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

• 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
• 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

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性目前是一些最难治疗的癌症的主要驱动因素。单体G蛋白如Ras突变并失去其作为分子开关并保持组成型活性的能力。其他家族成员如Rho的过度活动是由于过度表达。开发针对这些蛋白质过度活性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，但对于具有这些畸变的癌症没有有效的疗法。该提案采用迄今为止尚未探索的方法来解决这一问题，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。这是基于以前的研究表明，聚异戊二烯化途径的修饰是必不可少的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。这些研究将解决以下假设：聚异戊二烯化甲基化蛋白甲基酯酶（PMPMEase）在肺癌中过表达，PMPMEase的聚异戊二烯化半胱氨酰酰胺抑制剂（PCAIs）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蛋白的过度活性驱动了大量肺癌病例，我们自己的初步结果清楚地显示了83%的肺癌病例中PMPMEase的过度表达。此外，我们的其他研究结果表明，肺癌细胞过度表达的酶，当暴露于特定的抑制剂（L-28和PCAIs）进行细胞凋亡，而非细胞毒性浓度破坏F-肌动蛋白组织和抑制细胞迁移。PCAIs化合物家族的一个成员在无胸腺裸鼠模型中阻止肺癌A549异种移植肿瘤的生长。因此，所提出的研究旨在通过（1）进一步研究PMPMEase在肺癌和正常邻近组织的不同阶段中的表达和酶活性作为肺癌的早期/伴随诊断和/或筛查的新策略来拓宽这些研究，（2）确定PMPMEase对肺癌细胞生物学的作用，和（3）确定特异性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，继续开发一种全新的肺癌药物和治疗管理的明确理由将是显而易见的。