Sphingolipids in Cancer Therapy and Angiogenesis

描述(由申请人提供)：鞘磷脂代谢途径提供了一个非常丰富的生物活性分子网络，其新出现的功能表明在细胞功能调节中发挥关键作用。特别是，已发表的和初步的结果表明，与神经酰胺形成相关的通路在细胞因子和化疗诱导的癌细胞死亡中发挥关键作用，而鞘磷脂鞘氨醇-L-磷酸可能成为肿瘤新生血管的关键和新的调节因子。这一总体假设将通过3个不同的项目的活动来实现：项目1将解决特定的假设，即神经酰胺的从头合成和鞘磷脂的水解定义了两条不同的神经酰胺形成途径，这两条途径通过两种不同的机制介导了协同作用的肿瘤细胞死亡。项目2将测试特定的假设，即敏化未感染和/或耐药肿瘤细胞的能力(通过添加反义分子、化疗或诱导神经酰胺水平的药物)将促进更多的促凋亡表型，这将促进旁观者的活动，并实现更大的肿瘤细胞杀伤力。项目3将验证鞘氨醇激酶及其产物SIP调节肿瘤血管生成的假设，抑制这一途径可能会抑制肿瘤血管生成。这3个项目将由一个行政核心和一个独特的脂质组学核心提供支持，该核心将提供分析和合成脂质化学。这些互动研究的结果将把细胞生物化学(鞘磷脂代谢)的最后一个前沿引入癌症生物学研究，对癌细胞死亡和肿瘤血管生成产生重要而独特的见解。这些研究还应确定旨在诱导癌细胞死亡和/或抑制肿瘤血管生成的癌症治疗新策略。

DESCRIPTION (provided by applicant): Pathways of sphingolipid metabolism provide a very rich network of bioactive molecules whose emerging functions suggest key roles in the regulation of cell function. In particular, published and preliminary results suggest the global hypothesis that pathways linked to ceramide formation play key roles in cytokine- and chemotherapy-induced cancer cell death whereas the sphingolipid sphingosine-l-phosphate (SIP) may emerge as a key and novel regulator of tumor neo-vascularization. This overall hypothesis will be approached through the activities of 3 distinct projects: Project 1 will address the specific hypothesis that the de novo synthesis of ceramide and sphingomyelin hydrolysis define two distinct pathways of ceramide formation which mediate synergistic tumor cell death through two distinct mechanisms. Project 2 will test the specific hypothesis that the ability to sensitize uninfected and/or resistant tumor cells (by addition of antisense molecules, chemotherapy, or agents that induce ceramide levels), would promote a more proapoptotic phenotype, and this would facilitate bystander activity and achieve greater tumor cell killing. Project 3 will test the hypothesis that sphingosine kinase and its product SIP regulate tumor angiogenesis, and inhibiting this pathway could inhibit tumor angiogenesis. These 3 projects will be supported by an Administrative Core and by a unique Lipidomics Core that will provide analytical and synthetic lipid chemistry. The results of these interactive studies would bring this last frontier of cellular biochemistry (sphingolipid metabolism) into cancer biology research, generating significant and unique insights into cancer cell death and tumor angiogenesis. The studies should also result in the identification of novel strategies for cancer therapeutics aimed at inducing cancer cell death and/or inhibition of tumor angiogenesis.