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）：聚异戊二烯化蛋白质的过度活跃是目前一些最难治疗的癌症的主要驱动因素。 Ras 等单体 G 蛋白会发生突变，失去作为分子开关并保持组成型活性的能力。其他家族成员（例如 Rho）的过度活跃是由于过度表达。开发针对这些蛋白质过度活跃的癌症的有效药物一直非常具有挑战性。尽管做出了许多努力，但仍然没有针对具有这些畸变的癌症的有效疗法。该提案采用了迄今为止尚未探索的方法来解决这个问题，使用一类全新的针对聚异戊二烯化蛋白质代谢和功能的化合物。这是基于先前的研究表明，聚异戊二烯化途径修饰对于聚异戊二烯化蛋白对细胞增殖、分化、凋亡和细胞骨架组织的影响至关重要。这些研究将提出以下假设：聚异戊二烯化甲基化蛋白甲酯酶 (PMPMEase) 在肺癌中过度表达，而 PMPMEase 的聚异戊二烯化半胱氨酰胺抑制剂 (PCAI) 将抑制癌细胞增殖和肿瘤生长以及促进转移的细胞迁移。科学文献中的大量证据表明单体 G 蛋白的过度活跃导致大量肺癌病例，并且我们自己的初步结果清楚地表明 83% 的肺癌病例中 PMPMEase 过度表达，这证明了这一点。此外，我们的其他研究结果表明，肺癌细胞过度表达该酶，当暴露于特定抑制剂（L-28 和 PCAI）时会发生细胞凋亡，而非细胞毒性浓度会破坏 F-肌动蛋白组织并抑制细胞迁移。 PCAI 化合物家族的成员可预防无胸腺裸鼠模型中肺癌 A549 异种移植肿瘤的生长。因此，拟议的研究旨在通过以下方式扩大这些研究：（1）进一步研究 PMPMEase 在肺癌不同阶段和正常邻近组织中的表达和酶活性，作为肺癌早期/伴随诊断和/或筛查的新策略， (2)确定PMPMEase对肺癌细胞生物学的作用，以及(3)确定特定PMPMEase抑制剂对肺癌异种移植模型的作用。预计，在完成拟议的研究后，持续开发全新一类药物和肺癌治疗管理的明确理由将显而易见。