Disrupting Polyisoprenylated Protein Function for Lung Cancer Therapy

描述(由申请人提供)：聚异戊二烯基化蛋白的过度活性是目前一些最难治疗的癌症的主要驱动因素。RAS等单体G蛋白发生突变，失去作为分子开关的能力，并保持结构性活性。其他家庭成员的过度活动，如Rho，是由于过度表达。开发具有这些蛋白高活性的癌症有效药物一直是非常具有挑战性的。尽管做出了许多努力，但对于这些畸形的癌症还没有有效的治疗方法。这项建议采用了一种迄今未被探索的方法来解决这个问题，使用了一类全新的以聚异戊二烯基化蛋白质代谢和功能为靶标的化合物。这是基于先前的研究表明，聚异戊二烯基化途径的修饰对于聚异戊二烯基化蛋白对细胞的增殖、分化、凋亡和细胞骨架组织的影响是必不可少的。这些研究将解决这样的假设，即多异戊二烯甲基化蛋白甲基酯酶(PMPMEase)在肺癌中过表达，PMPMEase的多异戊二烯甲基化半胱氨酰胺抑制剂(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蛋白的高活性导致了大量的肺癌病例，我们自己的初步结果清楚地表明，83%的肺癌病例中PMPMEase过表达，这是合理的。此外，我们的其他发现表明，肺癌细胞过度表达该酶，当暴露于特定的抑制剂(L-28和PCAIs)时，肺癌细胞发生凋亡，而非细胞毒性浓度则破坏F-肌动蛋白的组织并抑制细胞迁移。PCAIs家族中的一个成员在裸鼠裸鼠模型中预防肺癌A549移植瘤的生长。因此，本研究旨在通过(1)进一步研究PMPMEase在肺癌不同阶段和正常癌旁组织中的表达和酶活性，作为肺癌早期/伴发诊断和/或筛查的新策略；(2)确定PMPMEase在肺癌细胞生物学中的作用；(3)确定特定的PMPMEase抑制剂对肺癌移植瘤模型的影响。预计在拟议的研究完成后，继续开发一种全新的肺癌药物和治疗方法的明确理由将是显而易见的。

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.