Development of a cell-based screen for inhibitors of ganglioside biosynthesis

描述(申请人提供)：这项建议的基本假设是，神经节苷脂生物合成的抑制剂将防止或减缓神经脊源性肿瘤(神经母细胞瘤、黑色素瘤、星形细胞瘤)的生长。这些肿瘤类型产生一系列改变的神经节苷脂，有助于它们的生长和扩散。遗传和药理学实验已经证明，神经节苷脂是治疗神经母细胞瘤和黑色素瘤的良好靶点。目前的神经节苷脂生物合成抑制剂已在小鼠癌症模型中显示出有效性；然而，这些化合物通过抑制所有神经节苷脂(GSLS)发挥作用。神经节苷脂只是GSLS的一小部分。目前的抑制剂介导的广泛的GSL抑制会产生副作用；因此，神经节苷脂特异性抑制剂应该是更好的。在这里，我们建议开发一种系统来识别神经节苷脂特异性抑制剂。这些抑制剂应该会减少非特异性GSL抑制的副作用，同时保持抗癌药物的疗效。这项提案的目标是开发一种系统，以发现阻止神经节苷脂产生的药物。神经节苷脂是细胞表面的碳水化合物，是某些类型的癌症所必需的，如黑色素瘤和神经母细胞瘤。使用这里描述的系统，可以发现新的药物，这将导致黑色素瘤或神经母细胞瘤患者的新疗法。

DESCRIPTION (provided by applicant): The underlying hypothesis of this proposal is that inhibitors of ganglioside biosynthesis will prevent or slow the growth of neural crest-derived tumors (neuroblastoma, melanoma, astrocytoma). These tumor types produce an altered array of gangliosides that contribute to their growth and spread. Genetic and pharmacological experiments have proven that gangliosides are good targets for the treatment of neuroblastoma and melanoma. The current inhibitors of ganglioside biosynthesis have shown efficacy in mouse cancer models; however, these compounds act by inhibiting all glycosphingolipids (GSLs). Gangliosides are only a small subset of GSLs. The broad GSL inhibition mediated by the current inhibitors causes side effects; therefore, a ganglioside specific inhibitor should be superior. Here, we propose to develop a system to identify ganglioside specific inhibitors. These inhibitors should reduce the side effects of non-specific GSL inhibition while maintaining efficacy as anti-cancer agents. The goal of this proposal is to develop a system to discover drugs that block the production of gangliosides. Gangliosides are cell surface carbohydrates that are required for certain types of cancer such as melanoma and neuroblastoma. Using the system described here, new drugs can be discovered which will lead to new treatments for patients with melanoma or neuroblastoma.