Components of Translation in Signal Transduction

描述（由申请人提供）：该项目的重点是建立一类新的天然蛋白质作为治疗癌症的治疗剂。下一阶段的具体目标是为将一流的生物制剂推进到治疗恶性黑色素瘤的人体临床试验中提供坚实的基础。本申请基于人tRNA合成酶的活化形式的新的扩展功能及其在肿瘤学中的应用。合成酶（每个氨基酸对应一个）是古老的通用蛋白质，在蛋白质合成的第一步催化每个氨基酸与其同源tRNA的连接（氨酰化）。我们专注于一种特殊的tRNA合成酶--一种天然产生的人TrpRS替代形式，命名为TrpRSAct，通过已经详细研究的机制具有有效的抗血管生成活性。特别是，它阻止新血管的组装，同时抑制与血管生成相关的基因的激活。因为它抑制新血管的形成，而不破坏现有的血管，TrpRSAct有吸引力的肿瘤治疗应用。除了其强大的抗血管生成特性之外，初步工作表明，外源性提供的TrpRSAct激活了参与许多癌症病因学的细胞蛋白的破坏，并且是新抗癌疗法的靶点。初步工作显示，当对携带两种不同黑色素瘤的小鼠给药时，对TrpRSAct有强烈的治疗反应。从这项工作中出现的概念和新疗法旨在改变和扩大专注于开发癌症治疗新方法的研究人员的视角和视野。具体来说，虽然几乎所有的癌症治疗方法都依赖于小分子化疗药物或单克隆抗体，但拟议的工作引入了一种全新的一流治疗蛋白质。此外，由于TrpRSAct的作用机制与批准的化疗剂或单克隆抗体的作用机制不同，因此其可与现有治疗剂组合使用。初步研究表明，TrpRSAct单独使用或与化学试剂组合使用时具有很强的活性。这种组合的成功无疑是因为TrpRSAct的作用机制不同。因此，除了使用本身，TrpRSAct可以导致许多新的和扩展的组合疗法。

DESCRIPTION (provided by applicant): This project focuses on the establishment of a new class of natural proteins as therapeutics for treatment of cancers. Specific aims for the next period focus on providing a solid foundation for advancing a first-in-class biologic into human clinical trials for treatment of malignant melanoma. The application is based on the novel, expanded function of an activated form of a human tRNA synthetase and its applications to oncology. The synthetases (one for each amino acid) are ancient, universal proteins that catalyze attachment (aminoacylation) of each amino acid to its cognate tRNA in the first step of protein synthesis. We focused on the ex-translational function of a specific tRNA synthetase-tryptophanyl tRNA synthetase--where physiological relevance is clear. A naturally produced alternative form of human TrpRS, named as TrpRSAct, has potent anti-angiogenic activity through a mechanism that has been worked out in some detail. In particular, it blocks the assembly of new blood vessels and simultaneously inhibits activation of genes associated with angiogenesis. Because it inhibits new blood vessel formation, with no disruption of existing blood vessels, TrpRSAct has appeal for therapeutic applications to oncology. In addition to its strong anti-angiogenic properties, preliminary work showed that exogenously provided TrpRSAct activates destruction of a cellular protein that is involved in the etiology of many cancers, and is the target of new anti-cancer therapeutics. Preliminary work showed a strong therapeutic response to TrpRSAct when administered to mice bearing two different melanomas. The concepts and new treatments that emerge from this work are intended to change and expand the perspective and vision of investigators who focus on developing new approaches to cancer treatment. Specifically, while virtually all approaches to cancer therapies rely on small molecule chemotherapeutics or monoclonal antibodies, the proposed work introduces an entirely new first-in-class therapeutic protein. In addition, because the mechanism of action of TrpRSAct is distinct from those of the approved chemotherapeutics or monoclonal antibodies, it may be used in combination with existing therapeutics. Preliminary studies show strong activity of TrpRSAct when used alone, or in combination with a chemical agent. This success of the combination is doubtless because the mechanism of action of TrpRSAct is different. Thus, beyond the use by itself, TrpRSAct could lead to many new and expanded combination therapies.