Disrupting Polyisoprenylated Protein Function for Lung Cancer Therapy

描述（由申请人提供）：多异戊二烯酰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。像Ras这样的单体g蛋白发生突变，失去了作为分子开关的能力，并保持了组成活性。其他家庭成员如Rho的多动症是由于过度表达。开发针对这些蛋白质过度活跃的癌症的有效药物非常具有挑战性。尽管做了很多努力，但对于这些异常的癌症，还没有有效的治疗方法。该建议采用迄今为止尚未探索的方法来解决这一问题，使用一类全新的化合物靶向聚异戊二烯酰化蛋白的代谢和功能。这是基于先前的研究表明，多异戊二烯化途径修饰对于多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。这些研究将解决PMPMEase在肺癌中过度表达的假设，以及PMPMEase的PCAIs会抑制癌细胞的增殖和肿瘤生长，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蛋白的过度活动导致了大量肺癌病例，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，这一点是合理的。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PCAIs）时，细胞凋亡，而非细胞毒性浓度破坏f -肌动蛋白组织并抑制细胞迁移。PCAIs家族化合物的一个成员在胸腺裸小鼠模型中阻止肺癌A549异种移植肿瘤的生长。因此，本研究旨在通过(1)进一步研究PMPMEase在不同阶段肺癌和正常邻近组织中的表达和酶活性，作为肺癌早期/伴诊和/或筛查的新策略，(2)确定PMPMEase在肺癌细胞生物学中的作用，(3)确定特异性PMPMEase抑制剂对肺癌异种移植模型的影响。预计在完成拟议的研究后，将会有一个明确的理由来继续开发一种全新的肺癌药物和治疗管理。

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.