Targeted Sphingolipid Metabolism for Treatment of AML

该项目广泛的长期目标是开发新的靶向治疗急性髓性白血病（AML）。该项目的首要假设是鞘脂代谢在AML中发生改变，并可用于指导治疗方案。这一假设的推论表明，针对功能失调的鞘脂代谢的新疗法可能对AML非常有效。程序的整合遵循神经酰胺的代谢。项目1利用基于神经酰胺的纳米疗法靶向神经酰胺代谢；项目2和3针对酸性神经酰胺酶和鞘氨醇激酶，它们协同产生促有丝分裂和抗凋亡的神经酰胺代谢物鞘氨醇- 1-磷酸，项目4针对p糖蛋白介导的神经酰胺糖基化。所有项目都在体外和体内AML模型中验证了治疗方式。该计划由五个整体核心支持。这些包括：合成和纳米配方核心，它提供了合成的化合物，不能在商业上用于生物研究；靶向Sphing“组学”核心，这是定量测定鞘脂代谢所必需的；动物建模和临床资源核心（Animal Modeling and Clinical Resources Core），提供最先进的带有临床结果注释的分子定义AML样本和小鼠白血病干细胞模型；生物统计核心，提供关键的研究设计和分析；行政核心，负责监督和协调所有科学、行政和财政活动。AML靶向治疗药物的开发将在该项目的以下总体目标中进行：

The Program's broad long-term objective is to develop new targeted therapeutics for acute myelogenous leukemia (AML). The overarching hypothesis of the Program Project is that sphingolipid metabolism is altered in AML and can be used to direct therapeutic regimens. A corollary of this hypothesis suggests that novel therapeutics that target dysfunctional sphingolipid metabolism may be highly efficacious in AML. The integration of the Program follows the metabolism of ceramide. Project 1 targets ceramide metabolism utilizing ceramide-based nanotherapeutics; Projects 2 and 3 target acid ceramidase and sphingosine kinase, which coordinately generate the pro-mitogenic and anti-apoptotic ceramide metabolite, sphingosine- 1-phosphate, and Project 4 targets P-glycoprotein-mediated glycosylation of ceramide. All Projects have validated therapeutic modalities in both in vitro and in vivo models of AML. The Program is supported by five integral Cores. These include the: Synthesis and Nanoformulation Core, which provides synthesized compounds not available commercially for biologic studies; Targeted Sphing"omics" Core, which is essential for quantification of sphingolipid metabolism; Animal Modeling and Clinical Resources Core, which provides state-of-the-art molecularly defined AML samples with annotated clinical outcomes and murine leukemia stem cells models; Biostatistics Core, which provides critical research design and analysis; Administrative Core, which provides oversight and coordination of all scientific, administrative, and fiscal activities. Development of targeted therapeutics for AML will be pursued in the following overall Specific Aims of the Program: 1. Engineer, characterize and optimize novel lipomimetic- or small molecule-based therapeutics for AML. 2. Validate the efficacy and toxicology of sphingolipid-targeted therapeutics in vivo using murine leukemia stem cells models. 3. Define the role of altered sphingolipid metabolism in cell survival, apoptosis, autophagy, and drug resistance in AML. To accomplish these Aims, we have assembled a transdisciplinary team of clinical and basic scientists, organic chemists, and material scientists. We are fortunate that NCI NanoCharacterization Laboratory has accelerated pre-clinical development of the Penn State ceramide liposomal nanoplatform. The clinical significance of the Program rests on the urgent and unmet needs for development of new therapeutics in AML. In the revised application, we have specifically responded to all of the reviewer's critiques, in particular, addressing the major issues associated with AML heterogeneity and humanized AML murine models. Importantly, we have documented engraftment in NSG mice of AML subsets defined by integrated genetic profiling.