Disrupting Polyisoprenylated Protein Function for Lung Cancer Therapy

破坏聚异戊二烯化蛋白功能用于肺癌治疗

基本信息

批准号：
9135271
负责人：
NAZARIUS SAAH LAMANGO
金额：
$ 33.3万
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：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9135271
关键词：
A549 Address Adenocarcinoma Adenosquamous Lung Carcinoma Adopted Amides Antineoplastic Agents Apoptosis Apoptotic Biology Cancer Cell Growth Cancer cell line Cell Culture Techniques Cell Cycle Cell Cycle Progression Cell Proliferation Cell Survival Cells Characteristics Clinical Companions Coupled Cytoskeletal Modeling Data Development Diagnosis Diagnostic Procedure Disease Drug Targeting Ductal Early Diagnosis Early treatment Effectiveness Enzyme Kinetics Enzymes Epidermal Growth Factor Receptor Erlotinib F-Actin Family Family member Female Breast Carcinoma Fibroblasts Fluorides Freezing Genes Genetic Goals Growth Health Human Hyperactive behavior KRAS2 gene Kinetics Laboratories Literature Lung Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Methods Modification Molecular Monomeric GTP-Binding Proteins Mutate Mutation Neoplasm Metastasis Normal tissue morphology Nude Mice Oncogenic Outcome Pathogenesis Pathway interactions Patients Pattern Pharmaceutical Preparations Phosphotransferases Predisposition Proteins Resistance Role Serine Hydrolase Specificity Squamous Cell Lung Carcinoma Staging Survival Rate Therapeutic Tissue Microarray Tissues Tumor Tissue Tumor Volume Work Xenograft Model Xenograft procedure base bevacizumab cancer cell cancer therapy cancer type cell motility companion diagnostics design drug candidate effective therapy esterase esterase inhibitor expectation improved in vivo inhibitor/antagonist lung cancer screening member migration mouse model mutant nanomolar neoplastic cell new therapeutic target novel novel strategies overexpression prevent protein function protein metabolism ras Oncogene rho targeted agent targeted treatment therapeutic target tumor tumor growth tumor microenvironment tumor progression tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Hyperactivities of polyisoprenylated proteins are currently the principal drivers of some of the most difficult to treat cancers. Monomeric G-proteins such as Ras mutate and lose their ability to act as molecular switches and remain constitutively active. The hyperactivities of other family members such Rho is due to overexpression. Developing effective drugs for cancers with hyperactivities of these 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 effects on cell proliferation, differentiation, apoptosis and the cytoskeletal organization. The studies will address the hypothesis that polyisoprenylated methylated protein methyl esterase (PMPMEase) is overexpressed in lung cancer and that polyisoprenylated cysteinyl amide inhibitors (PCAIs) of PMPMEase will inhibit cancer cell proliferation and tumor growth as well as the cell migration that promotes metastasis. This is rationalized by the vast evidence in the scientific literature showing that hyperactivities of monomeric G-proteins drive a large number of lung cancer cases and our own preliminary results clearly showing an overexpression of PMPMEase in 83% of lung cancer cases. Furthermore, our other findings reveal that lung cancer cells overexpress the enzyme and when exposed to specific inhibitors (L-28 and PCAIs) undergo apoptosis while non-cytotoxic concentrations disrupt F-actin organization and inhibit cell migration. A member of the PCAIs family of compounds prevents the growth of lung cancer A549 xenograft tumors in the athymic nude mouse model. The proposed studies are therefore aimed at broadening these studies by (1) further studying the expression and enzymatic activities of PMPMEase in different stages of lung cancer and normal adjacent tissues as a novel strategy for early/companion diagnosis and/or screening for lung cancer, (2) determining the role of PMPMEase on the biology of lung cancer cells and (3) determining the effect of the specific PMPMEase inhibitors on lung cancer xenograft model. It is anticipated that upon the completion of the proposed studies, a clear rationale for the continuous development of an entirely new class of drugs and therapeutic management of lung cancer will be evident.

描述（由申请人提供）：当前最难治疗的癌症的主要驱动因素是多分裂蛋白的过度活动。单体G蛋白（例如RAS突变）和失去其充当分子开关的能力并保持组成性活跃。此类RHO的其他家庭成员的过度活动是由于过表达引起的。为具有这些蛋白质过度生活的癌症开发有效的药物非常具有挑战性。尽管做出了许多努力，但对于患有这些畸变的癌症仍没有有效的疗法。该提案采用了迄今未开发的方法来解决这个问题，该化合物靶向多分散化的蛋白质代谢和功能。这是基于以前的研究表明，多分散性途径修饰对于多分散性蛋白质对细胞增殖，分化，凋亡和细胞骨架组织的影响至关重要。该研究将解决以下假设：肺癌中多异丙肾上腺素化的甲基化蛋白甲基酯化酯酶（PMPMEASE）过表达，PMPMESE的多异丙肾上腺肾上腺素化的胱烷基酰胺抑制剂（PCAI）将抑制癌细胞的扩散和肿瘤生长，以及促进转移的细胞迁移。科学文献中的广泛证据表明，单体G蛋白的过度生活驱动了大量肺癌病例，我们自己的初步结果清楚地表明，在83％的肺癌病例中，PMPMease过表达过表达。此外，我们的其他发现表明，肺癌细胞过表达酶并暴露于特定抑制剂（L-28和PCAI）时会凋亡，而非毒性浓度则破坏F-肌动蛋白组织并抑制细胞迁移。 PCAI的化合物家族的成员可以防止althymic裸鼠模型中肺癌A549异种移植肿瘤的生长。因此，提出的研究的目的是通过（1）进一步研究肺癌和正常组织在不同阶段的PMPMEASE的表达和酶促活性，作为早期/伴侣诊断和/或肺癌筛查的新策略（2）确定PMPMEASE对肺癌细胞和PMPES的作用（3）确定肺癌的作用（3）的作用（3）。模型。可以预计，在拟议的研究完成后，将很明显地为持续开发全新的药物和肺癌治疗管理的明确理由。