发针对 Ras 和 Ras 过度活跃的癌症的有效药物相关蛋白质一直非常具有挑战性。尽管做出了许多努力，但仍没有有效的治疗方法具有这些畸变的癌症。该提案采用了一种迄今为止尚未探索过的方法来解决这个问题使用针对聚异戊二烯化蛋白质代谢的全新化合物类的问题和功能。这是基于先前的研究表明聚异戊二烯化途径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 PCAI 破坏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促进TNBC转移。科学文献中的大量证据证明了这一点单体 G 蛋白的过度活跃导致大量 TNBC 病例和我们自己的病例初步结果清楚地显示了 PCAI 阻止 3D 球体入侵的有效性，细胞凋亡、血管生成和 TNBC 异种移植肿瘤体积的抑制。此外，我们的其他发现揭示非细胞毒性浓度会破坏 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范围通过 (1) 合成新的 PCAI 类似物并确定其详细的抑制作用基础和 EGF 和 VEGF 诱导的 3D 球状 TNBC 细胞生长和侵袭，(2) 测定 PCAI 的抗癌机制 (3) 确定 PCAI 在 3D 患者体内的作用- 衍生的 TNBC 类器官和 TNBC 异种移植物。预计该项目完成后研究为持续开发这一类治疗 TNBC 的全新药物提供了明确的理由不成比例地影响少数群体的这一点将得到牢固确立。