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Targeting Acid Ceramidase in AML

靶向 AML 中的酸性神经酰胺酶

基本信息

批准号：
10430089
负责人：
Thomas Patrick Loughran
金额：
$ 32.84万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-10 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10430089
关键词：
Acute Myelocytic Leukemia Acute leukemia Adult Age Age-Years Apoptosis Apoptotic BCL2 gene Behavior Biochemical Biochemical Genetics Biology Caspase Cell Line Cell Survival Cells Ceramides Chemoresistance Clinic Clinical DNMT3a mutation Data Diagnosis Disease Dose Drug Delivery Systems Drug Kinetics Enzymes Exhibits FLT3 gene Formulation Funding Future Genes Genetic Genetically Engineered Mouse Goals Hematopoietic stem cells Human In complete remission Individual Knowledge Lead Leukemic Cell Link Lipids MCL1 gene Mediator of activation protein Metabolism Minority Modeling Molecular Molecular Profiling Molecular Target Mus Mutation Myelogenous N-caproylsphingosine Patients Pharmacology Population Preclinical Testing Predisposition Protein Isoforms Proteins Public Health Regimen Relapse Role Sampling Sphingolipids Standardization System Technology Testing Therapeutic Therapeutic Agents Toxic effect Translating Tumor Burden Work Xenograft Model acute myeloid leukemia cell aggressive therapy chemotherapy clinical application combinatorial design drug development experience galactosylgalactosylglucosylceramidase genetically modified cells improved in vivo inhibitor knock-down leukemia leukemia treatment metabolomics molecular subtypes mouse model nanoencapsulated nanoliposome non-genetic novel novel therapeutics older patient outcome prediction overexpression patient population patient subsets pre-clinical preclinical efficacy preclinical study prognostic programs response small molecule inhibitor sphingosine 1-phosphate standard of care success synergism targeted agent targeted treatment treatment strategy

项目摘要

PROJECT SUMMARY Acute myeloid leukemia (AML) is the most common acute leukemia in adults and is a growing public health burden as the population ages. Dose-intensive induction and consolidation chemotherapy dramatically reduces tumor burden and induces clinical complete remission in the majority of younger individuals. However, AML patients rarely achieve durable response and typically relapse with chemoresistant disease. Thus, improved therapeutic approaches are imperative. AML is extremely heterogeneous in terms of clinical behavior as well as molecular alterations. The field increasingly utilizes molecular profiling to provide prognostic predictors of outcome and identify targets for selective inhibitors. The overarching hypothesis of this Program Project is that sphingolipid metabolism is dysregulated in AML and represents a promising target for therapy. Acid ceramidase (AC) is a central mediator in sphingolipid metabolism that controls the levels of the pro-apoptotic lipid ceramide and pro-survival lipid sphingosine 1-phosphate (S1P). AC expression and enzymatic activity are significantly elevated in primary AML samples. The premise of the project is supported by our recent data demonstrating that patients exhibiting high AC activity also showed reduced progression-free and overall survival. AC inhibitors and gene knockdown exhibited therapeutic benefit in human AML cell lines, primary AML samples, and murine AML models, thereby validating AC as a promising target in this disease. Two specific aims will be pursued to explore the hypothesis that new AC inhibitors will exhibit increased potency in AML and that molecular alterations modify the susceptibility to AC targeting agents. Specific Aim 1 will characterize the ability of new AC inhibitors to alter sphingolipid metabolism and the mechanism whereby they induce killing in AML cell lines and patient samples. Nano-encapsulation strategies will be optimized to enhance in vivo drug delivery of these compounds. The efficacy of these inhibitors will then be tested in combination with C6-ceramide nanoliposomes (CNL), the Bcl-2 inhibitor venetoclax, and the AraC/venetoclax combinatorial regimen that is investigated across all Projects. We demonstrate that AC inhibitors increase the efficacy of each of these agents. These approaches will be applied to state-of-the-art human AML xenograft models to demonstrate preclinical efficacy and will be compared to standard-of-care chemotherapy models. Specific Aim 2 will determine the relationship between AML molecular subtypes, AC activity, and sensitivity to AC inhibitors. These studies will be completed across diverse AML cell lines and primary patient samples and will include cooperative analysis together with the Systems Metabolomics Core (Core C). Next, the link between AC and mutations (NPM1c, FLT3-ITD, DNMT3AR882H) that are frequently detected in AML will be characterized. These studies will utilize genetically engineered cell lines and mouse models, which also provide the opportunity to validate AC targeting in vivo in the context of defined molecular drivers. The proposed studies will facilitate future clinical application of AC inhibitors in AML by identifying the optimal therapeutic agent as well as susceptible patient populations.

项目总结