Molecular and Cellular Determinants of Tubulin-targeted Drug Action

在发达国家，癌症是主要的死亡原因。尽管联合化疗的使用取得了进展，但耐药性仍是治疗失败的主要原因。许多儿童和成人癌症治疗中的一个重要组成部分是抗微管药物。这些药物针对细胞骨架的一个重要部分，称为微管-微管系统，该系统负责许多重要事件，包括细胞分裂。正是这些药物扰乱癌细胞分裂的能力，使它们如此有效，成为新药设计的重要目标。不幸的是，肿瘤对这些药物产生抗药性的原因甚至一些肿瘤反应良好的原因尚不清楚。这项提议将决定微管蛋白的组成和稳定性如何影响这些药物在儿童和成人肿瘤细胞中的作用。最后，将使用允许我们同时分离和识别数百种蛋白质的技术来检查耐药肿瘤细胞的成分，其中一些蛋白质可能为设计治疗癌症的新药提供有用的靶点。为了提高癌症存活率，必须准确地针对现有药物的使用，并确定抗癌药物开发的新靶点。

Cancer is the leading cause of death in developed countries. Despite advances in the use of combination chemotherapy, drug resistance is the major cause of treatment failure. An important component in the treatment of many childhood and adult cancers are the antimicrotubule agents. These drugs target an important part of the cell skeleton called the tubulin-microtubule system that is responsible for many important events including cell division. It is the ability of these drugs to disrupt cell division in cancer cells that makes them so effective and such important targets for new drug design. Unfortunately, the reasons why tumours develop resistance to these drugs or even why some tumours do respond well is not understood. This proposal will determine how the makeup and stability of the tubulin-microtubule proteins influences how these drugs work in both childhood and adult tumour cells. Finally, components of drug resistant tumour cells will be examined using technology that allows us to simultaneously separate and identify hundreds of proteins some of which may provide useful targets for the design of new drugs for the treatment of cancer. To improve cancer survival rates it is essential to accurately target the use of existing drugs and to identify new targets for anticancer drug development.