Targeted Sphingolipid Metabolism for Treatment of AML

靶向鞘脂代谢治疗 AML

• 批准号: 8732613
• 负责人: MARK KESTER
• 金额: $ 192.93万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-10 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8732613
• 关键词: Acute Myelocytic Leukemia; Acute leukemia; Address; Adult; Affect; Age; Animal Model; Apoptosis; Apoptotic; Autophagocytosis; Biochemistry; Biological; Biophysics; Biostatistics Core; Cell Line; Cell Survival; Cell model; Ceramides; Clinical; Core Facility; Critiques; Cytotoxic Chemotherapy; Data; Development; Disease; Disease remission; Drug resistance; Engineering; Engraftment; Enzymes; Goals; Heterogeneity; Human; In Vitro; Incidence; Institutes; Investigation; Laboratories; Left; Lipids; Liposomes; Malignant Neoplasms; Mediating; Medical center; Metabolism; Modality; Modeling; Mus; Oncologist; Outcome; P-Glycoprotein; Pathogenesis; Patients; Process; Proteomics; Regimen; Relapse; Research Design; Resources; Rest; Role; Sampling; Scientist; Sphingolipids; Stem cells; System; Testing; The Jackson Laboratory; Therapeutic; Therapeutic Uses; Toxicology; Validation; base; cell type; chemotherapy; clinically significant; combinatorial; experience; functional genomics; galactosylgalactosylglucosylceramidase; genetic profiling; glycosylation; in vivo; in vivo Model; inhibitor/antagonist; innovation; interest; leukemia; leukemic stem cell; nanoformulation; nanoscale; nanotherapeutic; new therapeutic target; novel; novel therapeutics; pre-clinical; programs; small molecule; sphingosine 1-phosphate; sphingosine kinase; therapeutic target; tumor progression

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.

该计划广泛的长期目标是开发治疗急性髓系白血病(AML)的新靶向疗法。该计划项目的主要假设是，急性髓细胞白血病患者的鞘脂代谢发生了变化，并可用于指导治疗方案。这一假说的推论表明，针对神经鞘脂代谢障碍的新疗法可能对AML非常有效。该计划的整合遵循神经酰胺的新陈代谢。项目1的目标是利用神经酰胺为基础的纳米疗法的神经酰胺代谢；项目2和3的目标是酸性神经酰胺酶和鞘氨醇激酶，它们协调地产生促有丝分裂和抗凋亡的神经酰胺代谢物-1-磷酸鞘氨醇，项目4的目标是P-糖蛋白介导的神经酰胺的糖基化。所有项目都在AML的体外和体内模型中验证了治疗方式。该计划由五个完整的核心支持。其中包括：合成和纳米制剂核心，提供无法用于生物研究的合成化合物；靶向Sphing“组学”核心，对鞘磷脂代谢的量化至关重要；动物建模和临床资源核心，提供带有注释的临床结果和小鼠白血病干细胞模型的最先进的分子定义的AML样本；生物统计核心，提供关键研究设计和分析；管理核心，监督和协调所有科学、行政和财政活动。针对急性髓细胞白血病的靶向疗法的开发将在该计划的以下总体具体目标中进行： 1.设计、表征和优化治疗急性髓系白血病的新型仿脂或小分子疗法。 2.用小鼠白血病干细胞模型验证鞘磷脂靶向治疗的体内疗效和毒理学。 3.明确鞘磷脂代谢改变在AML细胞存活、凋亡、自噬和耐药中的作用。 为了实现这些目标，我们组建了一个由临床和基础科学家、有机化学家和材料科学家组成的跨学科团队。我们很幸运，NCI纳米表征实验室加快了宾夕法尼亚州立大学神经酰胺脂质体纳米平台的临床前开发。该计划的临床意义在于急性髓细胞白血病新疗法开发的迫切和未得到满足的需求。在修订后的申请中，我们具体回应了审查员的所有批评，特别是针对主要 与AML异质性和人源化AML小鼠模型相关的问题。重要的是，我们已经记录了由整合遗传图谱定义的AML亚群在NSG小鼠中的植入。